Wake-promoting Agent Modafinil Research Articles

Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion

AbstractIntroductionSolriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The wake-promoting mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to further elucidate the molecular targets activated by solriamfetol and compare them to that of known WPAs and traditional stimulants.MethodsIn vitro binding and functional studies were conducted in a panel of cell lines or membrane preparations expressing transmembrane receptors and monoamine transporters to measure the activity of solriamfetol, comparator WPAs, and traditional stimulants. Electrophysiology studies were conducted in slice preparations from mouse ventral tegmental area (VTA). Studies to measure locomotor activity and wake-promoting effects were conducted in mice.ResultsIn vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 μM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity. Solriamfetol (1–10 μM) dose-dependently inhibited the firing frequency of dopaminergic VTA neurons in mouse brain slices, similar to known TAAR1 agonists; however, these effects were inhibited by a D2 antagonist, suggesting a DAT-mediated effect. Unlike traditional stimulants, solriamfetol did not increase locomotor activity in naive mice, but inhibited the increase in locomotor activity in DAT knockout mice.ConclusionsPreclinical studies have identified agonist activity at the TAAR1 receptor and, possibly, lower potency agonist activity at 5-HT1A receptors as potential pharmacological targets for solriamfetol, in addition to its activity as a DAT/NET inhibitor. Given the current understanding of TAAR1 agonists as modulators of monoamine transmission with potential wake-promoting effects in multiple preclinical species, agonist activity at the hTAAR1 receptor may represent an additional pharmacological target underlying the wake-promoting effects for solriamfetol, in addition to its DNRI activity.FundingAxsome Therapeutics, Jazz Pharmaceuticals

0756 Preclinical Pharmacology of Solriamfetol: Potential Mechanisms for Wake Promotion

Abstract Introduction Solriamfetol is a wake-promoting agent (WPA) approved for the treatment of excessive daytime sleepiness associated with narcolepsy and obstructive sleep apnea. The wake-promoting mechanism of solriamfetol may result from dopamine and norepinephrine reuptake inhibition. Preclinical pharmacology studies were conducted to further elucidate the molecular targets activated by solriamfetol and compare them to that of known WPAs and traditional stimulants. Methods In vitro binding and functional studies were conducted in a panel of cell lines or membrane preparations expressing transmembrane receptors and monoamine transporters to measure the activity of solriamfetol, comparator WPAs, and traditional stimulants. Electrophysiology studies were conducted in slice preparations from mouse ventral tegmental area (VTA). Studies to measure locomotor activity and wake-promoting effects were conducted in mice. Results In vitro functional studies showed agonist activity of solriamfetol at human, mouse, and rat TAAR1 receptors. hTAAR1 EC50 values (10–16 µM) were within the clinically observed therapeutic solriamfetol plasma concentration range and overlapped with the observed DAT/NET inhibitory potencies of solriamfetol in vitro. TAAR1 agonist activity was unique to solriamfetol; neither the WPA modafinil nor the DAT/NET inhibitor bupropion had TAAR1 agonist activity. Solriamfetol (1–10 µM) dose-dependently inhibited the firing frequency of dopaminergic VTA neurons in mouse brain slices, similar to known TAAR1 agonists; however, these effects were inhibited by a D2 antagonist, suggesting a DAT-mediated effect. Unlike traditional stimulants, solriamfetol did not increase locomotor activity in naive mice, but inhibited the increase in locomotor activity in DAT knockout mice. Conclusion Preclinical studies have identified agonist activity at the TAAR1 receptor and, possibly, lower potency agonist activity at 5-HT1A receptors as potential pharmacological targets for solriamfetol, in addition to its activity as a DAT/NET inhibitor. Given the current understanding of TAAR1 agonists as modulators of monoamine transmission with potential wake-promoting effects in multiple preclinical species, agonist activity at the hTAAR1 receptor may represent an additional pharmacological target underlying the wake-promoting effects for solriamfetol, in addition to its DNRI activity. Support (If Any) Jazz Pharmaceuticals

High cortical delta power correlates with aggravated allodynia by activating anterior cingulate cortex GABAergic neurons in neuropathic pain mice.

Patients with chronic pain often report being sensitive to pain at night before falling asleep, a time when the synchronization of cortical activity is initiated. However, how cortical activity relates to pain sensitivity is still unclear. Because sleep is characterized by enhanced cortical delta power, we hypothesized that enhanced cortical delta power may be an indicator of intensified pain. To test this hypothesis, we used pain thresholds tests, EEG/electromyogram recordings, c-Fos staining, and chemogenetic and pharmacological techniques in mice. We found that sleep deprivation or pharmacologic enhancement of EEG delta power by reserpine and scopolamine dramatically decreased mechanical pain thresholds, but not thermal withdrawal latency, in a partial sciatic nerve ligation model of neuropathic pain mice. On the contrary, suppression of EEG delta power using a wake-promoting agent modafinil significantly attenuated mechanical allodynia. Moreover, when EEG delta power was enhanced, c-Fos expression decreased in most regions of the cortex, except the anterior cingulate cortex (ACC), where c-Fos was increased in the somatostatin- and parvalbumin-positive GABAergic neurons. Chemogenetic activation of GABAergic neurons in ACC enhanced EEG delta power and lowered mechanical pain thresholds simultaneously in naive mice. However, chemogenetic inhibition of ACC GABAergic neurons could not block mechanical allodynia. These results provided compelling evidence that elevated EEG delta power is accompanied with aggravated neuropathic pain, whereas decreased delta power attenuated it, suggesting that enhanced delta power can be a specific marker of rising chronic neuropathic pain and that wake-promoting compounds could be used as analgesics in the clinic.

Structured cues or modafinil for fatigue amelioration in clinicians? A double-blind, randomized controlled trial of critical clinical information recall in fatigued clinicians

To evaluate the impact of modafinil on "free" and "cued" recall of clinical information in fatigued but nonsleep-deprived clinicians. Despite attempts to minimize sleep deprivation through redesign of the roster of residents and staff surgeons, evidence suggests that fatigue remains prevalent. The wake-promoting agent modafinil improves cognition in the sleep-deprived fatigued state and may improve information recall in fatigued nonsleep-deprived clinicians. Twenty-four medical undergraduates participated in a double-blind, parallel, randomized controlled trial (modafinil-200 mg:placebo). Medication was allocated 2 hours before a 90-minute fatigue-inducing, continuous performance task (dual 2-back task). A case history memorization task was then performed. Clinical information recall was assessed as "free"(no cognitive aids) and "cued"(using aid memoirs). Open and closed cues represent information of increasing specificity to aid the recall of clinical information. Fatigue was measured objectively using the psychomotor vigilance task at induction, before and after the dual 2-back task. Modafinil decreased false starts and lapses (modafinil = 0.50, placebo = 9.83, P < .05) and improved psychomotor vigilance task performance (Decreased Performance, modafinil = 0.006, placebo = 0.098, P < .05). Modafinil improved free information recall (modafinil = 137.8, placebo = 106.0, P < .01). There was no significant difference between groups in the amount of information recalled with open (modafinil = 62.3, placebo = 52.8, P = .1) and closed cues (modafinil = 80.1, placebo = 75.9, P = .3). Modafinil attenuated fatigue and improved free recall of clinical information without improving cue-based recall under the design of our experimental conditions. Memory cues to aid retrieval of clinical information are convenient interventions that could decrease fatigue-related error without adverse effects of the neuropharmacology.

Structured Cues or Modafinil for Fatigue Amelioration in Clinicians: A Double Blind Randomized Controlled Trial of Critical Clinical Information Recall in Fatigued Clinicians

Objectives To evaluate the impact of modafinil on “free” and “cued” recall of clinical information in fatigued but nonsleep-deprived clinicians. Summary background data Despite attempts to minimize sleep deprivation through redesign of the roster of residents and staff surgeons, evidence suggests that fatigue remains prevalent. The wake-promoting agent modafinil improves cognition in the sleep-deprived fatigued state and may improve information recall in fatigued nonsleep-deprived clinicians. Methods Twenty-four medical undergraduates participated in a double-blind, parallel, randomized controlled trial (modafinil-200 mg:placebo). Medication was allocated 2 hours before a 90-minute fatigue–inducing, continuous performance task (dual 2-back task). A case history memorization task was then performed. Clinical information recall was assessed as “free”(no cognitive aids) and “cued”(using aid memoirs). Open and closed cues represent information of increasing specificity to aid the recall of clinical information. Fatigue was measured objectively using the psychomotor vigilance task at induction, before and after the dual 2-back task. Results Modafinil decreased false starts and lapses (modafinil = 0.50, placebo = 9.83, P Conclusion Modafinil attenuated fatigue and improved free recall of clinical information without improving cue-based recall under the design of our experimental conditions. Memory cues to aid retrieval of clinical information are convenient interventions that could decrease fatigue-related error without adverse effects of the neuropharmacology.

Treatment of the sleep disorders associated with Parkinson's disease.

Sleep disorders are common in patients with Parkinson's disease (PD), and preliminary work has suggested viable treatment options for many of these disorders. For rapid eye movement sleep behavior disorder, melatonin and clonazepam are most commonly used, while rivastigmine might be a useful option in patients whose behaviors are refractory to the former. Optimal treatments for insomnia in PD have yet to be determined, but preliminary evidence suggests that cognitive-behavioral therapy, light therapy, eszopiclone, donepezil, and melatonin might be beneficial. Use of the wake-promoting agent modafinil results in significant improvement in subjective measures of excessive daytime sleepiness, but not of fatigue. Optimal treatment of restless legs syndrome and obstructive sleep apnea in PD are not yet established, although a trial of continuous positive airway pressure for sleep apnea was recently completed in PD patients. In those patients with early morning motor dysfunction and disrupted sleep, the rotigotine patch provides significant benefit.

From an Atypical Wake‐promoting Agent to Potent Histamine‐3 Receptor Inverse Agonists

Utilizing atypical wake-promoting agent modafinil (inactive in both rH(3) and hH(3) binding assays) as a launching pad, a series of sulfinyl- and sulfone-derived H(3) receptor inverse agonists were developed. Brain-permeable compound 27, a potent member of the series displayed excellent selectivity against related family members (H(1), H(2), and H(4) receptors).

Aryl‐Heteroaryl Derivatives as Novel Wake‐Promoting Agents

In search of a next generation molecule to the novel wake-promoting agent modafinil, a series of aryl-heteroayl-derived wakefulness enhancing agents (in rats) was developed. From this work, compound 16 was separated into its enantiomers to profile them individually.

Wake-promoting agents: Search for next generation modafinil: Part IV

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of diphenyl ether derived wakefulness enhancing agents (in rat) was developed. From this work, racemic compound 16 was separated into its chiral enantiomers to profile them individually.

A pilot randomised controlled trial of modafinil during acute methamphetamine withdrawal: Feasibility, tolerability and clinical outcomes

There are no medications approved for the treatment of methamphetamine withdrawal. Wake-promoting agent modafinil has recently been proposed as a viable option. This paper reports on the results of a pilot study that tested the feasibility of modafinil in an inpatient withdrawal setting during acute methamphetamine withdrawal. In a double-blind, randomised, placebo-controlled study, 19 methamphetamine dependent participants received modafinil (n = 9) or placebo (n = 10) daily for 7 days (200 mg for the first 5 days and 100 mg on days 6 and 7). Primary outcomes were retention in treatment and severity of withdrawal symptoms. Secondary outcomes were methamphetamine craving, sleep and physiological outcomes. There were no significant differences between groups on retention in treatment, withdrawal severity, craving, sleep or physiological outcomes. There were no adverse events or side-effects reported. Modafinil was found to be tolerable and well accepted by methamphetamine users and feasible for short-term inpatient withdrawal, but the sample was too small to detect treatment effects. Larger trials are needed to establish efficacy.

Wake promoting agents: Search for next generation modafinil, lessons learned: Part III

In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).

Wake-promoting agents: Search for next generation modafinil: Part I

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.

Modafinil treatment prevents REM sleep deprivation-induced brain function impairment by increasing MMP-9 expression

Previous work showed that sleep deprivation (SD) impairs hippocampal-dependent cognitive function and synaptic plasticity, and a novel wake-promoting agent modafinil prevents SD-induced memory impairment in rat. However, the mechanisms by which modafinil prevented REM-SD-induced impairment of brain function remain poorly understood. In the present study, rats were sleep-deprived by using the modified multiple platform method and brain function was detected. The results showed that modafinil treatment prevented REM-SD-induced impairment of cognitive function. Modafinil significantly reduced the number of errors compared to placebo and upregulated synapsin I expression in the dorsal hippocampal CA3 region. A synaptic plasticity-related gene, MMP-9 expression was also upregulated in modafinil-treated rats. Importantly, downregulation of MMP-9 expression by special siRNA decreased synapsin I protein levels and synapse numbers. Therefore, we demonstrated that modafinil increased cognition function and synaptic plasticity, at least in part by increasing MMP-9 expression in REM-SD rats.

Tail-pinch stress and REM sleep deprivation differentially affect sensorimotor gating function in modafinil-treated rats

Prepulse inhibition (PPI) is a phenomenon in which a mild stimulus attenuates a cross-modality startle response to later intense stimulation. PPI is thought to index the central inhibitory mechanism through which behavioural responses are filtered. The present study compared the effects of two stress paradigms on the acoustic startle response (ASR) and on PPI in a rat model. The tail-pinch (TP) method produces an acute and immediate stressful condition, whereas rapid eye movement (REM) sleep deprivation (REMSD) leads to a more persistent and long-term stress. Our results demonstrated that in rats, TP stress reduced the size of the ASR, and REMSD impaired PPI. The wake-promoting agent modafinil (MOD) had no effect on PPI if given alone. However, MOD reduced the ASR and PPI under TP stress, whereas only PPI was reduced by MOD after 96h of REMSD. These results suggest that distinct stress paradigms differentially mediated sensorimotor gating abilities in terms of either responsiveness to the stimulus or information-filtering capabilities.

Wake-promoting agent modafinil worsened attentional performance following REM sleep deprivation in a young-adult rat model of 5-choice serial reaction time task

Individuals who experience sleep loss may exhibit certain physiological abnormalities. Central stimulant drugs have been studied in sleep-loss conditions, and some of them might be therapeutically beneficial. Modafinil (diphenyl-methyl-sulfinyl-2-acetamide, MOD) has been increasingly employed for elevating alertness and vigilance in recent years, yet the underlying mechanism of actions for MOD is not fully understood. To examine the behavioral effect of MOD following rapid eye movement sleep deprivation (REMD) in rats. A five-choice serial reaction time task (5-CSRTT) was employed to investigate animals' attentional performance and impulsive reactivity. Rats of different ages were trained to learn the 5-CSRTT. REMD with the water platform method was applied for 96h. The impacts of REMD on 5-CSRTT in middle-age (32-weeks-old) and young-adult (12-week-old) rats were compared with baseline or a condition with shorter visual stimulus duration. The results revealed that following REMD, young-adult but not middle-age rats were liable to be affected in their performances of the 5-CSRTT. In young-adult rats, while MOD had no contributions to the effect of REMD, it worsened rats' performance following REMD when the stimulus duration was shortened, as shown by the reduced number of correct responses and prolonged magazine latency. These results suggest that aging might be a crucial factor for the physiological impact following REMD. MOD should be used cautiously, particularly, in conditions that require REM sleep.

Psychostimulant-like discriminative stimulus and locomotor sensitization properties of the wake-promoting agent modafinil in rodents

The present studies assessed the potential abuse liability and likely mechanism(s) of action of the wake-promoting agent modafinil. Methods Experiments assessed the locomotor sensitization (LS) and discriminative stimulus (DS) properties of modafinil in mouse and rat, respectively. Comparative data were generated with a range of psychostimulants and monoamine reuptake inhibitors. Results Repeated administration of d-amphetamine and cocaine, psychostimulants with high abuse liability, resulted in the induction and expression of LS in mice. Bupropion and caffeine, two psychostimulants not abused in humans, were not associated with LS. GBR12909 induced LS during repeated exposure, but there was no evidence of expression of LS after acute challenge following withdrawal. In contrast, repeated administration of modafinil resulted in the expression, but not induction, of LS. d-amphetamine, but not the μ-opioid agonist morphine or the nAChR agonist nicotine, fully substituted for the cocaine DS in rats. The selective dopamine transporter (DAT) inhibitor GBR12909 fully substituted, the preferential norepinephrine transporter (NET) inhibitor desipramine partially substituted, and the selective serotonin reuptake inhibitor citalopram failed to substitute for cocaine. Modafinil fully substituted for cocaine, similar to the mixed DAT/NET inhibitor bupropion. Conclusions Two preclinical assays indicated potential abuse liability of modafinil; drug discrimination studies suggest DAT blockade by modafinil is a likely mechanism of action in vivo.

The effects of modafinil on mood and cognition in Huntington’s disease

The wake-promoting agent modafinil selectively improves neuropsychological task performance in healthy volunteers, in adults with attention deficit hyperactivity disorder (ADHD) and in schizophrenia. We examined whether modafinil induced similar effects in individuals with Huntington's disease (HD). Twenty patients with genetically proven, mild HD participated in a double-blind, randomised, placebo-controlled cross-over study using a single 200 mg dose of modafinil. Patients undertook a battery of neuropsychological tests including measures of cognition and mood. Modafinil increased alertness as indexed by visual analogue scales. Modafinil did not elicit any significant improvements in cognitive function or mood. Modafinil had a deleterious effect on visual recognition and working memory. Two hundred milligrams acute modafinil administration did improve alertness but did not improve cognition or mood in patients with mild HD. A multiple dose, chronic administration study is needed before the potential clinical utility of modafinil in HD is discounted.

Modafinil in the treatment of excessive sleepiness

The wake-promoting agent modafinil is approved for the treatment of excessive sleepiness associated with obstructive sleep apnea (OSA), shift work disorder (SWD), and narcolepsy. In OSA, modafinil is recommended for use as an adjunct to standard therapies that treat the underlying airway obstruction. This article reviews the literature on modafinil (pharmacology, pharmacokinetics, efficacy, tolerability, and abuse potential), with emphasis on use of modafinil in the treatment of excessive sleepiness in patients with OSA, SWD, and narcolepsy. In large-scale, double-blind, placebo-controlled studies, modafinil improved objectively determined sleep latency, improved overall clinical condition related to severity of sleepiness, and reduced patient-reported sleepiness. Improvements in wakefulness were accompanied by improvements in behavioral alertness, functional status, and health-related quality of life. In patients with SWD, diary data showed modafinil reduced the maximum level of sleepiness during night shift work, level of sleepiness during the commute home, and incidence of accidents or near-accidents during the commute home when compared with placebo. Modafinil was well tolerated, without adversely affecting cardiovascular parameters or scheduled sleep. These findings and those of extension studies which reported improvements were maintained suggest modafinil has a beneficial effect on daily life and well-being in patients with excessive sleepiness associated with OSA, SWD, or narcolepsy.

Modafinil for Treatment of Residual Excessive Sleepiness in Nasal Continuous Positive Airway Pressure-Treated Obstructive Sleep Apnea/Hypopnea Syndrome

Nasal continuous positive airway pressure (nCPAP) usually reduces sleepiness in patients with obstructive sleep apnea/hypopnea syndrome. However, even with regular use of nCPAP, some patients experience residual excessive sleepiness. We evaluated the efficacy and safety of the wake-promoting agent modafinil for treating residual excessive sleepiness in nCPAP-treated patients. 12-week, multicenter, randomized, double-blind, parallel-group, placebo-controlled trial. Patients aged 18 to 70 years diagnosed with obstructive sleep apnea/hypopnea syndrome and having residual excessive sleepiness during nCPAP therapy were eligible. Once-daily modafinil, 200 mg or 400 mg, or placebo. Assessments included the Maintenance of Wakefulness Test, Epworth Sleepiness Scale, Clinical Global Impression of Change, and Functional Outcomes of Sleep Questionnaire. Both doses of modafinil significantly improved mean (SD) sleep latency on the Maintenance of Wakefulness Test at weeks 4, 8, and 12 compared with placebo (week 12: modafinil 400 mg, 15.0 [5.3] minutes; 200 mg, 14.8 [5.3] minutes; placebo, 12.6 [5.8] minutes; P < .0001). The Epworth Sleepiness Scale score decreased more in patients taking modafinil compared with those in the placebo group (week 12: modafinil 400 mg, -4.5 [4.3]; 200 mg, -4.5 [4.7]; placebo, -1.8 [3.5]; P < .0001). At week 12, overall clinical condition improved for 61% and 68% of patients treated with modafinil 200 mg and 400 mg, respectively, versus 37% of placebo-treated patients (P < .001). Modafinil was generally well tolerated and did not adversely affect nighttime sleep or nCPAP use. These results confirm previous shorter-term controlled trials, indicating modafinil is a useful adjunct therapy for improving wakefulness in patients with residual excessive sleepiness associated with obstructive sleep apnea/hypopnea syndrome who were treated with nCPAP.

Fatigue in multiple sclerosis: A rational approach to evaluation and treatment

With the publication of the Multiple Sclerosis Council Guideline on the management of multiple sclerosis (MS) fatigue, there has been increased appreciation for the role fatigue can play in MS. Secondary fatigue is fatigue caused by other etiologies than those directly related to MS. Once these causes are ruled out, fatigue is related to MS. Secondary MS-related fatigue comes as result of the symptoms of MS that drain energy. Once secondary MS causes are ruled out, then the patient is deemed as having primary MS fatigue. Fatigue management is both nonpharmacologic and pharmacologic. Occupational therapists are the major allied health providers that address the role fatigue plays in MS patients. Over the past two decades, numerous clinical trials have been conducted on drugs for treating MS-related fatigue. Of these agents, amantadine has been studied for the longest period, and has shown efficacy in about one third of patients with MS-related fatigue on several commonly used scales. Two randomized -trials of the central nervous system stimulant pemoline have yielded unimpressive results; efficacy was seen at higher doses but coupled with an unacceptable risk of adverse events. The wake-promoting agent modafinil is the only agent to show efficacy compared with placebo on the Fatigue Severity Scale, a measure that is highly resistant to "impulse answering" and is thus viewed as one of the most difficult scales on which to show -benefit. This article reviews fatigue in MS and proposes a rational strategy for evaluation and management of this most common MS symptom.