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PubMed2004

Determination of modafinil in plasma and urine by reversed phase high-performance liquid-chromatography.

Modafinil (Provigil) is a new wake-promoting drug that is being used for the management of excessive sleepiness in patients with narcolepsy. It has pharmacological properties similar to that of amphetamine, but without some of the side effects associated with amphetamine-like stimulants. Since modafinil has the potential to be abused, accurate drug-screening methods are needed for its analysis. In this study, we developed a high-performance liquid-chromatographic procedure (HPLC) for the quantitative analysis of modafinil in plasma and urine. (Phenylthio)acetic acid was used as an internal standard for the analysis of both plasma and urine. Modafinil was extracted from urine and plasma with ethyl acetate and ethyl acetate-acetic acid (100:1, v/v), respectively, and analyzed on a C18 reverse phase column with methanol-water-acetic acid (500:500:1, v/v) as the mobile phase. Recoveries from urine and plasma were 80.0 and 98.9%, respectively and the limit of quantitation was 0.1 microg/mL at 233 nm. Forty-eight 2-h post-dose urine samples from sham controls and from individuals taking 200 or 400 mg of modafinil were analyzed without knowledge of drug administration. All 16-placebo urine samples and all 32 2-h post-dose urine samples were correctly classified. The analytical procedure is accurate and reproducible and can be used for therapeutic drug monitoring, pharmacokinetic studies, and drug abuse screening.

Benzhydryl Compounds↗
PubMed2005

Detection of modafinil in human urine by gas chromatography-mass spectrometry.

The main purpose of this study was to detect and quantify modafinil in human urine by gas chromatography-mass spectrometry (GC-MS). Urinary samples were collected from three healthy male volunteers following oral administration of a clinical dose (100 mg) of modafinil (Provigil). Urine specimens were extracted with t-butylmethyl ether (TBME) prior to GC-MS analysis. The results demonstrate that the chromatographic characteristics and the mass spectrum of the unchanged parent drug extracted from urine samples were identical to that obtained from the authentic standard. The times for the unchanged modafinil to reach peak concentration in the urine of the three volunteers were at 2 h (6.14 microg/mL), 4 h (9.93 microg/mL) and 8 h (3.58 microg/mL), respectively. Total clearance occurred in approximately 48-72 h with 2-5% eliminated through urine as unchanged modafinil. The present study demonstrates that modafinil is detectable in the absence of hydrolysis and derivatization steps.

Adult↗
PubMed2006

Low-resolution brain electromagnetic tomography (LORETA) identifies brain regions linked to psychometric performance under modafinil in narcolepsy.

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.

Adult↗
PubMed1999

Does short-term treatment with modafinil affect blood pressure in patients with obstructive sleep apnea?

OBJECTIVE: To investigate the effects of modafinil, a central nonamphetamine awakening substance, on blood pressure and heart rate in hypersomnolent patients with obstructive sleep apnea. DESIGN: This double-blind, randomized, placebo-controlled crossover trial was performed over 2 days and 3 nights in a single-center study of hospitalized patients from a referred care center. Twenty-six otherwise healthy men (age range, 30 to 60 years) with mild to moderate obstructive sleep apnea were recruited by the outpatient department of the Marburg University Sleep Laboratory. Patients were given 200 mg oral modafinil in the morning and 100 mg at midday. Placebo was given in the same manner in a crossover design. Mean arterial (radial) blood pressure was monitored continuously during nocturnal sleep and during a series of standardized daytime physical and psychologic performance tests. RESULTS: The difference in the main end point between the treatment with modafinil and placebo was 1.17+/-0.83 (mean +/- SE) mm Hg (95% confidence interval: -0.56 to 2.91 mm Hg). The maximal differences in blood pressure values occurred under loaded conditions (systolic blood pressure, ergometry: 5.62+/-1.13 mm Hg; mental stress test: 6.19+/-1.33 mm Hg). CONCLUSION: Short-term administration of modafinil did not elicit a significant response with regard to the main end point. However, cardiovascular effects during mental and physical load were observed. Longterm studies that include subjects with hypertension are necessary to investigate the clinical relevance of the cardiovascular effects of modafinil.

Adult↗
PubMed2002

Comparison of the effects of modafinil and sleep deprivation on sleep and cortical EEG spectra in mice.

Modafinil is a wakefulness-promoting substance whose profile differs from that of the classical psychostimulants. It is still unknown whether waking induced by modafinil and wakefulness induced by sleep deprivation differ in terms of their effect on subsequent sleep. To investigate this problem sleep was recorded in two groups of OF1 mice. One group received modafinil (200 mg/kg, i.p.) at light onset which induced a period of wakefulness of approx. 5 h, while animals of the subsequent control group were injected with vehicle and kept awake for an equivalent duration. The effect of the two treatments on sleep was similar. REM sleep was initially reduced and slow-wave activity (SWA; EEG power in the 0.75-4.0 Hz range) in nonREM sleep was enhanced for several hours. The SWA increase was more prominent over the frontal cortex than over the occipital cortex after both treatments. A minor difference was seen at the occipital site where the initial rise of power in the low-frequency range was larger after vehicle combined with enforced waking than after modafinil. The study shows that the homeostatic sleep response following the modafinil-induced wakefulness corresponds largely to the response following a non-pharmacologically induced extended waking episode.

Analysis of Variance↗
PubMed2002

Improvement of learning processes following chronic systemic administration of modafinil in mice.

This study was aimed at determining the effects of a chronic modafinil intraperitoneal administration on the rate of learning in a series of five serial spatial discrimination reversals (SSDR) in a T-maze. Results showed that a daily modafinil administration at 64 mg/kg but not at 32 mg/kg induced a faster learning rate as compared to controls. This learning improvement in experimental mice was due to the faster emergence of a win-stay rule over days of testing. In contrast, a second experiment showed that the same modafinil treatment had no significant effect on contingently reinforced alternation rates over five successive days of testing, as compared to controls. Thus, the results show that modafinil spared the ability to shift responses over trials and consequently, that the use of the win-stay rule to solve the SSDR task observed in modafinil-treated animals is due to an improvement of learning processes.

Animals↗
PubMed1996

The vigilance promoting drug modafinil decreases GABA release in the medial preoptic area and in the posterior hypothalamus of the awake rat: possible involvement of the serotonergic 5-HT3 receptor.

The effect of modafinil on endogenous gamma-aminobutyric acid (GABA) release in the medial preoptic area (MPA) and posterior hypothalamus (PH) and the role of local 5-HT3 receptors in this effect was investigated in the awake rat using in vivo microdialysis. Modafinil (30-100 mg/kg i.p.) dose-dependently decreased GABA release from the MPA, while only the 100 mg/kg dose markedly reduced GABA release in the PH. The modafinil (100 mg/kg) induced inhibition of GABA release in the MPA and the PH was partially counteracted by the 5-HT3 receptor antagonist MDL72222 (1 microM) when perfused locally alone or together with the non-selective 5-HT receptor antagonist methysergide (1 microM). Thus, the reduction of GABA transmission induced by modafinil in the MPA and in the PH, at least in part, involves local 5-HT3 receptors. The GABA release inhibition by modafinil in the above areas may be relevant for its vigilance promoting action.

Animals↗
PubMed1999

Effects of the vigilance promoting drug modafinil on the synthesis of GABA and glutamate in slices of rat hypothalamus.

The effects of the vigilance promoting drug modafil were studied ex vivo (100 mg/kg; i.p.) and in vitro (10-1000 microM modafinil) on the synthesis of [3H]gamma-aminobutyric acid ([3H]GABA) and [3H]glutamate from [3H]glutamine within the rat hypothalamus. No effects of modafinil were observed on the overall synthesis of these neurotransmitters nor, in vitro (1-33 microM modafinil) on other parameters related to the compartmentalization of their synthesis (glutamate decarboxylase and phosphate-activated glutaminase activities, and [3H]glutamine uptake). It is suggested on these grounds, that the modafinil-induced reductions and increases in regional GABA and glutamate extracellular levels respectively using in vivo microdialysis may be a consequence of an indirect effect of modafinil on these neurons.

Animals↗
PubMed2003

Effects of modafinil on sustained attention performance and quality of life in OSA patients with residual sleepiness while being treated with nCPAP.

BACKGROUND: Some patients with obstructive sleep apnea/hypopnea syndrome (OSA/HS) who are regular users of nasal continuous positive airway pressure (nCPAP) therapy continue to experience daytime sleepiness that impairs performance and quality of life. A randomized, double-blind, placebo-controlled, parallel-group study was conducted to determine the effect of modafinil on sustained attention performance and functional quality of life in OSA/HS patients with residual daytime sleepiness, who were regular users of nCPAP therapy. METHODS: Seventy-seven patients received modafinil (200 mg/day, week 1; 400 mg/day, weeks 2-4) and 80 patients received matching placebo once daily for 4 weeks. Sustained attention performance on the psychomotor vigilance task (PVT) and functional status and quality of life using the Functional Outcomes of Sleep Questionnaire (FOSQ) were measured. RESULTS: The frequency of lapses of attention during PVT performance was significantly decreased, and both the median and slowest reaction times were significantly improved in patients receiving nCPAP plus modafinil compared with those receiving nCPAP plus placebo (P=0.010 for the number of lapses [transformed], P=0.023 for the median reaction time, and P=0.014 for the reciprocal of the 10% slowest reaction times). Treatment with nCPAP plus modafinil significantly improved the FOSQ total score (weeks 1 and 4), the vigilance subscale score (weeks 1 and 4), and the activity level subscale score (week 4) compared with treatment with nCPAP plus placebo (all P<0.05). CONCLUSIONS: Consistent with previous results for objective and subjective measures of sleepiness, modafinil used adjunctively improved performance on a test of behavioral alertness and reduced functional impairments in patients with OSA/HS who were regular users of nCPAP therapy but still experiencing sleepiness.

Adult↗
PubMed2005

A double-blind, placebo-controlled trial of modafinil for cocaine dependence.

Despite years of active research, there are still no approved medications for the treatment of cocaine dependence. Modafinil is a glutamate-enhancing agent that blunts cocaine euphoria under controlled conditions, and the current study assessed whether modafinil would improve clinical outcome in cocaine-dependent patients receiving standardized psychosocial treatment. This was a randomized, double-blind, placebo-controlled trial conducted at a university outpatient center (from 2002 to 2003) on a consecutive sample of 62 (predominantly African American) cocaine-dependent patients (aged 25-63) free of significant medical and psychiatric conditions. After screening, eligible patients were randomized to a single morning dose of modafinil (400 mg), or matching placebo tablets, for 8 weeks while receiving manual-guided, twice-weekly cognitive behavioral therapy. The primary efficacy measure was cocaine abstinence based on urine benzoylecgonine levels. Secondary measures were craving, cocaine withdrawal, retention, and adverse events. Modafinil-treated patients provided significantly more BE-negative urine samples (p=0.03) over the 8-week trial when compared to placebos, and were more likely to achieve a protracted period (> or =3 weeks) of cocaine abstinence (p=0.05). There were no serious adverse events, and none of the patients failed to complete the study as a result of adverse events. This study provides preliminary evidence, which should be confirmed by a larger study, that modafinil improves clinical outcome when combined with psychosocial treatment for cocaine dependence.

Adult↗
PubMed2005

Modafinil attenuates disruptions in cognitive performance during simulated night-shift work.

Common complaints among shift workers are sleep disruptions and increased sleepiness while working, which may contribute to shift workers being more susceptible to diminished performance and work-related accidents. The purpose of this double-blind, within-participant study was to examine the effects of the alerting agent modafinil on cognitive/psychomotor performance, mood, and measures of sleep during simulated shift work. In all, 11 participants completed this 23-day residential laboratory study. They received a single oral modafinil dose (0, 200, 400 mg) 1 h after waking for three consecutive days under two shift conditions: day shift and night shift. Shifts alternated three times during the study, and shift conditions were separated by an 'off' day. When participants received placebo, cognitive performance and subjective ratings of mood were disrupted during the night shift, relative to the day shift. Objective and subjective measures of sleep were also disrupted, but to a lesser extent. Modafinil reversed disruptions in cognitive performance and mood during the night shift. While modafinil produced few effects on sleep measures during the night shift, the largest dose produced several sleep alterations during the day shift. These data demonstrate that abrupt shift changes produced cognitive performance impairments and mood disruptions during night shift work. Therapeutic doses of modafinil attenuated night-shift-associated disruptions, but the larger dose produced some sleep impairments when administered during day-shift work.

Affect↗
PubMed2002

Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil.

The gene for catechol-O-methyltransferase (COMT) plays a key modulatory role in dopaminergic and noradrenergic neurotransmission. Recent evidence suggests that modafinil, like other stimulants, might act through the dopaminergic system. We have reported a sexual dimorphism and a strong effect of the COMT genotype on narcolepsy symptoms and hypothesized that response to modafinil treatment may be associated with the COMT genotype. Here we confirm that COMT genotype distribution between men and women narcoleptics is associated with response to modafinil. In addition, the optimal daily dose of modafinil is approximately 100 mg lower in women narcoleptics and lower in all narcoleptics with low activity COMT genotype. Our results suggest that a sexual dimorphism in COMT activity affects the response to modafinil and probably to other dopaminergic stimulants.

Adolescent↗
PubMed2006

Modafinil and cocaine interactions.

This Phase I trial evaluated the interaction between modafinil steady-state and cocaine. Twelve non-treatment seeking, cocaine dependent volunteers received four sets of randomized blinded infusions of saline, 20 mg IV cocaine, and 40 mg IV cocaine. Modafinil was given open label at 0 mg, 400 mg, or 800 mg. Modafinil combined with IV cocaine did not result in any significant hemodynamic interactions. Modafinil significantly dampened scores on Visual Analog Scale measures as compared to baseline cocaine conditions. No significant alterations in labs occurred. Further outpatient trials of modafinil appear to be warranted.

Benzhydryl Compounds↗
PubMedDate not supplied

Modafinil: preclinical, clinical, and post-marketing surveillance--a review of abuse liability issues.

Modafinil is an agent that is frequently used in the treatment of narcolepsy. More recently it has been used in the treatment of a variety of psychiatric, neurological, and medical illnesses. Due to its ability to improve wakefulness, modafinil has been viewed as a stimulant. Based on the potential for modafinil to become widely used in a variety of syndromes and settings, evidence from preclinical in vitro and in vivo studies, human laboratory studies, and post-marketing experiences examining the potential abuse liability of modafinil were reviewed. Initial evidence suggests that modafinil has limited potential for large-scale abuse.

Benzhydryl Compounds↗
PubMed1994

Modafinil: a double-blind multicentric study.

Modafinil is a central putative alpha-1 postsynaptic agonist with vigilance-promoting properties. Fifty narcoleptics (33 male and 17 female) participated in a multicentric study aimed at assessing the effects of the compound on night sleep, feeling on awakening, excessive daytime sleepiness and cataplexy. Modafinil was administered in a double-blind cross-over design at a daily dosage of 300 mg versus placebo. The duration of the study was 12 weeks, including a 2-week "run in" period with placebo, a first 4-week treatment period with either modafinil or placebo, a 2-week wash-out period with placebo and a second 4-week treatment period with either placebo or modafinil. Daily evaluation was based on a sleep log, visual analog scales, a sleep questionnaire and a clinical global index. Sleep laboratory evaluation took place on nights 1, 28, 42 and 70. It included 1 night of polysomnography preceded by a questionnaire on therapeutic and side effects, and a maintenance of wakefulness test (MWT). Sleep logs did not show any modification of night sleep, but a reduction of daytime sleepiness and sleep. Feeling on awakening was not modified. An overall benefit was noted by physicians as well as by patients. MWT disclosed a positive effect of modafinil on excessive daytime sleepiness. Cataplexy was not modified.

Adult↗
PubMed2004

Modafinil improves alertness, vigilance, and executive function during simulated night shifts.

STUDY OBJECTIVES: To assess the effect of 200 mg of modafinil compared to placebo on alertness, neurobehavioral performance, and executive function during 4 consecutive simulated night shifts. DESIGN: Double-blind, randomized, parallel groups. SETTING: Sleep research facility. PARTICIPANTS: 32 male and female volunteers between the ages of 18 and 55 years. INTERVENTIONS: 200 mg of modafinil or placebo given nightly on the 4 consecutive simulated night shifts. MEASUREMENTS AND RESULTS: Subjects were randomly assigned to 1 of the 2 treatment conditions, following medical, psychiatric, and polysomnographic screening. On 4 consecutive nights, subjects took study drug at 2200, and then from about 2300 to 0730 participated in a simulated night shift that included the Maintenance of Wakefulness Test, Psychomotor Vigilance Test, Digit Symbol Substitution Test, measures of subjective alertness, and multiple executive-function measures. At 0800, daytime sleep periods were recorded polysomnographically for 6 to 8 hours. Alertness--as measured by the MWT, vigilance and reaction time as indexed by Psychomotor Vigilance Test lapses, and slowest 10% of reaction times--and 3 executive-function tasks showed significant enhancement with modafinil versus placebo. Subjective sleepiness at night and some performance measures did not show consistent treatment differences. Daytime sleep showed minimal differences between conditions. CONCLUSIONS: The physiologic sleepiness and neurobehavioral deficits that occurred during the hours of a typical night shift were clearly attenuated by modafinil. Modafinil also had beneficial effects on some measures of executive function.

Adolescent↗
PubMed2006

Modafinil activates cortical and subcortical sites in the sleep-deprived state.

UNLABELLED: SUBJECT OBJECTIVES: To assess the effect of the wake-promoting drug modafinil on working memory and brain activation in the executive network, following a single night of sleep deprivation. DESIGN: Randomized, placebo-controlled, 4-arm, double-blind evaluation of a single 200-mg dose of modafinil on working memory (1-, 2-, and 3-back)-related functional brain activation and performance following overnight sleep deprivation. SETTING: General Clinical Research Center, Biomedical Imaging Center. SUBJECTS: Eight medication-free men, aged 21 to 35 years. INTERVENTIONS: Overnight sleep deprivation, single-dose 200-mg modafinil, functional magnetic resonance imaging MEASUREMENTS AND RESULTS: Brain activation patterns and regional signal intensity based on the blood-oxygen level-dependent signal were assessed. The following reaction times were used as measures of performance: (1) attention in the scanner before functional scanning, (2) "back" responses during the active-task block, and (3) attention during the baseline task block. Contrast of activation maps among conditions revealed sleep-deprivation and drug effects, and their interactions. Performance in the deprived state was enhanced by modafinil only at an intermediate (2-back) level of task difficulty and was associated with the recruitment of increased cortical activation volumes. Strong and consistent individual differences in performance were noted on the working memory tasks. CONCLUSIONS: Modafinil effectively counters the adverse effects of overnight sleep deprivation on working memory but only when task difficulty is moderate, recruiting extensive areas in the executive network to do so. Interindividual differences in working-memory performance are stable trait characteristics.

Adult↗
PubMed2001

First evidence of a delay-dependent working memory-enhancing effect of modafinil in mice.

This study investigated the effects of pretest injection of modafinil on delayed spontaneous alternation rates (SA) used to evaluate working memory in C57 Bl/6 mice. In a first experiment, systemic modafinil at 64 mg/kg, but not at 8 mg/kg or 32 mg/kg doses produced a significant increase of alternation scores (intertrial interval (ITI) 60s) when compared with controls. In a second experiment, modafinil (64 mg/kg) enhanced the alternation rates mainly at long (60 s and 180 s) but not at short (5 s) ITIs. Exploratory latencies and activity in a four hole-board apparatus were not modified by modafinil administration. These experiments are the first to demonstrate a delay-dependent working memory-enhancing effect of modafinil.

Animals↗