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International Journal of Molecular... Sep 2022Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can...
Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of (), () and () in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.
Topics: Adult; Atomoxetine Hydrochloride; Attention Deficit Disorder with Hyperactivity; Cell Differentiation; Central Nervous System Stimulants; Child; Guanfacine; Humans; Ligands; Methylphenidate; Modafinil; Nootropic Agents; Osteoprotegerin; Receptor Activator of Nuclear Factor-kappa B
PubMed: 36142172
DOI: 10.3390/ijms231810257 -
Aerospace Medicine and Human Performance Mar 2021Fatigue is a common problem in aviation. The identification of efficacious fatigue countermeasures is crucial for sustaining flight performance during fatigue-inducing... (Review)
Review
Fatigue is a common problem in aviation. The identification of efficacious fatigue countermeasures is crucial for sustaining flight performance during fatigue-inducing operations. Stimulants are not recommended for consistent use, but are often implemented during flight operations with a high risk of fatigue. As such, it is important to evaluate the efficacy of approved stimulants for sustaining flight performance, alertness, and mood. Four electronic databases (PubMed, PsycInfo, SPORTDiscus, Web of Science) were systematically searched to identify research on the effects of caffeine, dextroamphetamine, and modafinil during simulated or in-flight operations. There were 12 studies identified that assessed the effects of at least 1 stimulant. Overall, dextroamphetamine and modafinil were effective for sustaining flight performance and pilot mood during extended wakefulness. Results with caffeine were inconsistent. Dextroamphetamine and modafinil appear to sustain flight performance and mood during extended wakefulness. However, most studies have used flight simulators and short operation durations. Additional research is needed in realistic settings and during longer duration operations. Caffeines effects were inconsistent across studies, possibly due to differences in study methodology or individual caffeine responses. Despite fatigue being a common problem in civilian aviation as well, only one study in this review included civil aviators. More research should be conducted on the effects of caffeine during civil operations. Dextroamphetamine and modafinil appear to be effective fatigue countermeasures but should be further evaluated in more ecologically valid settings. The effects of caffeine are unclear at this time and should continue to be evaluated.
Topics: Aerospace Medicine; Aviation; Central Nervous System Stimulants; Fatigue; Humans; Modafinil; Sleep Deprivation
PubMed: 33754977
DOI: 10.3357/AMHP.5716.2021 -
Journal of Drug Assessment 2020In critically ill patients, sleep is generally interrupted. Some factors that lead to such sleep interruption include the intensive care unit (ICU) circumstance, primary... (Review)
Review
In critically ill patients, sleep is generally interrupted. Some factors that lead to such sleep interruption include the intensive care unit (ICU) circumstance, primary medical disease itself, mental stress, and impacts of many drugs and other managements utilized to treat ICU patients. Another illness that may cause profound daytime somnolence is narcolepsy. Modafinil, methylphenidate and amphetamines are used as stimulants to treat symptoms, such as extreme daytime sleepiness, cataplexy and nocturnal sleep disruption. Such stimulants can increase awareness, improve perception and thinking, as well as assist in keeping people awake. The exact mechanism of action of modafinil is unclear. studies have demonstrated that binding of modafinil to the dopamine reuptake pump can prevent the reuptake of dopamine, resulting in a boost in extracellular dopamine. Modafinil is a racemic compound containing and isomers. Peak plasma concentrations of the drug occur at 2-4 h after administration; therefore, the absorption of modafinil is considered fast. Modafinil is properly distributed in tissues by binding to plasma proteins moderately. Despite the likely role of modafinil in improving cognition and arousal in critically ill patients, the available data on the use of modafinil in the ICU setting is limited. The aim of the study was to review the novel usage of modafinil for alleviation of fatigue, excessive daytime somnolence (EDS), and/or depression in critically ill patients.
PubMed: 32341841
DOI: 10.1080/21556660.2020.1745209 -
Annals of Clinical Psychiatry :... Aug 2023Bipolar depression is a serious neuropsychiatric disorder associated with a high risk of morbidity and suicidality. Standard antidepressants approved for treating major...
BACKGROUND
Bipolar depression is a serious neuropsychiatric disorder associated with a high risk of morbidity and suicidality. Standard antidepressants approved for treating major depressive disorder fail to exert efficacy in bipolar depression. Although 5 agents have been developed for the treatment of bipolar depression, treatment resistance is still observed in some patients, and requires off-label pharmacotherapy. Modafinil and armodafinil have been reported to improve treatment-resistant bipolar depression, but with inconsistent results.
METHODS
We present a case of a 65-year-old woman with severe bipolar depression who failed to respond to electroconvulsive therapy and IV ketamine but later responded to high-dose armodafanil.
RESULTS
The patient responded to high-dose armodafinil (gradually titrated to 1,000 mg/d) and achieved remission with good tolerability for 5 years. Recently, she contracted COVID-19 and developed muscular weakness. After a lengthy workup, we became concerned for myopathy as an adverse effect from armodafinil. The patient's dose of armodafinil was significantly reduced and she subsequently became very depressed and functionally disabled before improving again when armodafinil 1,000 mg/d was reinstated.
CONCLUSIONS
We propose that some of the negative results seen in research of armodafinil for bipolar depression may be due to the use of low doses (100 to 200 mg/d), and higher doses may be needed for adequate response in treatment-resistant bipolar depression.
Topics: Female; Humans; Aged; Modafinil; Bipolar Disorder; Depressive Disorder, Major; Benzhydryl Compounds; COVID-19
PubMed: 37459498
DOI: 10.12788/acp.0113 -
Therapeutic Advances in Neurological... 2019Narcolepsy type 1 (NT1) is a chronic orphan disorder, caused by the selective and irreversible loss of hypocretin/orexin (ORX) neurons, by a probable autoimmune process.... (Review)
Review
Narcolepsy type 1 (NT1) is a chronic orphan disorder, caused by the selective and irreversible loss of hypocretin/orexin (ORX) neurons, by a probable autoimmune process. Little is known about NT2 etiology and prevalence, sharing with NT1 excessive daytime sleepiness (EDS) and dysregulation of rapid eye movement (REM) sleep, but without cataplexy and loss of ORX neurons. Despite major advances in our understanding of the neurobiological basis of NT1, management remains nowadays only symptomatic. The main and most disabling symptom, EDS, is managed with psychostimulants, as modafinil/armodafinil, methylphenidate, or amphetamines as a third-line therapy. Narcolepsy is an active area for drug development, and new wake-promoting agents have been developed over the past years. Pitolisant, a selective histamine H3 receptor inverse agonist, has been recently approved to treat patients with NT1 and NT2. Solriamfetol, a phenylalanine derivative with dopaminergic and noradrenergic activity will be soon a new therapeutic option to treat EDS in NT1 and NT2. Sodium oxybate, used for decades in adult patients with narcolepsy, was recently shown to be effective and safe in childhood narcolepsy. The discovery of ORX deficiency in NT1 opened new therapeutic options oriented towards ORX-based therapies, especially nonpeptide ORX receptor agonists that are currently under development. In addition, immune-based therapies administered as early as possible after disease onset could theoretically slow down or stop the destruction of ORX neurons in some selected patients. Further well-designed controlled trials are required to determine if they could really impact on the natural history of the disease. Given the different clinical, biological and genetic profiles, narcolepsy may provide a nice example for developing personalized medicine in orphan diseases, that could ultimately aid in similar research and clinical efforts for other conditions.
PubMed: 31632459
DOI: 10.1177/1756286419875622 -
The Medical Letter on Drugs and... Feb 2021
Review
Topics: Clinical Trials as Topic; Histamine Agonists; Histamine Antagonists; Humans; Hypothalamus; Narcolepsy; Piperidines; Receptors, Histamine H3
PubMed: 33647004
DOI: No ID Found -
Aerospace Medicine and Human Performance Jun 2022Modafinil, as a wake-promoting agent, is commonly used to relieve fatigue during military operations. However, there is a lack of clarity regarding the effects of... (Randomized Controlled Trial)
Randomized Controlled Trial
Modafinil, as a wake-promoting agent, is commonly used to relieve fatigue during military operations. However, there is a lack of clarity regarding the effects of modafinil on the equilibrium and vestibular organs, especially when prescribing this drug to flight crewmembers. The objective of this study was to evaluate the equilibrium- and vestibular-related safety effects of modafinil. In a randomized, double-blind, placebo-controlled, crossover study, 10 healthy male volunteers received a single 200-mg oral dose of modafinil or placebo. Equilibrium and vestibular functions were assessed 2 h after oral administration by the sensory organization test (SOT), adaptation test (ADT), and video head impulse test (v-HIT). There was no change in the equilibrium scores of the six SOT conditions or the composite scores between the modafinil and placebo groups. Statistically significant differences were not observed for the sway energy score (SES) in the toe-down test. In the toe-up test, the SES decreased by 16.7% in the modafinil group relative to the placebo group in trial 2, while the differences in other trials were not statistically significant. In the v-HIT, there was no significant difference in the gain of each semicircular canal between the two groups. A single 200-mg dose of modafinil did not cause any impairment to vestibular function, equilibrium ability, or adaptive balance response; in fact, modafinil might have a positive effect on adaptation function in healthy volunteers. These findings preliminarily suggest that there is no hidden risk of vestibular dysfunction among aviation employees using modafinil.
Topics: Benzhydryl Compounds; Central Nervous System Stimulants; Cross-Over Studies; Double-Blind Method; Healthy Volunteers; Humans; Male; Modafinil; Vestibule, Labyrinth
PubMed: 35729759
DOI: 10.3357/AMHP.6032.2022 -
Sleep Jun 2021Methamphetamine 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... (Review)
Review
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.
Topics: Central Nervous System Stimulants; Dopamine; Methamphetamine; Modafinil; Sleep
PubMed: 33406259
DOI: 10.1093/sleep/zsab001 -
Frontiers in Neuroscience 2022Sleep deprivation (SD) induces systemic inflammation that promotes neuronal pyroptosis. The purpose of this study was to investigate the effect of an antioxidant...
Sleep deprivation (SD) induces systemic inflammation that promotes neuronal pyroptosis. The purpose of this study was to investigate the effect of an antioxidant modafinil on neuronal pyroptosis and cognitive decline following SD. Using a mouse model of SD, we found that modafinil improved learning and memory, reduced proinflammatory factor (IL-1β, TNF-α, and IL-6) production, and increased the expression of anti-inflammatory factors (IL-10). Modafinil treatment attenuated inflammasome activity and reduced neuronal pyroptosis involving the NLRP3/NLRP1/NLRC4-caspase-1-IL-1β pathway. In addition, modafinil induced an upregulation of brain-derived neurotrophic factor (BDNF) and synaptic activity. These results suggest that modafinil reduces neuronal pyroptosis and cognitive decline following SD. These effects should be further investigated in future studies to benefit patients with sleep disorders.
PubMed: 35310096
DOI: 10.3389/fnins.2022.816752 -
Journal of Clinical Medicine Oct 2022Attention deficit hyperactivity disorder (ADHD) affects 6.4 million children in the United States of America. Children and adolescents, the main consumers of ADHD...
Attention deficit hyperactivity disorder (ADHD) affects 6.4 million children in the United States of America. Children and adolescents, the main consumers of ADHD medication, are in the bone growth phase, which extends over a period of up to two decades. Thus, impaired proliferation and maturation of chondrocytes and osteoblasts can result in impaired bone formation. The aim of this study is to investigate, for the first time, the effects of the ADHD-medication modafinil, atomoxetine and guanfacine on bone growth and repair in vitro. Using two-dimensional and three-dimensional cell models, we investigated the chondrogenic/osteogenic differentiation, proliferation and viability of human mesenchymal progenitor cells. Real-time cell proliferation was measured by xCELLigence. Live/dead staining and size measurement of hMSC- and MG63 monolayer and spheroids were performed after administration of therapeutic plasma concentrations of modafinil, atomoxetine and guanfacine. Chondrogenic differentiation was quantified by RTqPCR. The chondrogenic and osteogenic differentiation was evaluated by histological cryo-sections. Modafinil, atomoxetine and guanfacine reduced chondrogenic and osteogenic differentiation terms of transcript expression and at the histological level. Cell viability of the MG63- and hMSC monolayer was not impeded by ADHD-medication. Our in vitro results indicate that modafinil, atomoxetine and guanfacine may impair chondrogenic and osteogenic differentiation in a 3D model reflecting the in vivo physiologic condition.
PubMed: 36294540
DOI: 10.3390/jcm11206218