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PubMed2002

Determination of modafinil, modafinil acid and modafinil sulfone in human plasma utilizing liquid-liquid extraction and high-performance liquid chromatography.

An assay was developed to determine concentrations of modafinil (dl-2-[(diphenylmethyl)sulfinyl]acetamide; Provigil) and its two major circulating metabolites, modafinil acid and modafinil sulfone, in human plasma. The assay utilized liquid-liquid extraction of the analytes and an internal standard, (phenylthio)acetic acid, from plasma into a mixture of hexane-dichloromethane-glacial acetic acid (55:45:2, v/v). The analytes were resolved isocratically on a narrow-bore phenyl column at a mobile phase flow-rate of 0.3 ml/min and were monitored by UV detection at 235 nm. The method reported herein reduces the required sample volume of previously reported methods from 1.00 to 0.200 ml of plasma while lowering the limit of quantification (LOQ). The linear range of the assay was from 0.100 to 20.0 microg/ml for each of the three compounds.

Benzhydryl Compounds↗
PubMed2000

Randomized trial of modafinil as a treatment for the excessive daytime somnolence of narcolepsy: US Modafinil in Narcolepsy Multicenter Study Group.

OBJECTIVE: This is one of two separate clinical trials to evaluate the efficacy and safety of modafinil, a novel wake-promoting agent, in patients with excessive daytime sleepiness (EDS) associated with narcolepsy. METHODS: In this 9-week, randomized, placebo-controlled, double-blind, 21-center clinical trial, patients were randomized to receive fixed daily doses of modafinil 200 mg, modafinil 400 mg, or placebo. A placebo-controlled, 2-week treatment discontinuation phase was included to evaluate the effects of withdrawal on patients who had been receiving modafinil. A total of 271 patients who were naive to modafinil received study medication in the 9-week trial and 240 patients received study medication in the discontinuation phase. RESULTS: Treatment with modafinil resulted in significant improvement in two objective measures of EDS: the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. Additionally, patient self-assessment of sleepiness was significantly improved, as measured by the Epworth Sleepiness Scale, and level of illness was significantly reduced on the independent clinician assessment, the Clinical Global Impression of Change. Nighttime sleep, monitored by nocturnal polysomnography, was not adversely effected with modafinil treatment compared with placebo treatment. The most frequent adverse experience was headache, which was not significantly greater for modafinil than placebo. During treatment discontinuation, individuals who had been receiving modafinil experienced a return of their EDS to baseline levels. During treatment discontinuation, patients did not experience symptoms associated with amphetamine withdrawal syndrome. For up to 9 weeks of daily use there was no evidence for the development of dependence at the dose levels studied. CONCLUSION: The data indicate that modafinil has an excellent safety profile and is very well tolerated. Modafinil is an effective treatment for excessive daytime sleepiness in narcolepsy and shows continued efficacy with up to 9 weeks of daily use.

Adolescent↗
PubMed2005

Does modafinil activate the locus coeruleus in man? Comparison of modafinil and clonidine on arousal and autonomic functions in human volunteers.

RATIONALE: Modafinil is a wakefulness-promoting drug which is likely to activate some wakefulness-promoting and/or inhibit sleep-promoting neurones in the brain. The locus coeruleus (LC) is a wakefulness-promoting noradrenergic nucleus whose activity can be "switched off" by the alpha2-adrenoceptor agonist clonidine, leading to sedative and sympatholytic effects. OBJECTIVE: The aim of the study is to compare the effects of single doses of modafinil and clonidine on arousal and autonomic functions in human volunteers. METHODS: Sixteen healthy male volunteers participated in four experimental sessions (modafinil 200 mg; clonidine 0.2 mg; modafinil 200 mg + clonidine 0.2 mg; placebo) at weekly intervals, according to a balanced double-blind protocol. Arousal [pupillary "fatigue waves" (PFW), critical flicker fusion frequency, self-ratings of alertness] and autonomic functions (pupil diameter, pupillary light and darkness reflex responses, blood pressure, heart rate, salivation) were recorded. Data were analyzed with ANOVA, with multiple comparisons. RESULTS: Clonidine reduced subjective alertness, pupil diameter, the initial velocity and amplitude of the darkness reflex response, systolic and diastolic blood pressure and salivation, prolonged the recovery time of the light reflex response and increased PFW. Modafinil reduced PFW, increased pupil diameter and the initial velocity of the darkness reflex response and tended to reduce the effect of clonidine on pupil diameter and PFW. Modafinil had no effect on non-pupillary autonomic functions. CONCLUSIONS: Clonidine exerted sympatholytic and sedative effects, whereas modafinil had sympathomimetic and some alerting effects. Modafinil may activate noradrenergic neurones in the LC involved in arousal and pupillary control, without affecting extracoerulear noradrenergic neurones involved in cardiovascular and salivary regulation.

Adrenergic alpha-Agonists↗
PubMed1998

Randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. US Modafinil in Narcolepsy Multicenter Study Group.

Narcolepsy is a central nervous system disorder characterized by excessive daytime sleepiness and cataplexy. This placebo-controlled, double-blind, randomized, parallel-group, 18-center study assessed the efficacy and safety of modafinil, a new wake-promoting drug for treating sleepiness in narcolepsy. Subjects with narcolepsy (n = 283) received daily modafinil, 200 or 400 mg, or placebo, for 9 weeks, followed by an open-label treatment period. Subjective sleepiness was measured with the Epworth Sleepiness Scale. Objective sleepiness was assessed with the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test. Level of illness was measured with the Clinical Global Impression of Change. Modafinil significantly reduced all measures of sleepiness and was associated with significant improvements in level of illness. Medication-related adverse experiences were few, dose-dependent, and mostly rated mild to moderate. Modafinil taken once daily was a very well tolerated and effective wake-promoting agent in the treatment of excessive daytime somnolence associated with narcolepsy. Modafinil demonstrated an excellent safety profile for up to 40 weeks of open-label treatment and efficacy was maintained, suggesting that tolerance will not develop with long-term use. Modafinil is a pharmacologically and clinically promising compound for the treatment of pathological daytime somnolence.

Adolescent↗
PubMed2006

Modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, fixed-dose study followed by abrupt discontinuation.

OBJECTIVE: The objective of this fixed-dose study was to determine the efficacy and safety of a new formulation of modafinil (modafinil film-coated tablets) in children and adolescents with attention-deficit/hyperactivity disorder (ADHD). In addition, the effect of abrupt discontinuation of modafinil was evaluated in a 2-week observation period. METHOD: Patients aged 6 to 17 years with DSM-IV-TR-defined ADHD were randomly assigned to 7 weeks of double-blind treatment with modafinil or placebo in a 2:1 ratio, followed by abrupt discontinuation of modafinil and a 2-week, double-blind observation period in which 46% of patients receiving modafinil were switched to placebo without tapering and half continued to receive modafinil. Study drug was administered once daily and titrated over the first 7 to 9 days to daily doses of 340 mg for patients < 30 kg or 425 mg for patients > or = 30 kg. Assessment instruments included the Attention-Deficit/ Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) School and Home Versions and Clinical Global Impressions-Improvement scale (CGI-I). The study was conducted from November 2003 to June 2004. RESULTS: A total of 190 patients were randomly assigned to receive modafinil (340 mg, N = 44; 425 mg, N = 82) or placebo (N = 64). 189 patients were evaluated for safety. Modafinil significantly improved symptoms of ADHD as shown by reductions in ADHD-RS-IV School Version total scores compared with placebo at all visits (p < or = .009), including the final visit of the double-blind phase (p < .0001). With modafinil, ADHD-RS-IV School Version mean total scores changed from 37.8 at baseline to 29.3 at week 1 and 20.7 at final visit; corresponding placebo values were 36.6, 32.8, and 28.4, respectively; effect size at final visit was 0.76 (95% CI = 0.63 to 0.88). Total scores on the ADHD-RS-IV Home Version were also significantly reduced at all visits (p < or = .022) and final visit (p = .001) in patients receiving modafinil compared with those receiving placebo. Significantly higher proportions of patients receiving modafinil were rated "much improved" or "very much improved" in overall clinical condition (CGI-I) at all visits compared with patients receiving placebo (p < .001). No withdrawal symptoms were observed when modafinil was abruptly discontinued at the beginning of the final 2-week observation period. Modafinil was generally well tolerated. Insomnia, headache, and decreased appetite were the most commonly reported adverse events. Sixty-three percent of patients who received modafinil completed the study; 13% discontinued because of lack of efficacy; 10%, because of adverse events; and 13%, for other reasons (e.g., consent withdrawn, lost to follow-up). CONCLUSION: Modafinil significantly improved symptoms of ADHD both at school and at home and was well tolerated by children and adolescents. Abrupt discontinuation of modafinil was not associated with symptoms of withdrawal or with rebound of symptoms of ADHD.

Adolescent↗
PubMed1998

Single-dose pharmacokinetics of modafinil and methylphenidate given alone or in combination in healthy male volunteers.

Modafinil is a novel wake-promoting agent being developed for treatment of excessive daytime sleepiness associated with narcolepsy. An open, 3 x 3 Latin square, randomized, cross-over study was performed in healthy males to compare the pharmacokinetics of single-dose oral modafinil (200 mg) and methylphenidate (40 mg) administered alone or in combination. Blood samples were obtained for analysis of d- and l-threo-methylphenidate and modafinil and its acid and sulfone metabolites. Pharmacokinetic parameters were determined by noncompartmental methods, but could not be evaluated for modafinil sulfone due to plasma levels that were close to the assay quantitation limit. Although sporadic differences in plasma concentrations were observed between treatments, coadministration of modafinil and methylphenidate did not significantly alter the plasma concentrations of modafinil, modafinil acid, modafinil sulfone, or methylphenidate enantiomers compared with administration of these agents alone. Half-life (t1/2), maximum concentration (Cmax), area under the concentration-time curve (AUC0-infinity), total clearance (Cl/F), and apparent volume of distribution (Vd/F) for modafinil and t1/2, Cmax, and AUC0-infinity for modafinil acid were not affected by concomitant administration of methylphenidate. Small but statistically significant increases in time to Cmax (tmax) were observed for modafinil and modafinil acid after methylphenidate coadministration compared with modafinil alone. Modafinil coadministration did not significantly alter the pharmacokinetics of d- or l-threo-methylphenidate, except for a small decrease in Vd/F of l-threo-methylphenidate. Concomitant methylphenidate may cause a delay in the oral absorption of modafinil, but this delay might not be relevant clinically. Coadministration did not alter the extent of oral absorption and disposition of either agent. Therefore, a pharmacokinetic interaction between modafinil and methylphenidate would be unlikely.

Adolescent↗
PubMed2005

Assessment of modafinil on attentional processes in a five-choice serial reaction time test in the rat.

It is well known that modafinil is an effective wake-promoting agent, but there is growing evidence to suggest that modafinil may also enhance some aspects of cognition. In man, modafinil has been shown to enhance vigilance in sleep-deprived and/or narcoleptic subjects and also to improve executive-type functioning (predominantly inhibitory response control processes) across a variety of human patient population groups. Preclinically, a delay-dependent improvement has been reported with modafinil in a mouse T-maze test of working memory. To investigate further the role of modafinil as a potential cognition enhancer, the effects of modafinil on attentional processes were assessed in the rat. The aim of the present study was to evaluate the potential of modafinil to enhance five-choice serial reaction time test (5-CSRT) performance. Lister Hooded rats received 32-128 mg/kg modafinil and 5-CSRT performance was assessed under standard and test parametric conditions in which the attentional load was increased, and also under conditions of scopolamine pre-treatment. Modafinil failed to significantly enhance 5-CSRT performance under standard conditions. Similarly, modafinil was unable to reverse the deficits in accuracy and/or increased omission errors induced by either parametric or pharmacological manipulations. Indeed, at higher doses, modafinil caused an increase in premature responding under certain test conditions, suggestive of increased impulsivity. The present findings suggest that, although modafinil may enhance vigilance in sleep-deprived human subjects, attentional processes in normal awake rats remain unaffected. No evidence was found to support a modafinil-induced improvement in response control; rather, under conditions of increased attentional load, modafinil appeared to facilitate impulsive responding. Finally, the failure of modafinil to improve a scopolamine-induced performance deficit suggests that modafinil does not act on the cholinergic system directly.

Animals↗
PubMed2005

Efficacy and safety of modafinil film-coated tablets in children and adolescents with attention-deficit/hyperactivity disorder: results of a randomized, double-blind, placebo-controlled, flexible-dose study.

OBJECTIVE: Modafinil, which is structurally and pharmacologically different from other agents that are used for the treatment of children with attention-deficit/hyperactivity disorder (ADHD), selectively activates the cortex and has low potential for abuse. Initial studies of the use of modafinil to treat ADHD showed significant improvements in the core symptoms of the disorder, namely inattention, hyperactivity, and impulsivity. This study evaluated a new formulation of modafinil (modafinil film-coated tablets) in children and adolescents with ADHD. METHODS: This 9-week, multicenter, randomized, double-blind, placebo-controlled, flexible-dose study evaluated the film-coated tablet formulation of modafinil, which was titrated to an optimal dose on the basis of efficacy and tolerability (range: 170-425 mg once daily). Efficacy was assessed by clinicians who completed the Attention-Deficit/Hyperactivity Disorder Rating Scale-IV (ADHD-RS-IV) based on interviews with teachers (School Version) and parents (Home Version) and the Clinical Global Impression of Improvement scale. Safety evaluation was based on assessments of adverse event reports, laboratory tests, vital signs, and body weight. RESULTS: A total of 248 subjects were randomly assigned in a 2:1 ratio, and 246 were treated with modafinil (n = 164) or placebo (n = 82). Treatment groups were comparable with respect to demographics and baseline characteristics. Intention-to-treat analysis (ITT) showed that compared with placebo, treatment with modafinil significantly improved the core symptoms of ADHD as shown by greater reductions in the ADHD-RS-IV School Version total scores from baseline to final visit (mean change [SD]: -15.0 [11.8] vs -7.3 [9.7]) (effect size: 0.69; 95% confidence interval: 0.57-0.82). Significant improvements were observed with modafinil treatment on the ADHD-RS-IV School Version at week 1, with improvements maintained throughout the study. Similar differences in symptom improvements were observed on the ADHD-RS-IV Home Version between modafinil-treated and placebo-treated patients. Treatment with modafinil also significantly reduced subscale scores for inattention and hyperactivity-impulsivity on both School and Home Versions compared with placebo. At the final visit, 48% of modafinil-treated patients were rated as "much" or "very much" improved in overall clinical condition compared with 17% of placebo-treated patients (Clinical Global Impression of Improvement). Most adverse events were mild to moderate in severity, and the majority resolved during treatment. The most commonly reported adverse events in the modafinil group were insomnia (29%), headache (20%), and decreased appetite (16%). Three percent of modafinil-treated patients and 4% of placebo-treated patients discontinued treatment because of adverse events. CONCLUSIONS: Modafinil film-coated tablets significantly improved ADHD symptoms at school and home as evaluated by clinicians, teachers, and parents. Treatment with once-daily modafinil was generally well tolerated, with few discontinuations as a result of adverse events.

Adolescent↗
PubMed1999

A double-blind, placebo-controlled, ascending-dose evaluation of the pharmacokinetics and tolerability of modafinil tablets in healthy male volunteers.

A randomized, double-blind, placebo-controlled, ascending-dose study was conducted to evaluate the pharmacokinetic and safety profiles of increasing modafinil doses (200 mg, 400 mg, 600 mg, 800 mg) administered orally over a 7-day period in normal healthy male volunteers. Eight subjects (six modafinil; two placebo) were randomized to each of the four dose groups. Modafinil or a placebo was administered once daily for 7 days. Serial blood samples were obtained following administration of the day 1 and day 7 doses for characterization of pharmacokinetics, and trough samples were obtained prior to dosing on days 2 through 6 to assess the time to reach the steady state. Pharmacokinetic parameters were calculated using noncompartmental methods. Modafinil steady state was reached after three daily doses. Modafinil pharmacokinetics were dose and time independent over the range of 200 mg to 800 mg. Steady-state pharmacokinetics of modafinil were characterized by a rapid oral absorption rate, a low plasma clearance of approximately 50 mL/min, a volume of distribution of approximately 0.8 L/kg, and a long half-life of approximately 15 hr. Modafinil was primarily eliminated by metabolism. Modafinil acid was the major urinary metabolite. Stereospecific pharmacokinetics of modafinil were demonstrated. The d-modafinil enantiomer was eliminated at a threefold faster rate than 1-modafinil. Modafinil 200 mg, 400 mg, and 600 mg doses were generally well tolerated. The modafinil 800 mg dose panel was discontinued after 3 days of treatment due to the observation of increased blood pressure and pulse rate. The safety data from this study suggest that the maximum tolerable single daily oral modafinil dose, without titration, may be 600 mg.

Adolescent↗
PubMed2006

Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro.

2-[(Diphenylmethyl) sulfinyl]acetamide (modafinil), prescribed principally to treat narcolepsy, is undergoing assessment for other neuropsychiatric disorders and medical conditions. The neurochemical substrates of modafinil are unresolved. We postulated that modafinil enhances wakefulness by modulating dopamine (DAT), norepinephrine (NET), or serotonin (SERT) transporter activities. In vivo, we determined DAT and NET occupancy by modafinil by positron emission tomography imaging; in vitro, we determined modafinil activity at the DAT, NET, SERT, and rhesus monkey trace amine receptor 1 (TA1). In rhesus monkey, modafinil occupancy of striatal DAT was detected by [(11)C]2beta-carbomethoxy-3beta-4-(fluorophenyl)tropane and of thalamic NET by [(11)C](S,S)-2-(alpha-(2-methoxyphenoxy)-benzyl)morpholine. In vitro, modafinil effects in DAT-human embryonic kidney (HEK), NET-HEK, and SERT-HEK cells were investigated alone or combined with the TA1 receptor. Modafinil (i.v.) occupied striatal DAT sites (5 mg/kg: 35 +/- 12%, n = 4; 8 mg/kg: 54 +/- 3%, n = 3). In thalamus, modafinil occupied NET sites (5 mg/kg: 16 +/- 7.8%, n = 6; 8 mg/kg: 44 +/- 12%; n = 2). In vitro, modafinil inhibited [(3)H]dopamine (IC(50) = 6.4 microM), [(3)H]norepinephrine (IC(50) = 35.6 microM), and [(3)H]serotonin (IC(50) > 500 microM) transport via the human DAT, NET, and SERT. Modafinil did not activate the TA1 receptor in TA1-HEK cells, but it augmented a monoamine transporter-dependent enhancement of phenethylamine activation of TA1 in TA1-DAT and TA1-NET cells, but not in TA1-SERT cells. The present data provide compelling evidence that modafinil occupies the DAT and NET in living brain of rhesus monkeys and raise the possibility that modafinil affects wakefulness by interacting with catecholamine transporters in brain.

Animals↗
PubMed1999

Open-label, single-dose pharmacokinetic study of modafinil tablets: influence of age and gender in normal subjects.

An open-label, single-center, single-dose, parallel-group study was performed in healthy young males and females as well as healthy elderly males to examine the influence of age and gender on the pharmacokinetics of modafinil following administration of a single 200 mg oral dose. Twelve subjects were enrolled in each of the following three groups: young males, young females, and elderly males. Each fasted (overnight) subject received 2 x 100 mg modafinil tablets. Blood and urine samples were collected at various times up to 72 hours postdose for the determination of plasma and urine levels of modafinil as well as the acid and sulfone metabolites. The plasma concentrations of the individual isomers, d- and l-modafinil, were also determined. Pharmacokinetic parameters were determined by noncompartmental methods. Modafinil was well tolerated at a single oral dose of 200 mg. The most commonly reported adverse events were headache, fever, pharyngitis, and asthenia. There were no clinically meaningful differences with respect to the incidence rate of treatment-emergent adverse events among the young female, young male, and old male groups. Modafinil was rapidly absorbed after oral dosing and slowly cleared (t1/2 approximately 11-14 hr) from the body. Modafinil acid was the major urinary metabolite, which accounted for 35% to 60% of the dose. Results from this study indicated that there were age and gender effects on modafinil clearance processes. In this regard, the clearance rate of modafinil in males decreased with age while young females cleared modafinil at a faster rate than young males. Stereospecific pharmacokinetics of modafinil were also demonstrated. The d-modafinil was eliminated three times faster than the l-modafinil.

Adult↗
PubMedDate not supplied

Effects of modafinil on wakefulness and executive function in patients with narcolepsy experiencing late-day sleepiness.

OBJECTIVES: A modafinil daily dosing strategy promotes wakefulness in narcolepsy patients experiencing excessive daytime sleepiness; however, some patients may continue to experience late-day sleepiness. Excessive sleepiness in narcolepsy is associated with cognitive impairment. Modafinil has improved executive function in other models of excessive sleepiness. This study evaluated the effects of once-daily vs. split doses of modafinil on wakefulness and of combined doses on executive function in narcolepsy patients experiencing late-day sleepiness despite satisfactory modafinil treatment earlier in the day. METHODS: After a 2-week washout, 24 patients received 3 weeks of double-blind treatment with modafinil 400-mg once daily (7 AM) plus placebo (noon) or modafinil 600-mg split dose (400 mg, 7 AM; 200 mg, noon). Assessments included a Maintenance of Wakefulness Test (MWT) for individual regimens and the Wisconsin Card Sort Test (WCST) for treatments combined. RESULTS: Modafinil 600-mg split dose was significantly more effective than modafinil 400-mg once daily in improving late-day MWT scores (5 PM-7 PM; P < 0.05). Significant mean (+/- SEM) reductions from baseline of 8.2 +/- 2.7 in the total number of errors and 5.9 +/- 1.9 in total percent of errors (P < 0.05, both) were demonstrated for modafinil on the WCST. Modafinil was well tolerated; adverse events included headache (n = 1), emotional lability (n = 1), bronchitis (n = 1), and accidental injury (n = 2), with no reports of insomnia. CONCLUSIONS: For patients with residual late-day sleepiness associated with narcolepsy, an additional 200-mg dose of modafinil taken at midday was effective in sustaining wakefulness throughout the entire waking day. Treatment with modafinil also significantly improved executive function.

Adolescent↗
PubMed1996

Evaluation of the cocaine-like discriminative stimulus effects and reinforcing effects of modafinil.

Modafinil [(diphenyl-methyl)sulphinyl-2-acetamide] is a novel psychostimulant drug which is effective in the treatment of narcolepsy and idiopathic hypersomnia. It also has neuroprotective effects in animal models of striatal neuropathology. Although the cellular mechanisms of action of modafinil are poorly understood, it has been shown to have a profile of pharmacological effects that differs considerably from that of amphetamine-like stimulants. There is some evidence that modafinil has central alpha 1-adrenergic agonist effects. In the present study modafinil was evaluated for cocaine-like discriminative stimulus effects in rats and for reinforcing effects in rhesus monkeys maintained on intravenous cocaine self-administration. Modafinil, l-ephedrine and d-amphetamine all produced dose dependent increases in cocaine-lever responding, with maximal levels of 67%, 82% and 100%, respectively. Modafinil produced full substitution in four out of the six rats tested while the highest levels of substitution were associated with substantial response rate decreasing effects. Little evidence was obtained that the discriminative stimulus effects of modafinil were produced by alpha 1-adrenergic activation, based upon results of tests performed in combination with prazosin. In the self-administration procedure, modafinil and l-ephedrine functioned as reinforcers in rhesus monkeys. The reinforcing and discriminative stimulus effects of modafinil-required very high doses: modafinil was over 200 times less potent than d-amphetamine and was also less potent than l-ephedrine. These results show that modafinil has some cocaine-like discriminative stimulus effects and, like other abused stimulants, can serve as a reinforcer at high doses.

Adrenergic Agents↗
PubMed1992

Evidence for a protective action of the vigilance promoting drug modafinil on the MPTP-induced degeneration of the nigrostriatal dopamine neurons in the black mouse: an immunocytochemical and biochemical analysis.

Based on the observations that the psychostimulant drug amphetamine in combination with physiotherapy can promote recovery of brain function after brain injury, we have studied the ability of the vigilance promoting drug Modafinil to counteract 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-(MPTP)-induced degeneration of the nigrostriatal dopamine (DA) neurons of the black mouse. MPTP was given s.c. in a dose of 40 mg/kg and the mice were sacrificed 2 weeks later. The effects of acute and chronic treatment with Modafinil were studied on MPTP-induced DA neurotoxicity. The substantia nigra and neostriatum were taken to both biochemical and histochemical analysis of presynaptic parameters of the nigrostriatal DA neurons, the latter in combination with image analysis. In separate experiments in rats in vivo tests for DA uptake blocking activity were made using intrastriatal microdialysis to study superfusate levels of DA and its metabolites and the 4-alpha-dimethylmetatyramine (H77/77) model to test for a possible ability of Modafinil to protect against H77/77-induced depletion of forebrain DA stores. Chronic treatment with Modafinil in doses of 10 to 100 mg/kg counteracted the MPTP-induced disappearance of nigral TH IR nerve cell body profiles and neostriatal TH IR nerve terminal profiles as evaluated after 2 weeks with image analysis. Chronic treatment with Modafinil (10-100 mg/kg) also dose-dependently counteracted the MPTP-induced disappearance of striatal DA uptake binding sites as evaluated at the same time interval. Also in the dose range 10-100 mg/kg Modafinil counteracts the MPTP-induced depletion of DA stores both in the neostriatum and the substantia nigra. In the acute experiments Modafinil (30 mg/kg) protected against the MPTP-induced depletion of striatal DA, dihydrophenylacetic acid (DOPAC) and homovanillic acid (HVA) levels both when given 15 min before, at the same time and 3 h following the MPTP injection. In the substantia nigra, however, these protective actions of Modafinil were only observed when the drug was coadministered with MPTP. Experiments with microdialysis in intact rats failed to demonstrate any increases of superfusate DA levels in neostriatum with 30 mg/kg of Modafinil. Modafinil in high doses of 2 x 50 mg/kg, however, significantly counteracted the H77/77 induced DA depletion of striatal DA stores. Thus, morphological and biochemical evidence has been obtained that Modafinil in the dose range 10-100 mg/kg protects against MPTP-induced degeneration of the nigrostriatal DA neurons of the black mouse.(ABSTRACT TRUNCATED AT 400 WORDS)

3,4-Dihydroxyphenylacetic Acid↗
PubMed2002

Study of the addictive potential of modafinil in naive and cocaine-experienced rats.

RATIONALE: Modafinil is a drug that promotes wakefulness and, as such, is used to treat hypersomnia and narcolepsy. Preclinical and clinical studies suggest that modafinil could possess weak reinforcing effects in drug-experienced subjects. However, its abuse potential in drug-naive healthy individuals is still totally uninvestigated, despite the fact that availability of modafinil has recently increased. OBJECTIVES: The purpose of our study was to investigate the potential addictive properties of modafinil by testing its reinforcing effects in naive rats. The interactions of modafinil with the reinforcing effects of cocaine were also tested. METHODS: First, using i.v. self-administration and place conditioning tests, we studied the reinforcing and rewarding effects of a large range of doses of modafinil in naive rats. Second, we tested the influence of modafinil on reinforcing and incentive effects of cocaine in rats trained for cocaine self-administration. The effects of modafinil were compared with those of amphetamine and haloperidol. RESULTS: Modafinil did not produce reinforcing or rewarding effects and did not modify the effects of cocaine. CONCLUSIONS: Our results suggest that modafinil does not possess an addictive potential in naive individuals. Furthermore, it would be behaviorally distinct from classical central nervous system stimulants which are known to alter cocaine-induced effects. However, as shown previously in nonhuman primates and in humans, modafinil could possibly have reinforcing effects in cocaine-experienced individuals.

Animals↗
PubMed2003

Initiating treatment with modafinil for control of excessive daytime sleepiness in patients switching from methylphenidate: an open-label safety study assessing three strategies.

RATIONALE: Modafinil is a first-line wake-promoting medication and a useful therapeutic alternative to psychostimulant medications for excessive daytime sleepiness. OBJECTIVE: This 5-week, randomized, open-label study evaluated three strategies for switching patients from methylphenidate, a commonly used psychostimulant, to modafinil. METHODS: Patients ( n=40) with excessive daytime sleepiness related to narcolepsy, who had received previous treatment with methylphenidate, were switched from methylphenidate to modafinil (200 mg/day followed by 400 mg/day) without a washout period between treatments, with a 2-day washout period between treatments, or by using a taper-down/titrate-up protocol. Adverse events were recorded throughout the study, and Epworth Sleepiness Scale scores were determined at the end of the study. RESULTS: The majority of patients (95%) were successfully switched to modafinil. At the study end point, mean Epworth Sleepiness Scale scores were <12 for each treatment group. All three switching strategies were well tolerated, with adverse events mild or moderate in nature. Adverse events most frequently reported during modafinil treatment were among those seen previously in large-scale, placebo-controlled studies. There were no meaningful differences among the treatment groups in the frequency or severity of adverse events or in their relationship to modafinil treatment. Only one patient discontinued modafinil treatment because of a treatment-related adverse event (i.e. moderate headache); another patient discontinued due to insufficient efficacy. CONCLUSIONS: Switching from methylphenidate to modafinil was well tolerated with or without a washout period or when the methylphenidate dose is gradually tapered during initiation of modafinil therapy. Daytime wakefulness was maintained in patients who have switched from methylphenidate to modafinil. These data suggest that patients with narcolepsy may be switched from methylphenidate to modafinil with few complications and inconveniences.

Adolescent↗
PubMed1998

Brain regional substrates for the actions of the novel wake-promoting agent modafinil in the rat: comparison with amphetamine.

Modafinil is a novel wake-promoting compound for which the mechanism and sites of action are unknown. We examined the neural substrates in the brain for the actions of modafinil using 2-deoxyglucose autoradiography and compared the findings to those obtained with amphetamine. Modafinil showed a relatively restricted pattern of changes in brain regional metabolic activity, while amphetamine altered glucose utilization in a wide variety of brain regions. Both modafinil and amphetamine increased glucose utilization in all subregions of the hippocampus (subiculum, CA1-CA3 and dentate gyrus) and in the centrolateral nucleus of the thalamus. Modafinil also increased glucose utilization in the central nucleus of the amygdala, but amphetamine had no effect in this region. Brain structures in which amphetamine increased metabolic rate but modafinil had no effect included regions of the basal ganglia, other nuclei of the thalamus, the frontal cortex, the nucleus accumbens, the ventral tegmental area and the pontine reticular fields. These findings suggest that, while both modafinil and amphetamine promote wakefulness, they act via distinctly different mechanisms. Modafinil appears to act on a specific subset of brain pathways which regulate sleep and wakefulness, whereas amphetamine affects a greater number of cerebral structures involved in the regulation of these behavioral states. Modafinil also lacks the pronounced effects on the extrapyramidal motor system which are characteristic of amphetamine and other psychomotor stimulants, implying that the effects of modafinil are not mediated by the dopamine system and that modafinil may selectively increase wakefulness with fewer side effects.

Amygdala↗
PubMed2003

Modafinil maintains waking in the fruit fly drosophila melanogaster.

Fruit flies exhibit a sleep-like rest state that shares behavioral characteristics with mammalian sleep, including a homeostatic increase in rest after deprivation by mechanical methods. We tested the effect of modafinil, a novel wake-promoting agent, to discover whether its effect is conserved. Flies fed various concentrations of modafinil were compared to groups of control flies fed diluent only. Flies were also tested for a homeostatic response to the modafinil-related rest deprivation by examining rest and activity during recovery after 48H modafinil administration, compared to rest deprivation alone and to both treatments combined. The duration and consolidation of rest, and the duration, intensity, and circadian rhythms of activity were measured. Modafinil significantly and dose-dependently decreased rest when fed at concentrations from 2.5 mg/ml to 0.3125 mg/ml. Activity intensity was not increased, and circadian timing was unchanged, although the 2.5 mg/ml dose blunted the amplitude of overt circadian locomotor rhythms. Compared to controls, the duration of rest bouts was decreased in flies fed 2.5 mg/ml, and waking was frequently interrupted by 5-min periods of immobility. A rest rebound (significant increase in rest) followed withdrawal of either 2.5mg/ml or 0.625mg/ml modafinil after 48H. When directly compared to 6H total rest deprivation, the increase after withdrawal was briefer, reminiscent of the attenuated rest rebound seen in mammals, including humans, after modafinil. However, modafinil withdrawal combined with 6H total rest deprivation significantly enhanced the rebound, suggesting that a rest debt is accumulating during modafinil. We conclude that modafinil affects states of arousal in Drosophila in the same direction as it does in mammals. This discovery provides a tool for searching for conserved molecular mechanisms by which modafinil regulates rest and waking.

Animals↗