BACKGROUND: Modafinil is primarily used to treat narcolepsy but is also used as an off-label cognitive enhancer. Functional magnetic resonance imaging studies indicate that modafinil modulates the connectivity of neocortical networks primarily involved in attention and executive functions. However, much less is known about the drug's effects on subcortical structures. Following preliminary findings, we evaluated modafinil's activity on the connectivity of distinct cerebellar regions with the neocortex. We assessed the spatial relationship of these effects with the expression of neurotransmitter receptors/transporters. METHODS: Patterns of resting-state functional magnetic resonance imaging connectivity were estimated in 50 participants from scans acquired pre- and postadministration of a single (100 mg) dose of modafinil (n = 25) or placebo (n = 25). Using specific cerebellar regions as seeds for voxelwise analyses, we examined modafinil's modulation of cerebellar-neocortical connectivity. Next, we conducted a quantitative evaluation of the spatial overlap between the modulation of cerebellar-neocortical connectivity and the expression of neurotransmitter receptors/transporters obtained by publicly available databases. RESULTS: Modafinil increased the connectivity of crus I and vermis IX with prefrontal regions. Crus I connectivity changes were associated with the expression of dopaminergic D2 receptors. The vermis I-II showed enhanced coupling with the dorsal anterior cingulate cortex and matched the expression of histaminergic H3 receptors. The vermis VII-VIII displayed increased connectivity with the visual cortex, an activity associated with dopaminergic and histaminergic neurotransmission. CONCLUSIONS: Our study reveals modafinil's modulatory effects on cerebellar-neocortical connectivity. The modulation mainly involves crus I and the vermis and spatially overlaps the distribution of dopaminergic and histaminergic receptors.

• Klíčová slova
• Cerebellum, Crus, Modafinil, Receptors, Vermis, fMRI,
• MeSH
• dospělí MeSH
• lidé MeSH
• magnetická rezonanční tomografie MeSH
• mladý dospělý MeSH
• modafinil * farmakologie   MeSH
• mozeček * účinky léků   metabolismus   diagnostické zobrazování   MeSH
• nervové dráhy účinky léků   MeSH
• Check Tag
• dospělí MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• modafinil * MeSH

BACKGROUND: Excessive daytime sleepiness (EDS) is a frequent and disabling symptom of Parkinson's disease (PD) without approved treatment. THN102 is a novel combination drug of modafinil and low-dose flecainide. OBJECTIVE: The aim of this study is to evaluate the safety and efficacy of THN102 in PD patients with EDS. METHODS: The method involved a randomized, double-blind, placebo-controlled, crossover trial testing two doses of THN102 (200 mg/d modafinil with 2 mg/d [200/2] or 18 mg/d flecainide [200/18]) versus placebo; 75 patients were exposed to treatment. The primary endpoint was safety. The primary efficacy outcome was the change in Epworth Sleepiness Scale (ESS) score. RESULTS: Both doses of THN102 were well tolerated. ESS significantly improved with THN102 200/2 (least square means vs. placebo [95% confidence interval, CI]: -1.4 [-2.49; -0.31], P = 0.012) but did not change significantly with the 200/18 dosage. CONCLUSIONS: THN102 was well tolerated and showed a signal of efficacy at the 200/2 dose, supporting further development for the treatment of EDS in PD. © 2021 International Parkinson and Movement Disorder Society.

• Klíčová slova
• Parkinson's disease; sleepiness; clinical trial; modafinil; flecainide,
• MeSH
• dvojitá slepá metoda MeSH
• fixní kombinace léků MeSH
• flekainid * škodlivé účinky   MeSH
• lidé MeSH
• modafinil * škodlivé účinky   MeSH
• Parkinsonova nemoc * farmakoterapie   MeSH
• poruchy nadměrné spavosti * etiologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• fixní kombinace léků MeSH
• flekainid * MeSH
• modafinil * MeSH

BACKGROUND AND PURPOSE: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS), and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness (EDS) in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong); methylphenidate, amphetamine derivatives (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) EDS in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivatives (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

• Klíčová slova
• European, cataplexy, guideline, management, narcolepsy,
• MeSH
• dítě MeSH
• dospělí MeSH
• kataplexie * MeSH
• lidé MeSH
• modafinil terapeutické užití   MeSH
• narkolepsie * diagnóza   farmakoterapie   MeSH
• oxybát sodný * terapeutické užití   MeSH
• spánek MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• systematický přehled MeSH
• Názvy látek
• modafinil MeSH
• oxybát sodný * MeSH

BACKGROUND AND AIM: Narcolepsy is an uncommon hypothalamic disorder of presumed autoimmune origin that usually requires lifelong treatment. This paper aims to provide evidence-based guidelines for the management of narcolepsy in both adults and children. METHODS: The European Academy of Neurology (EAN), European Sleep Research Society (ESRS) and European Narcolepsy Network (EU-NN) nominated a task force of 18 narcolepsy specialists. According to the EAN recommendations, 10 relevant clinical questions were formulated in PICO format. Following a systematic review of the literature (performed in Fall 2018 and updated in July 2020) recommendations were developed according to the GRADE approach. RESULTS: A total of 10,247 references were evaluated, 308 studies were assessed and 155 finally included. The main recommendations can be summarized as follows: (i) excessive daytime sleepiness in adults-scheduled naps, modafinil, pitolisant, sodium oxybate (SXB), solriamfetol (all strong), methylphenidate, amphetamine derivates (both weak); (ii) cataplexy in adults-SXB, venlafaxine, clomipramine (all strong) and pitolisant (weak); (iii) excessive daytime sleepiness in children-scheduled naps, SXB (both strong), modafinil, methylphenidate, pitolisant, amphetamine derivates (all weak); (iv) cataplexy in children-SXB (strong), antidepressants (weak). Treatment choices should be tailored to each patient's symptoms, comorbidities, tolerance and risk of potential drug interactions. CONCLUSION: The management of narcolepsy involves non-pharmacological and pharmacological approaches with an increasing number of symptomatic treatment options for adults and children that have been studied in some detail.

• Klíčová slova
• European, cataplexy, guideline, management, narcolepsy,
• MeSH
• dítě MeSH
• dospělí MeSH
• kataplexie * MeSH
• lidé MeSH
• modafinil terapeutické užití   MeSH
• narkolepsie * diagnóza   farmakoterapie   MeSH
• oxybát sodný * terapeutické užití   MeSH
• spánek MeSH
• Check Tag
• dítě MeSH
• dospělí MeSH
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• systematický přehled MeSH
• Názvy látek
• modafinil MeSH
• oxybát sodný * MeSH

Methamphetamine is a potent and highly addictive psychostimulant, and one of the most widely used illicit drugs. Over recent years, its global usage and seizure have been on a rapid rise, with growing detrimental effects on mental and physical health, and devastating psychosocial impact pressing for intervention. Among the unwanted effects of methamphetamine, acute and long-term sleep impairments are of major concern, posing a significant therapeutic challenge, and a cause of addiction relapse. Unraveling mechanisms and functional correlates of methamphetamine-related sleep and circadian disruption are, therefore, of key relevance to translational and clinical psychiatry. In this article, we review the mounting evidence for the acute and long-term impairements of sleep-wake behavior and circadian activity caused by single or recurring methamphetamine usage and withdrawal. Factors contributing to the severity of sleep loss and related cognitive deficit, with risks of relapse are discussed. Key molecular players mediating methamphetamine-induced dopamine release and neuromodulation are considered, with wake-promoting effects in mesolimbic circuits. The effects on various sleep phases and related changes in dopamine levels in selected subcortical structures are reviewed and compared to other psychostimulants with similar action mechanisms. A critical appraisal is presented of the therapeutic use of modafinil, countering sleep, and circadian rhythm impairments. Finally, emerging knowledge gaps and methodical limitations are highlighted along with the areas for future research and therapeutic translation.

• Klíčová slova
• addiction, circadian rhythms, dopamine, dopamine transporter, drug abuse, methamphetamine, modafinil, sleep and insomnia,
• MeSH
• dopamin MeSH
• methamfetamin * škodlivé účinky   MeSH
• modafinil MeSH
• spánek MeSH
• stimulanty centrálního nervového systému * škodlivé účinky   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• dopamin MeSH
• methamfetamin * MeSH
• modafinil MeSH
• stimulanty centrálního nervového systému * MeSH

BACKGROUND: Modafinil is a psychostimulant drug prescribed mainly for treatment of narcolepsy but is used as a "smart drug" by wide populations to increase wakefulness, concentration and overall mental performance. The aim of this study was to assess potential developmental toxicity of modafinil. MATERIALS AND METHODS: Pregnant female mice were given either saline or modafinil (50 mg/kg orally) from gestational day (GD) 3 to GD 10 and then a challenge dose on the GD 17. The male offspring were treated analogously at the age of 10 weeks. Changes in the spontaneous locomotor/exploratory behaviour and anxiogenic profile in the open-field test were assessed in naive animals, after an acute and 8th modafinil dose and the challenge dose following a 7-day wash-out period. One month after completion of the behavioural study, the leukocyte phagocytosis was examined by zymosan induced and luminol-aided chemiluminiscence assay in vitro. RESULTS: The most important finding of this study was the immunosuppressing effect on leukocyte activity, hypolocomotion and increased behavioural response to modafinil-induced psychostimulation caused by prenatal exposure to the same drug. We did not detect significantly altered anxiety-related behaviour in any group disregarding the pre- and postnatal treatments. CONCLUSION: This is the first evidence of developmental toxicity of modafinil which needs to be taken into account as a potential risk factor when modafinil is administered to women who may become or are pregnant.

• MeSH
• fagocytóza účinky léků   MeSH
• gestační stáří MeSH
• leukocyty účinky léků   MeSH
• lokomoce účinky léků   MeSH
• luminiscenční měření MeSH
• luminol MeSH
• modafinil škodlivé účinky   MeSH
• modely nemocí na zvířatech * MeSH
• myši inbrední ICR MeSH
• myši MeSH
• těhotenství MeSH
• věkové faktory MeSH
• zpožděný efekt prenatální expozice * MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• luminol MeSH
• modafinil MeSH

Modafinil is a psychostimulant drug prescribed for treatment of narcolepsy. However, it is used as a "smart drug" especially by young adults to increase wakefulness, concentration and mental performance. Therefore, it can also be used by women with childbearing potential and its developmental effects can become a concern. The aim of this study was to assess behavioural and immune effects of prenatal modafinil exposure in mice and to evaluate the reaction to methamphetamine exposure on these animals in adult age. Pregnant female mice were given either saline or modafinil (50 mg/kg orally) from gestation day (GD) 3 to GD 10 and then a challenge dose on GD 17. The male offspring were treated analogously at the age of 10 weeks with methamphetamine (2.5 mg/kg orally). Changes in the spontaneous locomotor/exploratory behaviour and anxiogenic profile in the open field test were assessed in naïve animals, after an acute and 8th modafinil dose and the challenge dose following a 7-day wash-out period. One month after completion of the behavioural study, the leukocyte phagocytosis was examined by zymosan induced and luminol-aided chemiluminiscence assay in vitro. The modafinil prenatally exposed mice showed basal hypolocomotion, increased anxiety, lower locomotor effect of acute methamphetamine and increased vulnerability to behavioural sensitization. The leukocyte activity did not show significant differences. Prenatal modafinil exposure alters basal behavioural profile, decreases acute effect of methamphetamine and enhances vulnerability to development of behavioural sensitization at adulthood. This may lead to higher vulnerability to development of addiction.

• Klíčová slova
• Locomotion, Methamphetamine, Mice, Modafinil, Prenatal administration,
• MeSH
• analýza rozptylu MeSH
• benzhydrylové sloučeniny toxicita   MeSH
• fagocytóza účinky léků   MeSH
• gestační stáří MeSH
• leukocyty účinky léků   MeSH
• lokomoce účinky léků   MeSH
• methamfetamin farmakologie   MeSH
• modafinil MeSH
• myši inbrední ICR MeSH
• myši MeSH
• novorozená zvířata MeSH
• pátrací chování účinky léků   MeSH
• pohybová aktivita účinky léků   MeSH
• stimulancia toxicita   MeSH
• stimulanty centrálního nervového systému farmakologie   MeSH
• těhotenství MeSH
• věkové faktory MeSH
• zpožděný efekt prenatální expozice chemicky indukované   patofyziologie   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• benzhydrylové sloučeniny MeSH
• methamfetamin MeSH
• modafinil MeSH
• stimulancia MeSH
• stimulanty centrálního nervového systému MeSH

Idiopathic hypersomnia continues to evolve from the concept of "sleep drunkenness" introduced by Bedrich Roth in Prague in 1956 and the description of idiopathic hypersomnia with two forms, polysymptomatic and monosymptomatic, by the same Bedrich Roth in 1976. The diagnostic criteria of idiopathic hypersomnia have varied with the successive revisions of the International classifications of sleep disorders, including the recent 3rd edition. No epidemiological studies have been conducted so far. Disease onset occurs most often during adolescence or young adulthood. A familial background is often present but rigorous studies are still lacking. The key manifestation is hypersomnolence. It is often accompanied by sleep of long duration and debilitating sleep inertia. Polysomnography (PSG) followed by a multiple sleep latency test (MSLT) is mandatory, as well as a 24 h PSG or a 2-wk actigraphy in association with a sleep log to ensure a total 24-h sleep time longer than or equal to 66O minutes, when the mean sleep latency on the MSLT is longer than 8 min. Yet, MSLT is neither sensitive nor specific and the polysomnographic diagnostic criteria require continuous readjustment and biologic markers are still lacking. Idiopathic hypersomnia is most often a chronic condition though spontaneous remission may occur. The condition is disabling, sometimes even more so than narcolepsy type 1 or 2. Based on neurochemical, genetic and immunological analyses as well as on exploration of the homeostatic and circadian processes of sleep, various pathophysiological hypotheses have been proposed. Differential diagnosis involves a number of diseases and it is not yet clear whether idiopathic hypersomnia and narcolepsy type 2 are not the same condition. Until now, the treatment of idiopathic hypersomnia has mirrored that of the sleepiness of narcolepsy type 1 or 2. The first randomized, double-blind, placebo-controlled trials of modafinil have just been published, as well as a double-blind, placebo-controlled trial of clarithromycine, a negative allosteric modulator of the γ-aminobutyric acid-A receptor.

• Klíčová slova
• Diagnostic criteria, Genetics, Homeostatic and circadian regulation, Hypersomnolence, Idiopathic hypersomnia, Immunology, Neurochemistry, Treatment,
• MeSH
• benzhydrylové sloučeniny terapeutické užití   MeSH
• diferenciální diagnóza MeSH
• idiopatická hypersomnie diagnóza   farmakoterapie   patofyziologie   MeSH
• lidé MeSH
• modafinil MeSH
• narkolepsie diagnóza   patofyziologie   MeSH
• polysomnografie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• benzhydrylové sloučeniny MeSH
• modafinil MeSH

In the past decade, a large number of enantiopure drugs were introduced to clinical practice, since improved therapeutic effects were demonstrated for one of the enantiomers from originally racemic drug. While the therapeutic effects and safety of enantiopure drugs were tested prior to their approval, various biological enantiospecific activities of these, often "old" drugs, remain to be elucidated. In the current paper, we examined enantiospecific effects of clinically used enantiopure drugs containing one chiral center in the structure (i.e. zopiclone, tamsulosin, tolterodine, modafinil, citalopram) towards aryl hydrocarbon (AhR), glucocorticoid (GR) and pregnane X (PXR) receptors in human reporter cell lines. The cytotoxicity (IC50), agonist (EC50) and antagonist effects (IC50) of R-form, S-form and racemic mixture for each tested drugs were determined and compared in AhR-, GR- and PXR-gene reporter cell lines. Since AhR, GR and PXR are key regulators of drug metabolism, energy metabolism, immunity and play many other physiological functions, the data presented here might be of toxicological significance.

• Klíčová slova
• 2,3,7,8-tetrachlorodibenzo-p-dioxin, AhR, Chiral drugs, Cytotoxicity, DEX, Enantiospecificity, GR, Gene reporter assay, PXR, RIF, RU486, TCDD, Xenoreceptors, aryl hydrocarbon receptor, dexamethasone, glucocorticoid receptor, mifepristone, pregnane X receptor, rifampicin,
• MeSH
• azabicyklické sloučeniny chemie   farmakologie   MeSH
• benzhydrylové sloučeniny chemie   farmakologie   MeSH
• buněčné linie MeSH
• buňky Hep G2 MeSH
• citalopram chemie   farmakologie   MeSH
• fenylpropanolamin chemie   farmakologie   MeSH
• kresoly chemie   farmakologie   MeSH
• lidé MeSH
• modafinil MeSH
• nádorové buněčné linie MeSH
• piperaziny chemie   farmakologie   MeSH
• pregnanový X receptor MeSH
• receptory aromatických uhlovodíků agonisté   antagonisté a inhibitory   metabolismus   MeSH
• receptory glukokortikoidů agonisté   antagonisté a inhibitory   metabolismus   MeSH
• reportérové geny genetika   MeSH
• stereoizomerie MeSH
• steroidní receptory agonisté   antagonisté a inhibitory   metabolismus   MeSH
• sulfonamidy chemie   farmakologie   MeSH
• tamsulosin MeSH
• tolterodin tartarát MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• azabicyklické sloučeniny MeSH
• benzhydrylové sloučeniny MeSH
• citalopram MeSH
• fenylpropanolamin MeSH
• kresoly MeSH
• modafinil MeSH
• piperaziny MeSH
• pregnanový X receptor MeSH
• receptory aromatických uhlovodíků MeSH
• receptory glukokortikoidů MeSH
• steroidní receptory MeSH
• sulfonamidy MeSH
• tamsulosin MeSH
• tolterodin tartarát MeSH
• zopiclone MeSH Prohlížeč

The aim of the present study was to compare the behavioral effects of modafinil, an atypical psychostimulatory acting and cognitive-function improving drug, with the effects of the psychostimulants methamphetamine (MET) and MDMA (3,4-methylenedioxymethamphetamine, or "ecstasy") in a model of mouse agonistic behavior. This model enables the observation of ethologically well-defined sociable, timid, aggressive, and locomotor behavioral acts and postures. Singly-housed male mice (isolates) were separated into 4 groups. The observations were performed in 4 sessions, 1 week apart. In each interaction, singly-housed mice were paired with non-aggressive group-housed partners for 4 min in a neutral environment. The isolates received, in a Latin square design, either a) a vehicle or modafinil at doses 2.0, 10.0, or 50.0 mg/kg; or b) a vehicle or MET at doses 1.0, 5.0, or 10.0 mg/kg; or c) a vehicle or MDMA at doses 2.5, 10.0, or 30.0 mg/kg. The isolates were categorized as timid or aggressive according to their behavior in the control interaction (vehicle pre-treatment). Elements of locomotor, sociable, aggressive, and timid behavior were evaluated (one-way ANOVA). In the aggressive mice, no change in the sum of aggressive behavior was measured following modafinil administration, while both methamphetamine and MDMA produced dose-dependent inhibition of aggression (p<0.01). The substantial difference in the tested drug effects on agonistic behavior was an increased occurrence of sociable acts (p<0.01) accompanied by a simultaneous increase of timid acts (p<0.01) recorded after MDMA, but not after modafinil or methamphetamine administration. In the timid mice, at least some doses of modafinil decreased timidity (p<0.01) and increased aggression (p<0.01) with no effect on sociability. Administration of MDMA increased timid activities (p<0.01). Both MDMA and MET decreased sociability (p<0.01).

• MeSH
• agrese * MeSH
• benzhydrylové sloučeniny farmakologie   MeSH
• chování zvířat účinky léků   MeSH
• methamfetamin farmakologie   MeSH
• modafinil MeSH
• myši MeSH
• N-methyl-3,4-methylendioxyamfetamin farmakologie   MeSH
• stimulanty centrálního nervového systému farmakologie   MeSH
• vztah mezi dávkou a účinkem léčiva MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• benzhydrylové sloučeniny MeSH
• methamfetamin MeSH
• modafinil MeSH
• N-methyl-3,4-methylendioxyamfetamin MeSH
• stimulanty centrálního nervového systému MeSH