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Armodafinil and Modafinil Have Substantially Different Pharmacokinetic Profiles Despite Having the Same Terminal Half-Lives
Abstract
Armodafinil, a non-amphetamine, wakefulness-promoting medication, is the R- and longer-lasting isomer of racemic modafinil. Armodafinil has been shown to improve wakefulness in patients with excessive sleepiness (ES) associated with treated obstructive sleep apnoea, shift work disorder or narcolepsy. In comparison with modafinil, armodafinil maintains higher plasma concentrations later in the day in healthy subjects. The objective of this analysis was to characterize the pharmacokinetic parameters related to those higher concentrations.
Data from three randomized studies in healthy adult subjects receiving single doses of either armodafinil (50, 100, 200, 250, 300 or 400 mg) or modafinil (400 mg) were pooled, and subsequently dose-normalized to a 200 mg dose for each drug. Non-compartmental pharmacokinetic parameters were assessed.
Armodafinil and modafinil both had a mean single-dose terminal elimination half-life of approximately 13 hours, with similar mean maximum plasma drug concentration (C(max)) and median time to C(max) values. After reaching C(max), plasma concentrations appeared to decline in a monophasic manner with armodafinil, but in a biphasic manner with modafinil due to the initial rapid elimination of its S-isomer. As a result, mean area under the plasma drug concentration versus time curve (AUC) from time zero to the time of the last measurable concentration (AUC(last)) and AUC from time zero to infinity (AUC(infinity)) values were 33% and 40% higher, respectively, with armodafinil compared with modafinil on a milligram-to-milligram basis.
Despite similar half-lives, plasma concentrations following armodafinil administration are higher late in the day than those following modafinil administration on a milligram-to-milligram basis. The different pharmacokinetic profile of armodafinil may result in improved wakefulness throughout the day in patients with ES compared with modafinil.
... Modafinil is used as a racemic mixture of R-and S-enantiomers. The R-enantiomer has a half-life three to four times longer than the Senantiomer [21]. The R-enantiomer is marketed separately as armodafinil, which has a higher plasma concentration at the end of the day compared to modafinil, allowing for once-daily dosing, whereas modafinil typically requires twice-daily administration [21]. ...
... The R-enantiomer has a half-life three to four times longer than the Senantiomer [21]. The R-enantiomer is marketed separately as armodafinil, which has a higher plasma concentration at the end of the day compared to modafinil, allowing for once-daily dosing, whereas modafinil typically requires twice-daily administration [21]. ...
Background: Narcolepsy is characterized by excessive daytime sleepiness (EDS) and episodes of cataplexy, frequently triggered by psychological stress, significant disturbances in sleep-wake cycles, pregnancy, or trauma. Modafinil is widely used as the preferred treatment due to its effectiveness in alleviating EDS, improving disease outcomes, and enhancing overall quality of life. Nonetheless, long-term safety and efficacy data are still lacking, underscoring the importance of future research to advance treatment options for narcolepsy. Aim: In our systematic review and meta-analysis, we aim to assess the effectiveness of Modafinil in the treatment of Narcolepsy. Methods: We searched in electronic databases (PubMed, Embase, Google Scholar, Scopus, Science Direct, Web of Science) was performed to identify cohort studies and randomized controlled trials (RCTs) up to 8th July 2024. Data extraction focused on baseline characteristics of the included studies and efficacy outcomes, including scores on the Maintenance of Wakefulness Test (MWT) and Epworth Sleepiness Scale (ESS) . We performed the meta-analysis utilizing the Review Manager software, version 5.4. To assess the outcomes, we compared the Modafinil-treated group with the placebo group, employing the mean difference (MD) and a 95% confidence interval (CI) for statistical analysis. Result: In total, 3833 articles were identified for screening, with nine studies included in the systematic review and five in the meta-analysis. These studies involved 997 adult patients with Narcolepsy treated with Modafinil. MWT revealed a significant increase in total scores (MD= 3.56, 95% CI [2.25 to 4.86], p < 0.00001) and ESS revealed a significant decrease in scores (MD= -3.34, 95% CI [-4.13 to -2.56], p < 0.00001). Conclusion: The research emphasizes the potential of Modafinil in alleviating EDS associated with Narcolepsy. While the results are promising, they are based on short term scale studies. It is crucial to undertake larger-scale, extended-duration, placebo-controlled studies that include a broad range of demographic populations. These trials are essential to confirm the efficacy, verify the safety profile, and fine-tune dosing strategies to maximize the long-term therapeutic benefits.
... Modafinil has been found to be well-tolerated, with a low incidence of adverse effects and low potential for abuse [24]. It is well absorbed, reaching peak plasma concentration between two and four hours following oral administration, and has a half-life of approximately 12-15 hours [25,26]. Modafinil's mechanism of action, while not yet fully understood, is complex. ...
... This finding may, however, be explained by the pharmacokinetic profile of modafinil. As the half-life of modafinil is approximately 12-15 hours [25,26], daily use of modafinil would result in a constant, and possibly increasing, plasma concentration of modafinil, which also suggests constant, higher levels of synaptic DA and NE (in addition to other neurotransmitters that are modulated by modafinil). Increased synaptic DA and NE have been associated with improved cognitive function [28,53]. ...
Cognitive enhancing drugs are claimed to improve cognitive functions such as learning and attention. However, little is known presently about the characteristics of off-prescription cognitive enhancing drug users or their perceived everyday experience with these drugs. As modafinil is the most commonly used off-prescription cognitive enhancing drug, the current study aimed to provide a detailed profile of modafinil users and their experiences and perceptions of this drug. To this end, an online survey, targeting cognitive enhancing drug users and students, was advertised on forum sites. Information was obtained regarding demographic data, illicit drug use, psychiatric diagnosis and experience of modafinil. Of the 404 respondents, 219 reported taking modafinil. Of these the majority were male, American or British, university-educated and currently employed, with a mean age of 27. Overall, modafinil was perceived by users as being safe. Modafinil users reported higher levels of illicit drug use and psychiatric diagnosis than would be expected from population-based data. More frequent reported modafinil use was associated with higher numbers of perceived benefits whilst reported frequency of use was not associated with the number of perceived risks. There was also a tentative link between the reported use of modafinil and the reported presence of psychiatric disorders, largely depression and anxiety. Respondents who had reported a psychiatric diagnosis declared higher subjective benefits of modafinil. This may suggest further beneficial effects of modafinil or it may reflect insufficient medical treatment for psychiatric disorders in some people. Overall, the findings of the current study should be beneficial in informing clinicians and legislative bodies about the modafinil user profile and how modafinil is perceived.
... Studies comparing the effects of the two drugs have shown that armodafinil has a longer active duration than modafinil, suggesting that it may be better used as a single morning dose, rather than modafinil which is sometimes given in two doses (morning and lunchtime). 220 The mechanism of action of these medications is unclear, but it appears that modafinil acts upon the dopamine transporter, thus reducing dopamine reuptake and increasing the amount of dopamine in the synapse, but without increasing production of dopamine in the presynapse, like in amphetamines. 221,222 There is also a suggestion from these studies that modafinil works on norepinephrine transporters. ...
... 228,283 While both the S and R-enantiomers of racemic modafinil are thought to be active, the R-enantiomer (armodafinil) appears to be more slowly eliminated, leading to longer lasting plasma drug concentrations than the racemic modafinil. 220 Both modafinil and armodafinil have been trialled extensively as an adjunct to CPAP treatment (see Chapter 3) but neither has been trialled as an adjunct to weight loss in this or any population. In this factorial clinical trial, we aimed to reduce weight in overweight patients with moderate-severe OSA unable to tolerate standard treatments through a diet and exercise trial (Australian Guide to Healthy Eating (AGHE) versus Low-GI high protein diet) over six months (follow-up to 12 months) while trialling armodafinil versus placebo to reduce excessive daytime sleepiness over the first six months of the trial. ...
... As a result, plasma drug concentrations are 33% and 40% higher, respectively, with armodafinil compared with modafinil on a milligram-to-milligram basis. 58,59 New therapeutic possibilities such as pitolisant (acting on histamine receptors) and solriamfetol (dual action -norepinephrine and dopamine) have been used to treat drowsiness complaints but are unavailable in Brazil. 60,61 A new class of drugs for narcolepsy is in an advanced testing phase, which is orexin two receptor agonists. ...
Narcolepsy is a primary disorder of the central nervous system resulting from genetic, environmental, and immunological interactions defined as excessive daytime sleepiness plus cataplexy, hallucinations, sleep paralysis, and sleep fragmentation. The pathophysiology is not entirely known, but the interaction among genetic predisposition, environmental exposition, and immune component with consequent hypocretin-1 deficiency is the model to explain narcolepsy type I. The mechanism of narcolepsy type II is less understood. There is a delay of over ten years for the diagnosis of narcolepsy around the world. Patients with narcolepsy have many comorbidities with a negative impact on quality of life. The treatment of narcolepsy must contain an educational approach for the family, coworkers, and patients. Scheduled naps and sleep hygiene are essential to minimize the dose of medications. Much progress has been seen in the pharmacological treatment of narcolepsy with new stimulants, different presentations of oxybate, and recent studies with orexin agonists. Narcolepsy is a rare disease that needs to be more understood and highlighted to avoid delayed diagnosis and severe disabilities in patients.
... Hence, they may have excluded studies containing armodafinil to mitigate variations between trials. Indeed, studies have shown that the enantiomers have different pharmacokinetic profiles and that armodafinil, due to its sustained release, may be more potent (Darwish 2009). It is also possible, however, that the inclusion of armodafinil trials may have enhanced the quality of evidence for the outcomes studied in the Ortiz-Orendain 2019 meta-analysis and may have revealed nuanced improvements in negative and cognitive symptom domains. ...
Antipsychotics are the cornerstone of schizophrenia management but they are not adequate in treating the negative and cognitive symptoms of the illness. The Cochrane review discussed in this commentary examines the safety and effectiveness of the wakefulness-promoting agent, modafinil, as an adjunct to standard care in the mitigation of negative and cognitive symptoms of schizophrenia. Add-on modafinil, compared to add-on placebo and standard treatment, did not result in a clear benefit. Due to the heterogenous body of evidence, the quality of which ranged from very low to moderate, the review's conclusions are equivocal.
... it is metabolized in a monophasic manner, resulting in a slower initial clearance compared with the biphasic manner of modafinil. 13 To our knowledge, there have not yet been any trials comparing the efficacy and adverse event profile of modafinil against armodafinil in the treatment of narcolepsy. Clinically, choosing between the two formulations may depend on the patient's timing and duration of EDS. ...
Narcolepsy is a lifelong disorder that adversely affects daytime function and quality of life. Major symptoms include excessive daytime sleepiness with irrepressible sleep attacks and cataplexy. Recent developments in the understanding of the pathobiology of narcolepsy, as well as the neuronal systems involved in the regulation of wakefulness have led to development of new pharmacologic approaches to therapy. In this paper, we review available pharmacologic treatments for narcolepsy as well as agents currently under investigation.
... The common side effects related to armodafinil and modafinil are dizziness, headaches, nausea, and insomnia. However, armodafinil was shown to have higher plasma concentrations later in the day than modafinil, explaining the reason why armodafinil is generally preferred for the reduction of excessive sleepiness in patients with shift work disorder compared to modafinil [32,33]. ...
Objective: We aimed to evaluate the effectiveness of bright light exposure, modafinil, and armodafinil for improving alertness during working time among nurses on the night shift.
Methods: We carried out a literature search using the PubMed, Scopus, and Web of Science electronic databases regarding articles pertaining to workplace interventions for improving wakefulness among nurses working the night shift using the following medical subject headings: ((((Bright light exposure) OR wakefulness medications) AND Nurses AND Night Shift-work)).
Results: The searches generated a total of 34 records on the PubMed database, 130 on the Scopus database, and 32 on the Web of Science database. A total of 95 studies were identified after removal of duplicates. Nevertheless, the 95 articles were screened, 75 studies were excluded based on the review of titles and abstracts, and further 15 full-text articles were excluded because the studies did not meet the selection criteria. A total of 632 subjects from 5 studies were included.
Conclusion: Bright light exposure is beneficial in improving alertness during the night shift. On the other hand, armodafinil or modafinil taken before the commencement of night shift work is effective in the treatment of excessive sleepiness associated with shift work sleep disorder.
... Modafinil did not show a statistically significant effect relative to placebo on SL as measured in the MSLT overall or at any time point. Pharmacokinetic analyses of modafinil in plasma samples revealed levels in agreement with published data (Darwish et al., 2009;Wong et al., 1999) for the 200 mg dose of modafinil (data not shown). This contrasts with previous reports that modafinil increases SL in the MWT (Chapotot et al., 2003;Dinges et al., 2006;Iannone et al., 2010;James et al., 2011), and we did not expect the variation in primary endpoints to affect the outcome of modafinil. ...
Dopamine (DA) plays a key role in several central functions including cognition, motor activity and wakefulness. While efforts to develop D1 agonists have been challenging, a positive allosteric modulator (PAM), represents an attractive approach with potential better drug-like properties. Our previous study demonstrated an acceptable safety and tolerability profile of the D1 PAM mevidalen (LY3154207) in single and multiple ascending dose studies in healthy volunteers (Wilbraham et al., 2020). Herein, we describe the effects of mevidalen on sleep and wakefulness in the humanized dopamine D1 mice (hD1) and in sleep deprived healthy volunteers. Mevidalen enhanced wakefulness (latency to fall asleep) in the hD1 mouse in a dose dependent (3-100 mg/kg, PO) fashion when measured during the light (ZT-5) and predominantly inactive phase. Mevidalen promoted wakefulness in mice following prior sleep deprivation and delayed sleep onset by 5.5 and 15.2-fold compared to vehicle treated animals, after the 20 and 60 mg/kg PO doses respectively, when compared to vehicle treated animals. In humans, mevidalen demonstrated a dose-dependent increase in latency to sleep onset as measured by the multiple sleep latency test and all doses (15, 30, 75 mg) separated from placebo at the first 2-hour post dose time point. with a circadian effect at the 6-hour post-dose time point. Sleep-wakefulness should be considered as a translational biomarker for the D1PAM mechanism. Significance Statement This is the first translational study describing the effects of a selective D1PAM on sleep wakefulness in the hD1 mouse and in sleep deprived healthy volunteers. In both the human and mouse, drug exposure was correlated to sleep latency supporting the use of sleep-wake activity as a translational central biomarker for the mechanism. Overall, the wake promoting effects of D1PAMs including mevidalen may offer therapeutic opportunities in several conditions including sleep disorders and excessive daytime sleepiness related to neurodegenerative disorders.
... The anti-inflammatory and anti-fibrotic effects of MF-R and MF-S were similar when administered at the same dose to mice with TAA-induced or CDAHFD-induced liver disease, suggesting that there was no significant difference observed in the effects of the two isomers. The half-life of MF-S in humans is approximately 5 h, which is significantly shorter than that of MF-R, which is approximately 15 h [43]. The shorter half-life of MF-S suggests that the associated blood concentration is lower than that of MF-R. ...
Small- and intermediate-conductance Ca²⁺-activated K⁺ channels, KCa2.3 and KCa3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. KCa2.3 and KCa3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates KCa2.3 and KCa3.1, is elevated by modafinil in cells; accordingly, we investigated whether modafinil exerts anti-inflammatory and anti-fibrotic responses via KCa2.3- and KCa3.1-mediated pathways in high-fat diet (HFD)- or thioacetamide-induced liver disease models in mice. Modafinil was administered orally in the form of a racemate, (R)-isomer, or (S)-isomer. We also determined whether the treatment targeted the profibrotic activity of hepatic stellate cells using immortalized human hepatic stellate cells (LX-2 cells). Modafinil improved HFD- or thioacetamide-induced changes compared to the control, leading to a reduced inflammatory response, collagen deposition, and α-smooth muscle actin expression both in vivo and in vitro. However, modafinil did not relieve HFD-induced steatosis. There were no significant differences in the effects of the (R)- and (S)-isomers of modafinil. KCa2.3 and KCa3.1 were upregulated and catalase was downregulated in liver tissues from thioacetamide- or HFD-induced liver disease models or in TGF-β-treated LX-2 cells. TGF-β-induced upregulation of KCa2.3, KCa3.1, collagen, and α-smooth muscle actin and downregulation of catalase were reversed by modafinil, polyethylene glycol catalase, N-acetylcysteine, siRNA against KCa2.3 or KCa3.1, and Epac inhibitors. Our investigation revealed that modafinil attenuated inflammatory and fibrotic progression via KCa2.3- and KCa3.1-mediated pathways in nonalcoholic hepatitis, suggesting that inhibiting KCa2.3- and KCa3.1-mediated signaling may serve as a novel therapeutic approach for inflammatory and fibrotic liver diseases.
... They include wake-promoting therapeutics that enhance presynaptic dopaminergic release and anticataplectic agents that facilitate monoaminergic neurotransmission. First-line medications for EDS are stimulants and include modafinil/ armodafinil, pitolisant, and sodium oxybate (Black et al., 2016;Darwish et al., 2009;Dauvilliers et al., 2013;Group, 2005). For cataplexy, sodium oxybate, venlafaxine, and pitolisant are regarded as first-choice treatments (Alshaikh et al., 2012;Thorpy, 2015). ...
As one of the fundamental sleep states, rapid eye movement (REM) sleep is believed to be associated with dreaming and is characterized by low-voltage, fast electroencephalographic activity and loss of muscle tone. However, the mechanisms of REM sleep generation have remained unclear despite decades of research. Several models of REM sleep have been established, including a reciprocal interaction model, limit-cycle model, flip-flop model, and a model involving γ-amino butyric acid, glutamate, and aminergic/orexin/melanin-concentrating hormone neurons. In the present review, we discuss these models and summarize two typical disorders related to REM sleep, namely REM sleep behavior disorder and narcolepsy. REM sleep behavior disorder is a sleep muscle-tone-related disorder and can be induced by some medications, such as noradrenergic antidepressants. Narcolepsy, with core symptoms of excessive daytime sleepiness and cataplexy, is strongly connected with orexin in early adulthood.
... 10 Despite having the same half-life (13 h), MODA and the R-isomer armodafinil differ in their elimination profiles. 11 Conflicting results on the efficacy of MODA in multiple sclerosisrelated fatigue have been reported. 12 On the other hand, armodafinil was associated with improved sarcoidosis-associated fatigue compared with placebo. ...
Fatigue is a frequently reported and disabling symptom in patients with systemic lupus erythematosus (SLE). The management of Lupus-associated fatigue (LAF) is complex and requires the exclusion of disease activity and comorbidities as potentially treatable causes. Standard of care recommendations includes psychological counselling and regular physical activity. However, many SLE patients still report the persistence of LAF despite these measures. Therefore, pharmacological management may be required, which has been insufficiently investigated in clinical trials. Here, we report two patients who improved with pharmacological treatment with modafinil (MODA), a central nervous system stimulant. Both patients had an overall low disease activity (SLEDAI-2K score of 0). Their FACIT fatigue scores were 15 and 20, respectively (with a maximum score of 52, where 52 indicates the best quality of life). With MODA treatment, the first patient’s FACIT fatigue score improved from 15 to 42, the second patient’s score from 20 to 37. In the latter patient, it returned to 21 after stopping the drug and increased back again to 37 after re-treatment.
In conclusion, our report demonstrates, for the first time, that MODA treatment is a potential pharmacological treatment option in selected patients with LAF. Clinical trials in SLE are required to confirm our observations.
... Each treatment period lasted six weeks, and there was a two-week washout period between each treatment period. The two-week washout period was selected based on the elimination half-life of study medications [27][28][29] and the clinically-observed putative anti-fatigue effects (which quickly disappear after stopping the medications). All participants provided written informed consent. ...
Background
Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue.
Methods
In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed.
Findings
Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0–53·6) at baseline, 40·6 (38·2–43·1) with placebo, 41·3 (38·8–43·7) with amantadine, 39·0 (36·6–41·4) with modafinil, and 38·6 (36·2–41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil).
Interpretation
Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis.
Funding
Patient-Centered Outcomes Research Institute.
... In rare cases high doses of Mod may also induce psychosis [9]. Mod is well absorbed, with peak plasma concentration reaches between two and four hours following oral administration, its half-life is approximately 12-15 h in humans [10]. ...
Objective
Intestinal ischemia reperfusion (IR) is a pathophysiologic process that leads to oxidative stress and acute inflammatory responses. Understanding the mechanisms explaining this inflammation is essential to developing therapeutic strategies. Therefore, the purpose of this study was to evaluate the protective outcome of modafinil (Mod) against intestinal damages caused by intestinal IR injury.
Methods/materials
Fourty adult Male Wistar rats were randomly divided into four groups: sham control group; intestinal IR group; Mod pre-treated IR group and Mod post-treated IR group. Mod in a dose of 10 mg/kg was injected intraperitoneally once daily for 7 days pre or post IR treatment.
Results
Mod significantly attenuated the IR induced elevations in intestinal malondialdehyde (MDA), nitric oxide (NO), tumor necrosis factor alpha (TNF-α), interleukin 1-β (IL-1β) and P-glycoprotein (P-gp) levels, caspase-3 activity. However, a significant increase in TAC was reported as compared with the IR group but its post-treated IR group was highly protective. Mod post-treatment down-regulated the IR induced cyclo-oxygenase-2 (COX-2) over-expression. Distorted mucosa with loss of surface epithelial cells, epithelial separation oedematous lamina propria and inflammatory cellular infiltration detected by histopathological examination of intestinal tissue, were markedly ameliorated by Mod post-treatment.
On the other hand, Mod pre-treatment showed less protection against intestinal IR in rats.
Conclusion
Current study suggests that Mod post-treatment ameliorated intestinal damages, so it can be considered a potential therapeutic agent to protect against the major clinical challenge of intestinal injury resulting from IR.
... Sterically more demanding substituents (e.g., propyl group) cause a dramatic decrease of the reaction rate. Although we were able to obtain valuable chiral synthons in a practically enantiopure form, the substrate limitations prevent the method from utilizing more complicated and pharmaceutically relevant chiral sulfoxides, such as armodafinil and albendazole-(R)-sulfoxide. [17][18][19][20] In order to deal with this limitation we resolved to perform the directed evolution of wild type MsrA. In spite of the fact that the 3D NMR structure of MsrA (E. ...
We report on the development of high-throughput fluorogenic
assay that can streamline directed evolution of enantioselective
sulfoxide reductases. As a model, we have evolved methionine
sulfoxide reductase A (MsrA) to expand its limited substrate scope.
The resulting mutant MsrA can resolve a range of new challenging
racemic sulfoxides with high efficiency including the
pharmaceutically relevant albendazole sulfoxide. The simplicity and
the level of throughput is suitable for the future screening of
metagenomic libraries for the discovery of new enzymes with
similar reactivities.
... Although the half-life of armodafinil is similar to that of modafinil, its plasma concentration remains higher later in the day, which leads to a persistent wakefulness-promoting effect in the afternoon. Its efficacy was objectively and subjectively proven on a single class I evidence study [13]. The daily dose is 150-250 mg to be taken in the morning. ...
Purpose of review
The aim of this review is to discuss and summarize the main therapeutic strategies for the management of excessive daytime sleepiness (EDS) in patients with narcolepsy. An overview of novel therapies and potential future options are covered as well.
Recent findings
First line treatments for EDS in narcolepsy patients include modafinil/armodafinil and sodium oxybate. Other options with a stimulant effect, such as methylphenidate and amphetamines are considered if the former do not control the symptoms. More recently, pitolisant (H3 receptor inverse agonist) was approved by the European Medicines Agency, and solriamfetol (dopamine and norepinephrine reuptake inhibitor) by the Food and Drug Administration, for the treatment of EDS in adult narcolepsy patients. Sodium oxybate was recently approved for EDS management in paediatric patients from the age of seven. Further studies involving the paediatric population are warranted to have solid evidence in the management of children with narcolepsy. Ongoing research of new molecules is based on several mechanisms of action (histamine antagonists/inverse agonists, GABA receptor modulators), and potential future strategies involve immunologic treatment and hypocretin-based therapies.
Summary
Additionally to the wakefulness-promoting agents and stimulants classically used, other pharmacologic options have been recently approved for the treatment of EDS in Europe (pitolisant) and the US (solriamfetol). Emerging treatments are under development; newly developed wakefulness-promoting agents act via different mechanisms of action, whereas other forms of therapy are focused in the underlying hypocretin deficiency that characterizes narcolepsy type 1.
... In our subgroup analysis, we considered modafinil and armodafinil separately because of their distinct pharmacokinetic profiles. 39 The subgroup analysis suggests a more favorable response to modafinil, but these results have to be interpreted with caution because the 2 negative armodafinil trials have used a very rigorous methodology. ...
Background:
The negative symptoms of schizophrenia pose a heavy burden on patients and relatives and represent an unmet therapeutic need. The observed association of negative symptoms with impaired reward system function has stimulated research on prodopaminergic agents as potential adjunctive treatments.
Methods:
We conducted a systematic review and meta-analysis of published randomized controlled trials of amphetamine, methylphenidate, modafinil, armodafinil, lisdexamphetamine, L-dopa, levodopa, bromocriptine, cabergoline, quinagolide, lisuride, pergolide, apomorphine, ropinirole, pramipexole, piribedil, and rotigotine augmentation in schizophrenia and schizoaffective disorder.Medline, EMBASE, and several other databases as well as trial registries were searched for placebo-controlled trials.
Results:
Ten randomized controlled trials were included in the meta-analysis, 6 trials on modafinil, 2 on armodafinil, 1 on L-dopa, and 1 on pramipexole. Overall, prodopaminergic agents did not significantly reduce negative symptoms. Restricting the analysis to studies requiring a minimum threshold for negative symptom severity, modafinil/armodafinil showed a significant but small effect on negative symptoms. A subset of studies allowed for calculating specific effects for the negative symptom dimensions diminished expression and amotivation, but no significant effect was found. Prodopaminergic agents did not increase positive symptom scores.
Conclusions:
The currently available evidence does not allow for formulating recommendations for the use of prodopaminergic agents for the treatment of negative symptoms. Nevertheless, the observed improvement in studies defining a minimum threshold for negative symptom severity in the absence of an increase in positive symptoms clearly supports further research on these agents.
... 3,57 Though the half-lives of modafinil and armodafinil are similar, differences in pharmacokinetics result in the plasma concentration of armodafinil being higher late in the day leading to improved wakefulness throughout the day. 58 Solriamfetol Solriamfetol is a dopamine and norepinephrine reuptake inhibitor that received FDA approval in 2019 for EDS in OSA and narcolepsy. The approval was granted after ...
Excessive daytime sleepiness (EDS) can be caused by insufficient sleep but is also a manifestation of medical or sleep disorders and a side effect of medications. It impacts quality of life and creates safety concerns in the home, at work, and on the roads. Screening questionnaires can be used to estimate EDS, but further evaluation is necessary. EDS is a common symptom of both narcolepsy and obstructive sleep apnea (OSA). Polysomnography and multiple sleep latency testing are used to diagnose these disorders. However, isolating the primary etiology of EDS can be challenging and may be multifactorial. Untreated OSA can show polysomnographic findings that are similar to narcolepsy. The effects of sleep deprivation and certain medications can also affect the polysomnographic results. These challenges can lead to misdiagnosis. In addition, narcolepsy and OSA can occur as comorbid disorders. If EDS persists despite adequate treatment for either disorder, a comorbid diagnosis should be sought. Thus, despite advances in clinical practice, appropriate management of these patients can be challenging. This review is focused on EDS due to OSA and narcolepsy and addresses some of the challenges with managing this patient population.
... It has two stereo isomers (R-modafinil and S-modafinil) due to their asymmetric nature of chiral sulfoxide group. Modafinil is a non-amphetamine unique psycho stimulant, which improves cognitive, emotional and motivational functions of human neural systems [5][6][7][8][9][10]. Moreover, modafinil has potential to treat narcolepsy, obstructive sleep apnoea hypopnoea syndrome (OSAHS) and shift work disorders, which also has defensive effects in hypoxia, ischemic injury and Parkinson's diseases [11][12][13]. ...
Chiral sulfoxide based smart drug modafinil were studied experimentally and theoretically. Vibrational spectra were recorded in the mid IR region and electronic spectra were recorded in UV–Visible region. The molecular geometry, vibrational spectra, magnetic spectra and electronic spectra were simulated using Density Functional Theory (DFT) employed with B3LYP/6–311++G(d,p) basis set. The molecular geometry optimization, vibrational frequencies, chemical shifts and solvent effect on electronic properties were reported. The intermolecular interactions have been studied by Hirshfeld surface analysis. There is good agreement was found between calculated and observed values, thereby to confirm the molecular structure of modafinil.
... Armodafinil ist das (R)-Enantiomer von Modafinil. Vorteilhaft ist seine längere Wirkdauer [27]. Es ist bisher nur in den USA als Medikament registriert. ...
Pharmacotherapy of Sleep-Wake Disorders Abstract. Sleep is a complex behavior, coordinated by many different brain regions and neurotransmitters. These neurochemical systems can be pharmacologically influenced to modulate wakefulness and sleep. Excessive daytime sleepiness (EDS) is often treated with dopaminergic drugs, which in mild cases range from caffeine via (ar)modafinil to amphetamine derivatives. Tricyclic antidepressants and melatonin-based drugs are also used to promote alertness, but to a lesser extent. The drugs used to promote sleep include GABA-ergic drugs such as benzodiazepines and Z-hypnotics as well as histamine H1 receptor antagonists. Exogenous melatonin or a pharmacological combination of melatonin receptor agonists and 5-HT2C receptor antagonists are also used in mild cases. Selective and dual orexin (hypocretin) receptor antagonists (DORA) as well as drugs binding to specific 5-HT receptors are currently being investigated as future sleep-promoting drugs. However, pharmacological treatment is not always the primary treatment option, insomnia is treated first-line with cognitive behavioral therapy, and continuous positive airway pressure is used to treat sleep apnea.
... Armodafinil. Because armodafinil has a longer half-life than modafinil, we may predict its better effect at treating patients with excessive daytime sleepiness [48]. In a 12week pilot trial of oral armodafinil therapy (120-250 mg daily), DLB patients with hypersomnia showed improved scores on the Epworth Sleepiness Scale, Maintenance of Wakefulness Test, and Clinical Global Impression of Change. ...
Dementia with Lewy bodies (DLB) is a complex, multisymptom disorder. When making decisions regarding the treatment of DLB, the patient’s quality of life (QoL) should always be the main consideration. To our knowledge, this is the first review article focusing on the QoL in DLB patients. We searched the PubMed database using the keywords “quality of life” and “dementia with Lewy bodies.” Previously, no specific instrument had been developed for assessing the QoL in DLB patients. Patients with DLB have a decreased QoL compared to patients with Alzheimer’s disease, which is reportedly caused by several factors including level of independence in instrumental activities of daily living, whether the patient is living with the caregiver, apathy, delusion, and dysautonomia. The direct effect of visual hallucination, sleep, and movement disorders on the QoL in DLB patients has not been previously studied. The role of cognitive function on the QoL is still controversial. In a randomized controlled study, memantine may improve the QoL in PDD or DLB patients. We concluded that it is important to develop a specific instrument to assess the QoL in DLB patients. Furthermore, there is an urgent need for large clinical trials to identify factors associated with the QoL and how they can be managed.
... Although weight loss can be efficacious, it can take time, during which symptoms of daytime sleepiness and dysfunction may persist in patients with OSA. Wakefulness promoters modafinil and armodafinil (the R-enantiomer, which results in higher plasma concentrations late in the day) (10) have been trialled extensively adjunctive to CPAP when patients still suffer residual excessive daytime sleepiness (11). This is one of the listed indications in both Australia and the United States (11)(12)(13). ...
Secondary outcomes:
Epworth Sleepiness Scale, Functional Outcomes of Sleep Questionnaire, fat mass measured by dual-emission X-ray absorptiometry (DXA). MAIN RESULTS Armodafinil improved driving task performance over placebo at three months (12.9cm, 95%CI 4.1 to 21.7, p=0.004), but not the primary timepoint of six months (5.5cm, 95%CI -3.3 to 14.3, p=0.223). Patients on armodafinil lost 2.4kg more fat than those on placebo at six months (95%CI 0.9 to 4.0, p=0.002). Other secondary outcomes were not significantly improved. CONCLUSIONS Armodafinil did not improve driving task performance at the primary endpoint of six months. Armodafinil might be a useful adjunctive to weight loss in OSA patients rejecting conventional treatments but this needs to be directly tested in a specifically designed, properly powered clinical trial. Clinical trial registration available at www.anzctr.org.au, ID ACTRN12611000847910.
... Cocaine, unlike amphetamine, acts as a simple inhibitor that binds to the DAT and inhibits its transport activity without stimulating reverse transport activity [8]. Although a multitude of DAT inhibitors that share cocaine-like behavioral effects exists, a number of atypical DAT inhibitors (e.g., analogs of benztropine, RTI-371, GBR12909, modafinil) exhibit different behavioral properties with a minimal abuse liability [9][10][11][12][13][14]. Moreover, benztropine and modafinil have been reported to antagonize the effect of cocaine [15,16], suggesting a unique therapeutic potential for treatment of stimulant dependence. ...
Dopamine reuptake inhibitors have been shown to improve cognitive parameters in various tasks and animal models. We recently reported a series of modafinil analogues, of which the most promising, 5-((benzhydrylsulfinyl)methyl) thiazole (CE-123), was selected for further development. The present study aims to characterize pharmacological properties of CE-123 and to investigate the potential to enhance memory performance in a rat model. In vitro transporter assays were performed in cells expressing human transporters. CE-123 blocked uptake of [3H] dopamine (IC50 = 4.606 µM) while effects on serotonin (SERT) and the norepinephrine transporter (NET) were negligible. Blood-brain barrier and pharmacokinetic studies showed that the compound reached the brain and lower elimination than R-modafinil. The Pro-cognitive effect was evaluated in a spatial hole-board task in male Sprague-Dawley rats and CE-123 enhances memory acquisition and memory retrieval, represented by significantly increased reference memory indices and shortened latency. Since DAT blockers can be considered as indirect dopamine receptor agonists, western blotting was used to quantify protein levels of dopamine receptors D1R, D2R and D5R and DAT in the synaptosomal fraction of hippocampal subregions CA1, CA3 and dentate gyrus (DG). CE-123 administration in rats increased total DAT levels and D1R protein levels were significantly increased in CA1 and CA3 in treated/trained groups. The increase of D5R was observed in DG only. Dopamine receptors, particularly D1R, seem to play a role in mediating CE-123-induced memory enhancement. Dopamine reuptake inhibition by CE-123 may represent a novel and improved stimulant therapeutic for impairments of cognitive functions.
... Compared to its S-enantiomer, R-Modafinil (R-MO) binds to DAT with approximately three times more affinity [20]. After a single administration, R-MO has higher and long lasting plasma concentrations compared to MO, whereas the halflife is comparable [21]. ...
Modafinil is a wake promoting drug approved for clinical use and also has cognitive enhancing properties. Its enantiomer R-Modafinil (R-MO) is not well studied in regard to cognitive enhancing properties. Hence we studied its effect in a spatial memory paradigm and its possible effects on dentate gyrus long-term potentiation (DG-LTP). Clinically relevant doses of R-MO, vehicle dimethyl sulfoxide (DMSO) or saline were administered for three days during the hole-board test and in in vivo DG-LTP. Synaptic levels of dopamine receptors D1R, D2R, dopamine transporter (DAT), and its phosphorylated form (ph-DAT) in DG tissue 4 h after LTP induction were quantified by western blot analysis. Monoamine reuptake and release assays were performed by using transfected HEK-293 cells. Possible neurotoxic side effects on general behaviour were also studied. R-MO at both doses significantly enhanced spatial reference memory during the last training session and during memory retrieval compared to DMSO vehicle but not when compared to saline treated rats. Similarly, R-MO rescues DG-LTP from impairing effects of DMSO. DMSO reduced memory performance and LTP magnitude when compared to saline treated groups. The synaptic DR1 levels in R-MO groups were significantly decreased compared to DMSO group but were comparable with saline treated animals. We found no effect of R-MO in neurotoxicity tests. Thus, our results support the notion that LTP-like synaptic plasticity processes could be one of the factors contributing to the cognitive enhancing effects of spatial memory traces. D1R may play an important regulatory role in these processes.
Acute neurological injury affects thousands of patients each year with significant associated morbidity and mortality. In addition to physical disabilities, these patients often have neurocognitive and behavioral deficits including impaired processing and memory, inattention, depression, anxiety, psychosis, and decreased wakefulness that persist for weeks to months after the initial injury that may impede recovery. Neurostimulants may be beneficial in restoring imbalances in dopaminergic, noradrenergic, cholinergic, and serotonergic systems, promoting cognitive recovery, improving communication skills, and increasing engagement with rehabilitation efforts to optimize patient outcomes.
Background
Abnormalities in dopamine and norepinephrine signaling are implicated in cognitive impairments in bipolar disorder (BD) and attention-deficit hyperactivity disorder (ADHD). This systematic review by the ISBD Targeting Cognition Task Force therefore aimed to investigate the possible benefits on cognition and/or ADHD symptoms and safety of established and off-label ADHD therapies in BD.
Methods
We included studies of ADHD medications in BD patients, which involved cognitive and/or safety measures. We followed the procedures of the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) 2020 statement. Searches were conducted on PubMed, Embase and PsycINFO from inception until June 2023. Two authors reviewed the studies independently using the Revised Cochrane Collaboration's Risk of Bias tool for Randomized trials.
Results
Seventeen studies were identified (N = 2136), investigating armodafinil (k = 4, N = 1581), methylphenidate (k = 4, N = 84), bupropion (k = 4, n = 249), clonidine (k = 1, n = 70), lisdexamphetamine (k = 1, n = 25), mixed amphetamine salts (k = 1, n = 30), or modafinil (k = 2, n = 97). Three studies investigated cognition, four ADHD symptoms, and 10 the safety. Three studies found treatment-related ADHD symptom reduction: two involved methylphenidate and one amphetamine salts. One study found a trend towards pro-cognitive effects of modafinil on some cognitive domains. No increased risk of (hypo)mania was observed. Five studies had low risk of bias, eleven a moderate risk, and one a serious risk of bias.
Conclusions
Methylphenidate or mixed amphetamine salts may improve ADHD symptoms in BD. However, there is limited evidence regarding the effectiveness on cognition. The medications produced no increased mania risk when used alongside mood stabilizers. Further robust studies are needed to assess cognition in BD patients receiving psychostimulant treatment alongside mood stabilizers.
An electrochemical strategy for the synthesis of unsymmetrical sulfoxides has been explored using Bunte salts and aryldiazonium tetrafluoroborates under constant current electrolysis at room temperature. Besides eco-safe and mild conditions,...
In this account, we further describe our already developed N-sp2 hybrid guanidinium as an efficient phase-transfer catalyst and ion pair catalysis based on N-sp2 hybrid pentanidinium and its application in some new reactions. The sp3 hybrid quaternary ammonium salt has a tetrahedral structure, which means that three sides of it can be effectively steric, allowing the remaining side to be close to the substrate. However, the sp2 hybrid ammonium salt allows the substrate to form ion pairs from both directions respectively, so it is a greater challenge to control the stereoselectivity of the reaction. Van der Waals forces, such as hydrogen bonds and π - π interactions, have been used to make electrophiles approach from a certain direction, leading to a higher enantioselectivity. Based on the above idea, we designed an N-sp2 hybrid phase-transfer catalyst, pentanidinium. Pentanidinium has five conjugated nitrogen atoms, one of which has a formal positive charge, which is necessary for it to become an ion pair catalyst. We have confirmed that pentanidinium can catalyze α-hydroxylation of 3-substituted-2-oxindoles, Michael addition of 3-alkyloxindoles with vinyl sulfone, and alkylation reactions of sulfenate anions and dihydrocoumarins, desymmetrization of pro-chiral sulfinate to afford enantioenriched sulfinate esters. Pentanidinium with side chain structure changes can also be catalyzed efficiently with enantioconvergent halogenophilic nucleophilic substitution, including azidation and thioesterification. In the reaction catalyzed by pentanidinium, it always attracts us with the advantages of low catalytic load and good enantioselectivity.
Excessive daytime sleepiness (EDS) is defined as "irresistible sleepiness in a situation when an individual would be expected to be awake, and alert." EDS has been a big concern not only from a medical but also from a public health point of view. Patients with EDS have the possibility of falling asleep even when they should wake up and concentrate, for example, when they drive, play sports, or walk outside. In this article, clinical characteristics of common hypersomnia and pharmacologic treatments of each hypersomnia are described.
BACKGROUND: 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.METHODS: 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).RESULTS: 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.DISCUSSION: 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.Liu F, Zhang M, Chen T, Zhai L, Zhang Z, Xue J. Equilibrium and vestibular safety of modafinil in healthy volunteers. Aerosp Med Hum Perform. 2022; 93(6):487-492.
A selective GC-MS method was developed and evaluated for the determination of genotoxic impurities Chloroacetic acid (Cl-AcOH) and Dichloroacetic acid (DCl-AcOH) in Armodafinil ( AMD) drug substance. Chromatographic separation of Cl-AcOH and DCl-AcOH was achieved on DB-624 column (30 m x 0.32 mm, 1.8 µm), which contains 6% cyanopropylphenyl and 94% dimethylpolysiloxane stationary phase by helium carrier gas. Mass fragment m/z 59 was selected for the quantification of both Cl-AcOH and DCl-AcOH impurities. Further, mass fragments m/z=108 was selected for Cl-AcOH and m/z=83 was selected for DCl-AcOH as qualifier ion. The performance of the method was assessed by evaluating the specificity, linearity, sensitivity, precision and accuracy experiments. The limits of detection (LOD) and limits of quantification (LOQ) values for Cl-AcOH were 0.00003 µg mL⁻¹, 0.00009 µg mL⁻¹ and for DCl-AcOH analyte were 0.00003 µg mL⁻¹ and 0.00009 µg mL⁻¹ respectively. The correlation coefficient values of linearity experiment were 0.9929 for Cl-AcOH, 0.9908 for DCl-AcOH. The average recovery for Cl-AcOH was in the range of 104.7% to 111.4% and for DCl-AcOH was in the range of 108.2% to 111.7%. The results proved that the method is suitable for the determination of Cl-AcOH and DCl-AcOH contents in Armodafinil drug substance and method can be successfully applied in the quality control analysis.
The field of sleep medicine has made several strides forward in the understanding and treatment of various sleep disorders. These discoveries have further highlighted the intricate nature of sleep regulation and the multiple concerted processes required for normal sleep behavior. In this chapter, we will review current pathophysiologic understanding and available treatments for the conditions of hypersomnia and parasomnias. In recent years, advances in the understanding of hypersomnia have been particularly exciting with the discovery of hypocretin/orexin signaling and several newly FDA-approved pharmaceuticals for hypersomnia treatment. Each section concludes with a summary of the available pharmaceuticals, and comprehensive table is provided at the end of the chapter.
With the range of psychotropic drugs expanding and the usages of existing medications diversifying, we are pleased to present the Seventh Edition of the world's best-selling formulary in psychopharmacology. The new edition features nine new compounds as well as information about several new formulations of existing drugs. Many important new indications are covered for existing drugs, as are updates to the profiles of the entire content and collection, including new injectable and transdermal formulations, as well as updated warnings and indications. The Pearls have all been refreshed and the antipsychotics section has been completely revised. With its easy-to-use, full-colour template-driven navigation system, Prescriber's Guide combines evidence-based data with clinically informed advice to support everyone who is prescribing in the field of mental health.
Study objectives:
Excessive daytime sleepiness (EDS) associated with obstructive sleep apnea (OSA) affects 9%-22% of continuous positive airway pressure (CPAP)-treated patients. An indirect treatment comparison (ITC) meta-analysis was performed to compare efficacy and safety of medications (solriamfetol, modafinil, and armodafinil) approved to treat EDS associated with OSA.
Methods:
Efficacy and safety measures assessed in this ITC included Epworth Sleepiness Scale (ESS), 20-minute Maintenance of Wakefulness Test (MWT20), Clinical Global Impression of Change (CGI-C), Functional Outcomes of Sleep Questionnaire (FOSQ), and incidence of treatment-emergent adverse events (TEAEs; any, serious, or leading to discontinuation).
Results:
A systematic literature review (SLR) identified 6 parallel-arm, placebo-controlled randomized controlled trials (RCTs) that randomized 1714 total participants to placebo, solriamfetol, modafinil, or armodafinil. In this ITC, all comparators were associated with greater improvements than placebo on the ESS, the MWT20, and CGI-C after 4, 8 and 12 weeks of treatment. Relative to comparators and placebo at 12 weeks, solriamfetol at 150 mg or 300 mg had the highest probabilities of improvement in the ESS, MWT, and CGI-C. Modafinil (200 or 400 mg) and solriamfetol (150 or 300 mg) were associated with greater improvement on the FOSQ than placebo at 12 weeks. Less than 2% of patients using placebo or comparators experienced serious or discontinuation-related TEAEs.
Conclusions:
The results of this ITC show 12 weeks of treatment with solriamfetol, modafinil, and armodafinil resulted in varying levels of improvement on the ESS, MWT20, and CGI-C and similar safety risks in participants with EDS associated with OSA.
Purpose of review:
This article discusses the central disorders of hypersomnolence, a group of disorders resulting in pathologic daytime sleepiness, particularly narcolepsy type 1 and narcolepsy type 2, idiopathic hypersomnia, and Kleine-Levin syndrome. Disease features, diagnostic testing, epidemiology, pathophysiology, and treatment are reviewed.
Recent findings:
Increasing evidence implicates autoimmunity in narcolepsy type 1, including a strong association with human leukocyte antigen-DQB1*06:02, association with a polymorphism in the T-cell receptor alpha locus in genome-wide association, and the identification of autoreactive T cells in patients with this type of narcolepsy. In contrast, the cause or causes of narcolepsy type 2 and idiopathic hypersomnia are unknown. Multiple treatment options exist, including two medications approved for the treatment of narcolepsy by the US Food and Drug Administration (FDA) in 2019. These include solriamfetol, a dopamine- and norepinephrine-reuptake inhibitor, and pitolisant, an H3-inverse agonist/antagonist that increases histaminergic neurotransmission.
Summary:
The central disorders of hypersomnolence all cause severe sleepiness but can be differentiated based on ancillary symptoms, diagnostic testing, and pathophysiology. It is important that these disorders are identified because multiple treatments are available to improve functioning and quality of life.
Excessive daytime sleepiness (EDS) is related to medical and social problems, including mental disorders, physical diseases, poor quality of life, and so forth. According to the International Classification of Sleep Disorders, Third Edition, diseases that result from EDS are narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, hypersomnia due to a medical disorder, and others. EDS is usually treated using amphetamine-like central nervous system stimulants or modafinil and its R-enantiomer, armodafinil, wake-promoting compounds unrelated to amphetamines; a variety of new drugs are under development. The side effects of some stimulants are potent and careful selection and management are required.
Background: There are reports of prescription stimulants being purchased online for use as cognitive enhancers or “smart drugs.” Objectives: The aim of this study was to investigate availability of modafinil and methylphenidate from internet suppliers from the perspective of a typical United Kingdom (UK) based customer. Methods: Using European Monitoring Center for Drugs and Drug Addiction (EMCDDA) internet snapshot methodology, we undertook an English language internet snapshot survey in July-August 2018 to gather information on the availability and price of modafinil and methylphenidate from online retailers. Results: A total of 55 modafinil and 14 methylphenidate websites were identified from which the drug could be purchased without a prescription. Minimum purchase quantities ranged from 10 to 90 tablets for modafinil and 1–1,005 tablets for methylphenidate with no apparent upper limit to the number that could be purchased. The price per tablet varied from £0.38–5.31 for modafinil and £0.16–5.70 for methylphenidate. Free shipping was offered if more than a certain amount was spent on 46 (83.6%) modafinil and 7 (50.0%) methylphenidate websites and discounts were offered on 43 (78.2%) modafinil and 4 (28.6%) methylphenidate websites. Conclusions: Modafinil and methylphenidate are widely available to purchase via internet from the UK without a prescription. The pricing on websites encourages users to buy greater quantities to qualify for discounts and free shipping. The quantities available suggest these purchases may be used in greater amounts than would be legitimately prescribed, increasing the risk of misuse or diversion to other individuals.
Armodafinil is a wake‐promoting agent approved in 2007 by the US Food and Drug Administration for the treatment of excessive sleepiness. A rapid, sensitive and selective liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method for the determination of armodafinil in human plasma was developed and validated. Armodafinil and internal standard (armodafinil d‐10) were extracted from human plasma using protein precipitation combined with liquid‐liquid extraction. This developed method only requires 50 μL of plasma for the analysis. The chromatographic separation was performed with a Waters symmetry, C18, 4.6 × 150 mm, 5 μm column using formic acid, water, and acetonitrile as solvent delivered at a 0.7 mL/min flow rate. The total run time of the method was 3 min. The method was validated according to regulatory guidance in terms of specificity, selectivity, linearity, matrix effect, recovery and stability. Optimized Q1/Q3 mass transitions for armodafinil and armodafinil d‐10 were 274.1/167.2 (m/z) and 284.4/177.4 (m/z) respectively. The method showed linearity within the tested concentration range of 10‐10,000 ng/mL. The method was successfully applied to quantify armodafinil concentrations after single oral administration of a 250 mg tablet in a clinical study conducted in healthy volunteers. Significant advantages of this method are minimal sample volume, short run time and a lower LLOQ.
Since the enantio or diastereoselective preparation of sulfoxides is a current challenge, we explore the possibility of inducing diastereoselectivity in the oxidation of the sulfur atom of thiodisaccharides, according to their substitution patterns. Thus, a series of 3-deoxy-4-S-(β-D-glucopyranosyl)-4-thio-β-D-xylo-hexopyranoside derivatives, with different substituents at C-6 (OH, OAc or OTBS) of the reducing end, have been synthesized and treated with m-CPBA for the oxidation of the sulfur atom at C-4, which is vicinal to C-6. The absolute configuration at the sulfur stereocenter of the resulting sulfoxides was established taking into account shielding/deshielding anisotropic effects of the SO bond on the chemical shift of the NMR signals of selected protons, in the most populated syn ϕ/syn ψ conformation of the thiodisaccharide S-oxides. The OAc and OTBS derivatives afforded diastereomeric mixtures of R and S sulfoxides in a similar ratio (1.4:1 and 1.6:1, respectively). In contrast, the oxidation of thiodisaccharide with a free hydroxyl group at C-6 was completely diastereoselective in favor of the R sulfoxide. The influence of the thiodisaccharide C-6 substituent on the stereochemical course of the oxidation is discussed.
Excessive daytime sleepiness (EDS) is related to medical and social problems, including mental disorders, physical diseases, poor quality of life, and so forth. According to the International Classification of Sleep Disorders, Third Edition, diseases that result from EDS are narcolepsy type 1, narcolepsy type 2, idiopathic hypersomnia, hypersomnia due to a medical disorder, and others. EDS is usually treated using amphetamine-like central nervous system stimulants or modafinil and its R-enantiomer, armodafinil, wake-promoting compounds unrelated to amphetamines; a variety of new drugs are under development. The side effects of some stimulants are potent and careful selection and management are required.
Introduction
Narcolepsy is an orphan neurological disease and presents with sleep- wake, motoric, neuropsychiatric and metabolic symptoms. Narcolepsy with cataplexy is most commonly caused by an immune-mediated process including genetic and environmental factors, resulting in the selective loss of hypocretin-producing neurons. Narcolepsy has a major impact on workableness and quality of life.
Areas covered
This review provides an overview of the temporal available treatment options for narcolepsy (type 1 and 2) in adults, including authorization status by regulatory agencies. First- and second-line options are discussed as well as combination therapies. In addition, treatment options for frequent co-exiting co-morbidities and different phenotypes of narcolepsy are presented. Finally, this review considers potential future management strategies. Non-pharmacological approaches are important in the management of narcolepsy but will not be covered in this review.
Expert opinion
Concise evaluation of symptoms and type of narcolepsy, co-existing co-morbidities and patients´ distinct needs is mandatory in order to identify a suitable, individual pharmacological treatment. First-line options include Modafinil/Armodafinil (for excessive daytime sleepiness, EDS), Sodium Oxybate (for EDS and/with cataplexy), Pitolisant (for EDS and cataplexy) and Venlafaxine (for cataplexy (off-label) and co-morbid depression). New symptomatic and causal treatment most probably will be completed by hypocretin-replacement and immune-modifying strategies.
Narcolepsy is a chronic sleep disorder that is characterized by excessive daytime sleepiness, cataplexy, hypnagogic hallucinations, and sleep paralysis. Since these symptoms are often disabling, most patients need lifelong treatments. Non-pharmacological treatments (i.e., behavioral modification) are often helpful for the clinical management of narcoleptic patients. However, over 90 % of diagnosed narcoleptic patients are reported to take medications to control their symptoms. Traditionally, the amphetamine-like CNS stimulants have been used for clinical management to improve EDS and tricyclic antidepressants as anticataplectics, but the treatment has evolved recently with new and better tolerated compounds such as modafinil (and its R-enantiomer, armodafinil) for EDS and adrenergic/serotonergic selective reuptake inhibitors as anticataplectics. Nighttime administration of a short-acting sedative, gamma-hydroxybutyrate (sodium oxybate in the USA) has also been used for the treatment for EDS and cataplexy. Since a large majority of human narcolepsy patients are hypocretin peptide deficient, hypocretin replacement therapy may also be a new therapeutic option, but this is still not available for human patients. If hypocretin replacement is effective in hypocretin-deficient narcolepsy, cell transplantation and/or gene therapy may be developed in the near future. In this review, we first describe clinical symptoms of narcolepsy and then the state-of-the-art knowledge about both pharmacological and non-pharmacological treatments of narcolepsy.
Modafinil is regarded as a first-line treatment for the treatment of excessive sleepiness associated with narcolepsy; however it does not help cataplexy or the other ancillary features of narcolepsy, such as hypnagogic hallucinations or sleep paralysis.
In 2004, the indication for modafinil (Provigil) was expanded from treatment of narcolepsy to include the treatment of excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome (OSAHS) and shift work sleep disorder (SWSD). Since that time modafinil and, the longer acting form, armodafinil (Nuvigil) have become the most widely prescribed agents in the USA for excessive sleepiness of all types.
Armodafinil, the r-enantiomer of modafinil (racemic), was approved in 2007 for the treatment of excessive sleepiness associated with narcolepsy, OSAHS, and SWSD. Armodafinil has become widely used in the USA because of its longer action than modafinil and that one tablet of 250 mg is clinically equivalent to two tablets of modafinil 400 mg. The only limitation in its use is that it is more expensive than generic modafinil although slightly less expensive than brand modafinil (Provigil).
Narcolepsy is a chronic sleep disorder that has a typical onset in adolescence and is characterized by excessive daytime sleepiness, which can have severe consequences for the patient. Problems faced by patients with narcolepsy include social stigma associated with this disease, difficulties in obtaining an education and keeping a job, a reduced quality of life and socioeconomic consequences. Two subtypes of narcolepsy have been described (narcolepsy type 1 and narcolepsy type 2), both of which have similar clinical profiles, except for the presence of cataplexy, which occurs only in patients with narcolepsy type 1. The pathogenesis of narcolepsy type 1 is hypothesized to be the autoimmune destruction of the hypocretin-producing neurons in the hypothalamus; this hypothesis is supported by immune-related genetic and environmental factors associated with the disease. However, direct evidence in support of the autoimmune hypothesis is currently unavailable. Diagnosis of narcolepsy encompasses clinical, electrophysiological and biological evaluations, but simpler and faster procedures are needed. Several medications are available for the symptomatic treatment of narcolepsy, all of which have quite good efficacy and safety profiles. However, to date, no treatment hinders or slows disease development. Improved diagnostic tools and increased understanding of the pathogenesis of narcolepsy type 1 are needed and might lead to therapeutic or even preventative interventions.
Excessive sleepiness associated with narcolepsy lasts throughout the waking day. The authors conducted two randomized, double-blind studies to compare the efficacy of modafinil once-daily versus split doses in maintaining wakefulness throughout the day. Fifty-six patients received modafinil. The split-dose regimens were significantly more effective than the 200-mg once-daily regimen for sustaining wakefulness in the late afternoon/evening. All modafinil dosing regimens were well tolerated. In patients who experience excessive sleepiness in the late afternoon/evening, despite satisfactory treatment earlier in the day, a split dose of modafinil may promote wakefulness throughout the waking day.
Residual excessive sleepiness (ES) and impaired cognition can occur despite effective and regular nasal continuous positive airway pressure (nCPAP) therapy in some patients with obstructive sleep apnea (OSA). A pooled analysis of two 12-week, randomized, double-blind studies in nCPAP-adherent patients with ES associated with OSA evaluated the effect of armodafinil on wakefulness and cognition. Three hundred and ninety-one patients received armodafinil (150 or 250 mg) and 260 patients received placebo once daily for 12 weeks. Efficacy assessments included the Maintenance of Wakefulness Test (MWT), Cognitive Drug Research cognitive performance battery, Epworth Sleepiness Scale, and Brief Fatigue Inventory. Adverse events were monitored. Armodafinil increased mean MWT sleep latency from baseline to final visit by 2.0 min vs a decrease of 1.5 min with placebo (P < 0.0001). Compared with placebo, armodafinil significantly improved quality of episodic secondary memory (P < 0.05) and patients' ability to engage in activities of daily living (P < 0.0001) and reduced fatigue (P < 0.01). The most common adverse events were headache, nausea, and insomnia. Armodafinil did not adversely affect desired nighttime sleep, and nCPAP use remained high (approximately 7 h/night). Adjunct treatment with armodafinil significantly improved wakefulness, long-term memory, and patients' ability to engage in activities of daily living in nCPAP-adherent individuals with ES associated with OSA. Armodafinil also reduced patient-reported fatigue and was well tolerated.
Background and objectives: Armodafinil R-modafinil) is the R- and longer-lasting isomer of the racemic compound modafinil, a wakefulness-promoting medication. Armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil. Published studies have demonstrated the efficacy of armodafinil for treating excessive sleepiness associated with obstructive sleep apnoea, shift work disorder and narcolepsy. The objectives of this study were to describe the pharmacokinetic profile, tolerability and safety of armodafinil in healthy subjects. Results: Armodafinil was readily absorbed and exhibited linear pharmacokinetics over the 50–400 mg dose range. Peak plasma concentrations were reached around 2 hours after administration in the fasted state. Food had no effect on the overall bioavailability of armodafinil; however, the peak concentration was delayed by approximately 2–4 hours. In the multiple-dose study, dose proportionality was confirmed by linear regression analyses of the log-transformed area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) values as a function of dose. After reaching the peak, plasma concentrations of armodafinil declined in a monophasic manner, with a mean elimination half-life of approximately 15 hours. Steady state appeared to be reached within 7 days. At steady state, the systemic exposure to armodafinil was 1.8 times that observed after single-dose administration. Armodafinil was generally well tolerated, the most frequent adverse events being headache, dizziness and nausea.
To assess the effect of armodafinil, 150 mg, on the physiologic propensity for sleep and cognitive performance during usual night shift hours in patients with excessive sleepiness associated with chronic (> or =3 months) shift work disorder (SWD) of moderate or greater severity.
This 12-week, randomized controlled study was conducted at 42 sleep research facilities in North America from April 2 through December 23, 2004, and enrolled 254 permanent or rotating night shift workers with SWD. Entry criteria included excessive sleepiness during usual night shifts for 3 months or longer (corroborated by mean sleep latency of < or =6 minutes on a Multiple Sleep Latency Test), insomnia (sleep efficiency < or =87.5% during daytime sleep), and SWD that was judged clinically to be of moderate or greater severity. Patients received armodafinil, 150 mg, or placebo 30 to 60 minutes before each night shift. Physiologic sleep propensity during night shift hours, clinical impression of severity, patient-reported sleepiness, and cognitive function were assessed during laboratory night shifts at weeks 4, 8, and 12.
Armodafinil significantly improved mean (SD) sleep latency from 2.3 (1.6) minutes at baseline to 5.3 (5.0) minutes at final visit, compared with a change from 2.4 (1.6) minutes to 2.8 (2.9) minutes in the placebo group (P<.001). Clinical condition ratings improved in more patients receiving armodafinil (79%) vs placebo (59%) (P=.001). As reported by patients' diaries, armodafinil significantly reduced sleepiness during laboratory nights (P<.001), night shifts at work (P<.001), and the commute home (P=.003). Armodafinil improved performance on standardized memory (P<.001) and attention (power, P=.001; continuity, P<.001) tests compared with placebo. Armodafinil was well tolerated and did not affect daytime sleep, as measured by polysomnography.
In patients with excessive sleepiness associated with chronic SWD of moderate or greater severity, armodafinil significantly improved wakefulness during scheduled night work, raising mean nighttime sleep latency above the level considered to indicate severe sleepiness during the daytime. Armodafinil also significantly improved measures of overall clinical condition, long-term memory, and attention.
clinicaltrials.gov Identifier: NCT00080288.
Armodafinil, the R- and longer-lasting isomer of modafinil, may maintain higher plasma drug concentrations compared with racemic modafinil because of stereospecific differences in elimination of its isomers. This analysis set out to compare the steady-state pharmacokinetic profiles of armodafinil and modafinil on a milligram-to-milligram basis following once-daily administration.
A post hoc analysis of two multiple-dose pharmacokinetic studies in healthy male subjects aged 18-50 years was conducted to compare dose-normalized (200 mg/day) plasma drug concentration and pharmacokinetic data for subjects in each study who completed 7 days of once-daily (morning) administration of armodafinil (n = 34) or modafinil (n = 18).
Dose-normalized plasma concentrations of armodafinil on day 7 were higher than those of modafinil, with the greatest differences being observed later in the day. Across the 24-hour dose interval, plasma drug concentration fluctuation and swing were 28% and 42% less, respectively, with armodafinil than with modafinil. In addition, average late-day (3 pm to 7 pm after an 8 am dosing) plasma drug concentrations and partial values for the area under the plasma concentration versus time curve for 7-11 hours after dosing were both 44% higher with armodafinil.
At steady state, armodafinil produces consistently higher plasma drug concentrations late in the day than modafinil when compared on a milligram-to-milligram basis. The distinct pharmacokinetic profile of armodafinil compared with that of the racemate may result in fundamentally different durations of action. These differences between the two medications cannot be made equivalent by increasing the dose of the racemate without introducing potential safety concerns.
Armodafinil (R-modafinil) is the R- and longer-lasting isomer of the racemic compound modafinil, a wakefulness-promoting medication. Armodafinil is eliminated approximately three times more slowly than the S-isomer of racemic modafinil. Published studies have demonstrated the efficacy of armodafinil for treating excessive sleepiness associated with obstructive sleep apnoea, shift work disorder and narcolepsy. The objectives of this study were to describe the pharmacokinetic profile, tolerability and safety of armodafinil in healthy subjects.
Pooled pharmacokinetic data from three separate randomized studies in 119 healthy subjects who received single or multiple (once daily for up to 14 days) oral doses of armodafinil ranging between 50 and 400 mg were analysed. The impact of food on the single-dose pharmacokinetic profile of armodafinil was also assessed in subjects following an overnight fast and after the consumption of a standard fatty meal.
Armodafinil was readily absorbed and exhibited linear pharmacokinetics over the 50-400 mg dose range. Peak plasma concentrations were reached around 2 hours after administration in the fasted state. Food had no effect on the overall bioavailability of armodafinil; however, the peak concentration was delayed by approximately 2-4 hours. In the multiple-dose study, dose proportionality was confirmed by linear regression analyses of the log-transformed area under the plasma concentration versus time curve (AUC) and maximum plasma concentration (Cmax) values as a function of dose. After reaching the peak, plasma concentrations of armodafinil declined in a monophasic manner, with a mean elimination half-life of approximately 15 hours. Steady state appeared to be reached within 7 days. At steady state, the systemic exposure to armodafinil was 1.8 times that observed after single-dose administration. Armodafinil was generally well tolerated, the most frequent adverse events being headache, dizziness and nausea.
In the present analysis, armodafinil exhibited linear pharmacokinetics over the dose range of 50-400 mg. While food affected the rate but not the extent of absorption, peak plasma concentrations were reached in approximately 2 hours when the drug was taken on an empty stomach. With once-daily dosing, steady state appeared to be reached within 7 days. After reaching peak plasma levels, concentrations of armodafinil declined monophasically, with a mean elimination half-life of around 15 hours. Armodafinil was generally well tolerated.
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.
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.
Modafinil is a unique wake-promoting agent for oral administration. Its pharmacological properties are distinct from those of other CNS agents, and it selectively targets neuronal pathways in the sleep/wake centres of the brain. Modafinil is primarily eliminated via metabolism, mainly in the liver, with subsequent excretion in the urine. Less than 10% of the dose is excreted as unchanged drug. Metabolism is largely via amide hydrolysis, with lesser contributions from cytochrome P450 (CYP)-mediated oxidative pathways. In patients who are renally or hepatically compromised, the elimination processes can be slowed, and in a similar manner (although to a lesser extent), elimination in the elderly may be reduced due to normal effects of aging. Because modafinil is administered concomitantly with other medications, the potential for metabolic drug-drug interactions has been examined both in vitro and in vivo. In vitro, modafinil was observed to produce a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small, but concentration-dependent, induction of CYP1A2, CYP2B6 and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamfetamine, warfarin, ethinylestradiol and triazolam. The only substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. Overall, the results of the interaction studies suggest that modafinil has potential to affect the pharmacokinetics of drugs that are metabolised by certain CYP enzymes. Compounds that induce or inhibit CYP activity are unlikely to have major effects on the pharmacokinetics of modafinil. In summary, the results show that modafinil is a moderately long-lived drug that is well absorbed and extensively metabolised.
In a multicenter, randomized, double-blind study the authors compared the efficacy of modafinil 400 mg once daily, 400 mg given in a split dose, or 200 mg once daily for maintaining wakefulness throughout the day in patients (N = 32) with narcolepsy reporting a positive daytime response to modafinil but late-afternoon/evening sleepiness. Efficacy evaluations included an extended Maintenance of Wakefulness Test (9:00 am to 9:00 pm), the Clinical Global Impression of Change scale, and the Epworth Sleepiness Scale. Modafinil demonstrated significant improvement in wakefulness as assessed by the Epworth Sleepiness Scale compared with placebo at baseline (all P < 0.001). Modafinil significantly improved patients' ability to sustain wakefulness, as demonstrated by mean sleep latency at week 3 compared with placebo at baseline (all P < 0.001). The 400-mg split-dose regimen improved wakefulness significantly in the evening compared with the 200-mg and 400-mg once-daily regimen (both P < 0.05). The percentage of patients rated as "much improved" or "very much improved" with respect to evening sleepiness was 27%, 82%, and 80% in the 200-mg, 400-mg once-daily, and 400-mg split-dose groups, respectively. Adverse events were mild to moderate in nature and included headache, nausea, nervousness, dyspepsia, pain, and vomiting (all 6%). Some patients may benefit from 400-mg doses of modafinil taken once daily compared with 200-mg doses. A split-dose 400-mg regimen may be superior to once-daily dosing for sustaining wakefulness throughout the entire waking day.
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.
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.
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.
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.
To assess the pharmacodynamics of armodafinil compared with modafinil and placebo on measures of alertness in healthy volunteers undergoing sleep loss.
In a double-blind, active- and placebo-controlled, parallel-group study, 107 healthy male volunteers (aged 18-40 years) were randomized to receive a single oral dose of armodafinil (100, 150, 200, or 300 mg), modafinil (200 mg), or placebo administered at 19:25 h.
The primary outcome was the Maintenance of Wakefulness Test (MWT), administered every 2 hours from 22:00-08:00 h. Secondary outcomes included the Psychomotor Vigilance Task (PVT) and the Karolinska Sleepiness Scale. Blood samples for pharmacokinetic analysis were collected hourly. Adverse events were evaluated throughout the 2-day laboratory stay and by telephone on day 9.
All four doses of armodafinil, and the dose of 200 mg modafinil, improved wakefulness as measured by increased MWT latencies (treatment effect, p < 0.0001) and reduced PVT lapses of attention (treatment effect, p < 0.0001). The magnitude and duration of these effects at the later time points appeared to be dose and concentration dependent. Armodafinil at 200 mg resulted in comparable C(max), a later t(max), and higher plasma concentrations 6-14 hours post-drug administration than with 200 mg modafinil. Following armodafinil, longer MWT latencies and fewer PVT lapses 6 to approximately 14 hours post-drug administration were observed compared with modafinil. Armodafinil doses were well tolerated, with the most common adverse events including abdominal pain, nausea, and headache. There were reports of tachycardia/palpitations. Decreased mean sleep efficiency and increased mean blood pressure were also observed.
Armodafinil improved alertness at all doses studied. Relative to modafinil 200 mg, armodafinil 200 mg showed a comparable peak plasma concentration with higher concentrations 6-14 hours post-drug, and improved wakefulness and sustained attention for a longer time post-dose. Both drugs were well tolerated; however, further research on the efficacy, safety, and tolerability of armodafinil in patients with disorders of excessive sleepiness (ES) is required.
This study assessed the efficacy and safety of armodafinil, the longer half-life enantiomer of modafinil, for the treatment of excessive sleepiness in patients with narcolepsy.
This was a multicenter double-blind study with 196 patients (aged 18-65 years) randomized to receive armodafinil 150 mg (n = 65), armodafinil 250 mg (n = 67), or placebo (n = 64) once daily for 12 weeks.
Efficacy was assessed using the Maintenance of Wakefulness Test (MWT) (six 20-min subtests across the day), the Clinical Global Impression of Change (CGI-C), subjective measures of sleepiness (Epworth Sleepiness Scale), patient diaries, and evaluations of cognitive performance (Cognitive Drug Research) and fatigue (Brief Fatigue Inventory).
Armodafinil significantly increased MWT mean sleep latency (at 0900-1500) compared with placebo. The mean change from baseline at final visit for armodafinil was an increase of 1.3, 2.6, and 1.9 min in the 150-mg, 250-mg, and combined groups, respectively, compared with a decrease of 1.9 min for placebo (p < 0.01 for all three comparisons). Mean late-day MWT latency (1500-1900) was also significantly improved (difference of armodafinil combined group relative to placebo at final visit: 2.8 min, p = 0.0358). The proportions of patients who showed at least minimal improvement in the CGIC rating from baseline to final visit in the armodafinil 150-mg, 250-mg, and combined groups were 69%, 73%, and 71%, respectively, compared with 33% for placebo (p < 0.0001). Both doses were associated with statistically significant improvements in memory, attention, and fatigue (p < 0.05). The most common adverse events in patients receiving armodafinil were headache, nausea, and dizziness.
Armodafinil significantly improved ability to sustain wakefulness throughout the day in patients with narcolepsy. Armodafinil also significantly improved overall clinical condition, memory, attention, and fatigue when compared with placebo.
Some patients with obstructive sleep apnea/hypopnea syndrome (OSA/HS) experience excessive sleepiness (ES) that might not resolve with nasal continuous positive airway pressure (nCPAP) treatment.
The aim of the present study was to assess the efficacy and tolerability of armodafinil 150 or 250 mg QD when used as adjunctive treatment for residual ES associated with OSA/HS in patients who are adherent to nCPAP therapy.
This 12-week, multicenter, double-blind, randomized, placebo-controlled study was conducted at 37 centers in the United States and Canada. Male and female patients aged 18 to 65 years with residual ES associated with OSA/HS were enrolled. Patients were randomly assigned to receive armodafinil 150 or 250 mg or placebo PO QD for 12 weeks. Assessments were conducted at baseline and study weeks 4, 8, and 12 and included the Maintenance of Wakefulness Test (MWT) to determine wakefulness, the Clinical Global Impression of Change (CGI-C) to determine improvement in clinical condition, the Epworth Sleepiness Scale (ESS) to determine patient-estimated wakefulness, the Brief Fatigue Inventory (BFI) to determine global fatigue, and the Cognitive Drug Research computerized assessment battery. To distinguish between earlier and later effects, sleep latencies, assessed using the MWT, were averaged across the first 4 (9 and 11 AM, and 1 and 3 PM) and last 3 (3, 5, and 7 PM) tests. Tolerability assessments included monitoring of adverse events (AEs), clinical laboratory tests, vital sign measurements, and electrocardiography.
A total of 395 patients were enrolled in the study (armodafinil 150 mg/d, 133; armodafinil 250 mg/d, 131; placebo, 131); 392 received >or=1 dose of study drug (armodafinil 150 mg/d, 131; armodafinil 250 mg/d, 131; placebo, 130). The armodafinil and placebo groups were well matched with regard to age (mean [SD], 49.2 [8.9] vs 50.1 [9.4] years), sex (71 vs 69% men), race (84% vs 87% white), and body weight (mean [SD], 110.3 [24.9] vs 111.9 [24.0] kg). At the final visit, the mean (SD) change from baseline in MWT sleep latency across the morning and afternoon was significantly greater in the armodafinil combined group compared with the placebo group (+1.9 [7.3] vs 1.7 [8.6] minutes; P < 0.001). Also at the final visit, the proportions of patients who showed at least minimal improvement on the CGI-C, and the mean (SD) changes from baseline in ESS and BFI scores, were significantly greater in the armodafinil group compared with those in the placebo group (72% vs 37%, -5.5 [5.0] vs -3.3 [4.7], and -1.2 [2.2] vs -0.6 [2.0], respectively; P < 0.001, P < 0.001, and P < 0.01, respectively). No significant effects on nighttime sleep, as assessed using polysomnography, were found with armodafinil. AEs reported in the armodafinil combined and placebo groups were headache, nausea, insomnia, anxiety, and dizziness. Serious AEs (ulcerative colitis, migraine, worsening of Axis II and mood disorder, and duodenal ulcer) were reported in 4 (1.5%) patients receiving armodafinil and were considered by the investigator not or unlikely to be drug related.
In this selected population of patients with OSA/HS and residual ES despite effective treatment with nCPAP, armodafinil QD used as an adjunct to nCPAP treatment was associated with improved wakefulness and overall clinical condition. Clinical benefit was shown at the first assessment and maintained for the 12-week duration of the study. Armodafinil was also associated with significantly reduced interference of ES with daily activities and global fatigue. Armodafinil was well tolerated, with no adverse effect on nighttime sleep or nCPAP use.
Armodafinil is the R-enantiomer of racemic modafinil and has a significantly longer half-life than the S-enantiomer. This study evaluated armodafinil 150 mg/day as an adjunct treatment for residual excessive sleepiness in patients with obstructive sleep apnea/hypopnea syndrome (OSA/HS) who were otherwise well controlled with nasal continuous positive airway pressure (nCPAP). We assessed the ability of armodafinil to improve wakefulness and cognition and reduce fatigue in this population.
In this 12-week, randomized, double-blind study, patients (n=259) received armodafinil (150 mg) or placebo once daily. Efficacy assessments at baseline and weeks 4, 8, and 12 included the Maintenance of Wakefulness Test (MWT), Clinical Global Impression of Change (CGI-C), Cognitive Drug Research battery, Epworth Sleepiness Scale, and Brief Fatigue Inventory.
At final visit, mean (SD) MWT sleep latency increased from baseline by 2.3 (7.8) min with armodafinil and decreased by 1.3 (7.1) min in the placebo group (P=0.0003). Armodafinil improved clinical condition (CGI-C, 71% vs. 53% for armodafinil and placebo, respectively; P=0.0069). Armodafinil significantly improved episodic secondary memory (P=0.0102) and patient-estimated wakefulness (P<0.01) and reduced fatigue (P<0.05) compared with placebo. Armodafinil did not adversely affect nCPAP use. The most common adverse event associated with armodafinil was headache. Sleep macroarchitecture was not altered by armodafinil.
Adjunct treatment with armodafinil significantly improved alertness, overall clinical condition, and long-term memory. Armodafinil also reduced fatigue and the impact of sleepiness on daily activities in patients with OSA/HS who have residual excessive sleepiness notwithstanding regular use of nCPAP. Armodafinil was well tolerated.
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