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.
- 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
CONTEXT: A novel genomically defined subset of higher-risk myelodysplastic syndrome (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive by a blood-based biomarker test (Vigil 2017). Tamibarotene is an oral selective RARα agonist with potential for clinical benefit in RARA-positive HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA-positive relapsed/refractory HR-MDS showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene/azacitidine led to a CR/CRi rate of 61% with rapid onset of response in RARA-positive newly diagnosed (ND) unfit AML patients, including those with low blast count (≤30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/azacitidine was generally well tolerated with no increase in myelosuppression compared with azacitidine alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and low blast count AML (Estey 2022) supports further development of tamibarotene/azacitidine in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). OBJECTIVE: To characterize and compare the CR rate of tamibarotene/azacitidine to placebo/azacitidine in RARA-positive ND HR-MDS patients. Secondary objectives include comparisons of overall response rate, event-free survival, overall survival, transfusion independence, and safety. DESIGN: Global, Phase 3, randomized, double-blind, placebo-controlled trial (NCT04797780). Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms. PATIENTS: The included patients will be RARA-positive based on investigational assay and ND with HR-MDS by WHO classification (Arber 2016) with an IPSS-R risk category of very high, high, or intermediate and a blast count >5% at baseline. Patients with prior treatment for MDS with any HMA, chemotherapy, or transplant are excluded. INTERVENTION: Azacitidine will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally on days 8-28 of each 28-day cycle. MAIN OUTCOME MEASURES: Response is assessed per the modified IWG MDS criteria (Cheson 2006).
- MeSH
- akutní myeloidní leukemie * MeSH
- azacytidin farmakologie terapeutické užití MeSH
- benzoáty MeSH
- dospělí MeSH
- lidé MeSH
- modafinil terapeutické užití MeSH
- myelodysplastické syndromy * diagnóza MeSH
- tetrahydronaftaleny MeSH
- výsledek terapie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie 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.
- 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
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.
- 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
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.
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
- MeSH
- dospělí MeSH
- hyperkinetická porucha * diagnóza etiologie terapie MeSH
- inhibitory vychytávání adrenergních neurotransmiterů aplikace a dávkování škodlivé účinky MeSH
- inhibitory vychytávání dopaminu aplikace a dávkování škodlivé účinky MeSH
- komorbidita MeSH
- lidé MeSH
- modafinil aplikace a dávkování škodlivé účinky MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
Onemocnění spojená s narušením nebo zkrácením spánku a s nadměrnou denní spavostí svými zdravotními důsledky významně snižují kvalitu života. Narůstající výskyt nespavosti vede k nadměrnému a neracionálnímu užívání hypnotik namísto nefarmakologických postupů, které jsou léčbou první volby. Farmakoterapie je indikována u akutní insomnie, u chronické insomnie má její krátkodobé použití podporovat režimová opatření a psychoterapeutické postupy. V léčbě insomnie se upřednostňují nebenzodiazepinová hypnotika. Dalšími používanými léčivy jsou benzodiazepiny, antidepresiva a melatonin. Častým neurologickým onemocněním je syndrom neklidných nohou, který může způsobovat chronickou nespavost a vyžaduje specifickou farmakoterapii (dopaminergní léky, ligandy kalciových kanálů, opioidy). Vzácnými chorobami, obvykle s potřebou celoživotní léčby, jsou centrální hypersomnie (narkolepsie a idiopatická hypersomnie). V této indikaci se užívají stimulancia a k potlačení projevů kataplexie antidepresiva.
Disorders associated with fragmentation or shortening of sleep and/or with excessive daytime sleepiness may have a serious health consequences, and significantly decrease quality of life. The growing prevalence of insomnia leads to frequent and irrational use of hypnotics instead of nonpharmacologic approaches which are considered as a first line treatment. Pharmacotherapy is indicated in acute insomnia. In chronic insomnia, the short‑term drug administration should supplement behavioral, and psychotherapeutic methods. Nonbenzodiazepine hypnotics are preferred drugs for treatment of insomnia. Benzodiazepines, antidepressants and melatonin are used as well. Restless leg syndrome is a common neurological disease which can cause chronic insomnia and requires specific pharmacotherapy (dopaminergic drugs, calcium channel ligands, opioids). Central hypersomnias (narcolepsy and idiopathic hypersomnia) are rare disorders usually necessitating life‑long therapy. Stimulants and antidepressants are used in central hypersomnias to improve vigilance and supress cataplexy, respectively.
- MeSH
- agonisté dopaminu škodlivé účinky terapeutické užití MeSH
- antidepresiva škodlivé účinky terapeutické užití MeSH
- benzhydrylové sloučeniny škodlivé účinky terapeutické užití MeSH
- benzodiazepiny škodlivé účinky terapeutické užití MeSH
- hypnotika a sedativa terapeutické užití MeSH
- levodopa škodlivé účinky terapeutické užití MeSH
- lidé MeSH
- melatoninové receptory agonisté terapeutické užití MeSH
- modafinil MeSH
- narkolepsie farmakoterapie MeSH
- oxybát sodný škodlivé účinky terapeutické užití MeSH
- poruchy iniciace a udržování spánku * diagnóza farmakoterapie patofyziologie MeSH
- poruchy nadměrné spavosti * diagnóza farmakoterapie patofyziologie MeSH
- psychotropní léky škodlivé účinky terapeutické užití MeSH
- receptory GABA-A - agonisté terapeutické užití MeSH
- selektivní inhibitory zpětného vychytávání serotoninu škodlivé účinky terapeutické užití MeSH
- syndrom neklidných nohou * diagnóza farmakoterapie patofyziologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
- Klíčová slova
- mentální funkce, přípravky zvyšující mentální funkce, mozkový doping, ritalin, neurointenzivní péče,
- MeSH
- benzhydrylové sloučeniny škodlivé účinky MeSH
- dopamin MeSH
- lidé MeSH
- medicína založená na důkazech MeSH
- methylfenidát škodlivé účinky MeSH
- modafinil MeSH
- mozek účinky léků MeSH
- stimulanty centrálního nervového systému MeSH
- studenti MeSH
- Check Tag
- lidé MeSH
