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Biomedicine & Pharmacotherapy =... Dec 2021Small- and intermediate-conductance Ca-activated K channels, K2.3 and K3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. K2.3...
Small- and intermediate-conductance Ca-activated K channels, K2.3 and K3.1, are involved in cellular signaling processes associated with inflammation and fibrosis. K2.3 and K3.1 are upregulated by proinflammatory cytokines and profibrotic growth factors. Cyclic AMP, which downregulates K2.3 and K3.1, is elevated by modafinil in cells; accordingly, we investigated whether modafinil exerts anti-inflammatory and anti-fibrotic responses via K2.3- and K3.1-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. K2.3 and K3.1 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 K2.3, K3.1, collagen, and α-smooth muscle actin and downregulation of catalase were reversed by modafinil, polyethylene glycol catalase, N-acetylcysteine, siRNA against K2.3 or K3.1, and Epac inhibitors. Our investigation revealed that modafinil attenuated inflammatory and fibrotic progression via K2.3- and K3.1-mediated pathways in nonalcoholic hepatitis, suggesting that inhibiting K2.3- and K3.1-mediated signaling may serve as a novel therapeutic approach for inflammatory and fibrotic liver diseases.
Topics: Actins; Animals; Anti-Inflammatory Agents, Non-Steroidal; Cell Line; Collagen; Diet, High-Fat; Fatty Liver; Hepatic Stellate Cells; Humans; Intermediate-Conductance Calcium-Activated Potassium Channels; Liver Cirrhosis; Male; Mice; Mice, Inbred C57BL; Modafinil; Non-alcoholic Fatty Liver Disease; Small-Conductance Calcium-Activated Potassium Channels; Stereoisomerism; Thioacetamide
PubMed: 34794237
DOI: 10.1016/j.biopha.2021.112372 -
Current Opinion in Pharmacology Feb 2021Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication... (Review)
Review
Pharmacotherapeutics for treatment of psychostimulant use disorder are still an unmet medical goal. Recently, off label use of modafinil (MOD), an approved medication for treatment of sleep disturbances, has been tested as a therapeutic for cocaine and methamphetamine use disorder. Positive results have been found in subjects dependent on psychostimulants without concurrent abuse of other substances. Novel structural analogs of MOD have been synthesized in the search for compounds with potentially broader therapeutic efficacy than the parent drug. In the present report we review their potential efficacy as treatments for psychostimulant abuse and dependence assessed in preclinical tests. Results from these preclinical proof of concept studies reveal that some modafinil analogs do not possess typical cocaine-like neurochemical and behavioral effects. Further, they might blunt the reinforcing effects of psychostimulants in animal models, suggesting their potential efficacy as pharmacotherapeutics for treatment of psychostimulant use disorders.
Topics: Animals; Benzhydryl Compounds; Central Nervous System Stimulants; Cocaine; Dopamine Uptake Inhibitors; Humans; Modafinil
PubMed: 32927246
DOI: 10.1016/j.coph.2020.07.007 -
Journal of Palliative Medicine Dec 2012
Topics: Benzhydryl Compounds; Central Nervous System Stimulants; Disorders of Excessive Somnolence; Humans; Modafinil; Palliative Care
PubMed: 23206152
DOI: 10.1089/jpm.2012.9542 -
Sleep Dec 2007The purpose of this paper is to summarize current knowledge about treatment of narcolepsy and other hypersomnias of central origin. (Review)
Review
OBJECTIVE
The purpose of this paper is to summarize current knowledge about treatment of narcolepsy and other hypersomnias of central origin.
METHODS
The task force performed a systematic and comprehensive review of the relevant literature and graded the evidence using the Oxford grading system. This paper discusses the strengths and limitations of the available evidence regarding treatment of these conditions, and summarizes key information about safety of these medications. Our findings provide the foundation for development of evidence-based practice parameters on this topic by the Standards of Practice Committee of the American Academy of Sleep Medicine.
RESULTS
The majority of recent papers in this field provide information about use of modafinil or sodium oxybate for treatment of sleepiness associated with narcolepsy. Several large randomized, placebo-controlled studies indicate that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy. We identified no studies that report direct comparison of these newer medications versus traditional stimulants, or that indicate what proportion of patients treated initially with these medications require transition to traditional stimulants or to combination therapy to achieve adequate alertness. As with the traditional stimulants, modafinil and sodium oxybate provide, at best, only moderate improvement in alertness rather than full restoration of alertness in patients with narcolepsy. Several large randomized placebo-controlled studies demonstrate that sodium oxybate is effective for treatment of cataplexy associated with narcolepsy, and earlier studies provide limited data to support the effectiveness of fluoxetine and tricyclic antidepressants for treatment of cataplexy. Our findings indicate that very few reports provide information regarding treatment of special populations such as children, older adults, and pregnant or breastfeeding women. The available literature provides a modest amount of information about improvement in quality of life in association with treatment, patient preferences among the different medications, or patient compliance.
CONCLUSION
Several recent studies provide evidence that modafinil and sodium oxybate are effective for treatment of hypersomnia due to narcolepsy. No studies were identified that report direct comparison of these newer medications with traditional stimulants. Despite significant advances in understanding the pathophysiology of narcolepsy, we do not have an ideal treatment to restore full and sustained alertness. Future investigations should be directed toward development of more effective and better tolerated therapies, and primary prevention.
Topics: Antidepressive Agents, Tricyclic; Benzhydryl Compounds; Cataplexy; Central Nervous System Stimulants; Disorders of Excessive Somnolence; Evidence-Based Medicine; Fluoxetine; Humans; Modafinil; Narcolepsy; Randomized Controlled Trials as Topic; Sodium Oxybate
PubMed: 18246981
DOI: 10.1093/sleep/30.12.1712 -
Turk Kardiyoloji Dernegi Arsivi : Turk... Jan 2022Modafinil is a central nervous system stimulant that promotes wakefulness and is approved for the treatment of narcolepsy and several other conditions. However, there is...
Modafinil is a central nervous system stimulant that promotes wakefulness and is approved for the treatment of narcolepsy and several other conditions. However, there is a big concern about drug abuse, especially among students to enhance cognitive performance and to reduce the need for sleep. In this case report, we present a 23-year-old female admitted to the cardiology outpatient clinic owing to recurrent palpitations. She stated that she started modafinil 100 mg twice a day one month earlier to increase performance while studying for her exams. Her electrocardiogram (ECG) demonstrated sinus rhythm and a right bundle branch block (RBBB). No structural heart disease or metabolic pathology was detected. A 24-hour ambulatory ECG record showed 11 attacks of non-sustained ventricular tachycardia (NSVT), the longest of which was eight beats. The drug was discontinued and two weeks later, the patient was symptom-free, and her control ECG showed normal sinus rhythm with no RBBB. A control ambulatory ECG was performed, and no ventricular tachycardia was observed. Modafinil, which is considered safer than amphetamine derivatives in terms of cardiovascular side effects, rarely causes serious arrhythmic events, even in healthy subjects. Thus, we suggest evaluating patients for cardiac symptoms after starting on modafinil, and they should be also interrogated regarding the abuse of this drug.
Topics: Adult; Arrhythmias, Cardiac; Bundle-Branch Block; Electrocardiography; Female; Humans; Modafinil; Tachycardia, Ventricular; Young Adult
PubMed: 35197237
DOI: 10.5543/tkda.2022.21084 -
Journal of Psychopharmacology (Oxford,... Feb 2023Fatigue remains an important factor in major aviation accidents. Stimulants may counteract fatigue's adverse effects, with modafinil as a promising alternative to... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Fatigue remains an important factor in major aviation accidents. Stimulants may counteract fatigue's adverse effects, with modafinil as a promising alternative to caffeine. However, the effect of a single dose of modafinil after a limited period of sleep deprivation remains unknown.
AIMS
This study aims to determine the effect of 200 mg modafinil on vigilance during a limited period of sleep deprivation compared to 300 mg caffeine and placebo.
METHODS
Thirty-two volunteers of the Royal Netherlands Air Force (RNLAF) were double-blindly administered modafinil, caffeine, and placebo on three non-consecutive trial days after being awake for median 17 h. Afterwards, subjects completed six series of the Vigilance and Tracking test (VigTrack), psychomotor vigilance task (PVT), and Stanford Sleepiness Scale (SSS), yielding six primary endpoints.
RESULTS
This study revealed statistically significant effects of caffeine and modafinil compared with placebo on all endpoints, except for VigTrack mean tracking error. PVT results were less impaired 2 h after administration, followed by VigTrack parameters and SSS scores 2 h thereafter. Compared with caffeine, modafinil significantly improved PVT and SSS scores at 8 h after administration.
CONCLUSIONS
The present study demonstrates that 200 mg modafinil and 300 mg caffeine significantly decrease the effects of a limited period of sleep deprivation on vigilance compared with placebo. Although PVT parameters already improved 2 h after administration, the most notable effects occurred 2-4 h later. Modafinil seems to be effective longer than caffeine, which is consistent with its longer half-life.
Topics: Humans; Modafinil; Caffeine; Wakefulness; Sleep Deprivation; Benzhydryl Compounds; Psychomotor Performance; Central Nervous System Stimulants; Fatigue; Sleepiness; Double-Blind Method
PubMed: 36515156
DOI: 10.1177/02698811221142568 -
The Cochrane Database of Systematic... Sep 2022Fatigue is a common and disabling symptom in people with a primary brain tumour (PBT). The effectiveness of interventions for treating clinically significant levels of... (Review)
Review
BACKGROUND
Fatigue is a common and disabling symptom in people with a primary brain tumour (PBT). The effectiveness of interventions for treating clinically significant levels of fatigue in this population is unclear. This is an updated version of the original Cochrane Review published in Issue 4, 2016.
OBJECTIVES
To assess the effectiveness and safety of pharmacological and non-pharmacological interventions for adults with PBT and clinically significant (or high levels) of fatigue.
SEARCH METHODS
For this updated review, we searched CENTRAL, MEDLINE and Embase, and checked the reference lists of included studies in April 2022. We also searched relevant conference proceedings, and ClinicalTrials.gov for ongoing trials.
SELECTION CRITERIA
We included randomised controlled trials (RCTs) that investigated any pharmacological or non-pharmacological intervention in adults with PBT and fatigue, where fatigue was the primary outcome measure. We restricted inclusion specifically to studies that enrolled only participants with clinically significant levels of fatigue to improve the clinical utility of the findings.
DATA COLLECTION AND ANALYSIS
Two review authors (JD, DC) independently evaluated search results for the updated search. Two review authors (JD, SYK) extracted data from selected studies, and carried out a risk of bias assessment. We extracted data on fatigue, mood, cognition, quality of life and adverse events outcomes.
MAIN RESULTS
The original review identified one study and this update identified a further two for inclusion. One study investigated the use of modafinil, one study the use of armodafinil and one study the use of dexamfetamine. We identified three ongoing studies. In the original review, the single eligible trial compared modafinil to placebo for 37 participants with a high- or low-grade PBT. One new study compared two doses of armodafinil (150 mg and 250 mg) to placebo for 297 people with a high-grade glioma. The second new study compared dexamfetamine sulfate to placebo for 46 participants with a low- or high-grade PBT. The evidence was uncertain for both modafinil and dexamfetamine regarding fatigue outcome measures, compared to controls, at study endpoint. Two trials did not reach the planned recruitment target and therefore may not, in practice, have been adequately powered to detect a difference. These trials were at a low risk of bias across most areas. There was an unclear risk of bias related to the use of mean imputation for one study because the investigators did not analyse the impact of imputation on the results and information regarding baseline characteristics and randomisation were not clear. The certainty of the evidence measured using GRADE was very low across all three studies. There was one identified study awaiting classification once data are available, which investigated the feasibility of 'health coaching' for people with a PBT experiencing fatigue. There were three ongoing studies that may be eligible for an update of this review, all investigating a non-pharmacological intervention for fatigue in people with PBT.
AUTHORS' CONCLUSIONS
There is currently insufficient evidence to draw reliable and generalisable conclusions regarding potential effectiveness or harm of any pharmacological or non-pharmacological treatments for fatigue in people with PBT. More research is needed on how best to treat people with brain tumours with high fatigue.
Topics: Adult; Brain Neoplasms; Dextroamphetamine; Fatigue; Glioma; Humans; Modafinil
PubMed: 36094728
DOI: 10.1002/14651858.CD011376.pub3 -
Sleep Medicine Dec 2023Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and...
STUDY OBJECTIVES
Modafinil is a common treatment for excessive daytime sleepiness (EDS) in narcolepsy. The long-term use of modafinil can lead to tolerance with the loss of efficacy and the continuous increase of its dose. Pharmacological strategies to deal with the tolerance to modafinil are lacking. We investigated the efficacy and safety of pitolisant-supported bridging during drug holidays in patients with tolerance to modafinil.
METHODS
Narcolepsy patients on monotherapy with modafinil who developed symptoms of tolerance were eligible. The following alternating therapy regimen was established: Monday to Friday patients continued on modafinil whereas Saturday and Sunday they switched to pitolisant to "bridge" the EDS symptoms. Patients were assessed at baseline and after three months with the Epworth Sleepiness Scale (ESS) and the Ullanlinna Narcolepsy Scale (UNS). Health-related quality of life (HrQol) was evaluated by EuroQol5D. Adverse events were documented in the patients' diaries.
RESULTS
41 patients aged 30.9 ± 5.6 years were included. After three months of the alternating therapy regimen, the symptoms of tolerance decreased and the modafinil dose could be reduced by 41% (p < 0.01) resulting in better safety. The EDS improved on ESS (baseline: 18.2 ± 4.2, follow-up: 12.6 ± 4.0, p < 0.0001) and UNS (baseline: 25.8 ± 7.9, follow-up: 18.9 ± 5.9, p < 0.0001). The HrQol increased significantly.
CONCLUSION
Patients with tolerance to modafinil could benefit from pitolisant-supported bridging during drug holidays. This alternating pharmacological strategy proved to be safe and helped to reduce EDS and to decrease the modafinil dose. Further randomized controlled studies are required to evaluate the different strategies to deal with the tolerance to modafinil.
CLINICAL TRIAL REGISTRATION NUMBER
Clinical Trials.gov Identifier NCT05321355.
Topics: Humans; Modafinil; Quality of Life; Narcolepsy; Piperidines; Disorders of Excessive Somnolence; Benzhydryl Compounds
PubMed: 37839272
DOI: 10.1016/j.sleep.2023.10.005 -
American Journal of Neurodegenerative... 2021Various articles show the high prevalence of sleep disorders and especially excessive daytime sleepiness (EDS) in patients with refractory epilepsy and the importance of...
Evaluation of the effectiveness of methylphenidate and modafinil in the treatment of daily drowsiness in patients with refractory epilepsy and their comparison with the control group.
BACKGROUND
Various articles show the high prevalence of sleep disorders and especially excessive daytime sleepiness (EDS) in patients with refractory epilepsy and the importance of personal and social burden of this complication on individuals. Considering the insufficient evidence to draw efficacy and safety of modafinil and methylphenidate to treat EDS in the patient with intractable seizures, we decided to compare the effect of methylphenidate and modafinil with the control group. It is hoped that this study will pave the way for further studies.
METHODS
This study is a clinical trial (IRCT20171030037093N22) (URL: https://www.irct.ir/trial/42485). The study population was patients with refractory epilepsy referred to the neurology clinic of Al-Zahra Hospital, Isfahan, Iran, from 2019 to 2020. The patients were randomly divided into three groups. The first group was treated with methylphenidate, the second group was treated with modafinil, and the third group was not received any medication such as modafinil and methylphenidate. Methylphenidate dosage was 10-20 mg/day. The patients were treated with modafinil at a dose of 200-600 mg/day. EPWORTH sleepiness scale (ESS) and Total Sleep Time (TST) were calculated before and 8 weeks after the intervention for the patients.
RESULTS
47 patients were included and divided into 3 groups, methylphenidate (10 males and 9 females), modafinil (7 males and 13 females), and control (4 males and 4 females). There was no significant difference among the groups based on ESS before and after intervention and TST after the intervention (P>0.05), but the mean of TST was significantly lower in the control group than in methylphenidate and modafinil groups before the intervention (P=0.003). The change of ESS and TST before compared to after intervention in the methylphenidate and modafinil group were significant (P<0.001), but the changes of ESS and TST in the control group were not significant (P>0.05). The frequency of complications (P=0.74) and outcomes (P=0.07) were similar in both groups.
CONCLUSION
Modafinil and methylphenidate are two effective and safe drugs to increase the quality of sleep in the patients. Additionally, ESS and TST scores are better in the patients who used modafinil and methylphenidate.
PubMed: 34824900
DOI: No ID Found -
Sleep Medicine Reviews Feb 2019Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons.... (Review)
Review
Excessive daytime sleepiness (EDS) and cataplexy are common symptoms of narcolepsy, a sleep disorder associated with the loss of hypocretin/orexin (Hcrt) neurons. Although only a few drugs have received regulatory approval for narcolepsy to date, treatment involves diverse medications that affect multiple biochemical targets and neural circuits. Clinical trials have demonstrated efficacy for the following classes of drugs as narcolepsy treatments: alerting medications (amphetamine, methylphenidate, modafinil/armodafinil, solriamfetol [JZP-110]), antidepressants (tricyclic antidepressants, selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors), sodium oxybate, and the H-receptor inverse agonist/antagonist pitolisant. Enhanced catecholamine availability and regulation of locus coeruleus (LC) norepinephrine (NE) neuron activity is likely central to the therapeutic activity of most of these compounds. LC NE neurons are integral to sleep/wake regulation and muscle tone; reduced excitatory input to the LC due to compromise of Hcrt/orexin neurons (likely due to autoimmune factors) results in LC NE dysregulation and contributes to narcolepsy/cataplexy symptoms. Agents that increase catecholamines and/or LC activity may mitigate EDS and cataplexy by elevating NE regulation of GABAergic inputs from the amygdala. Consequently, novel medications and treatment strategies aimed at preserving and/or modulating Hcrt/orexin-LC circuit integrity are warranted in narcolepsy/cataplexy.
Topics: Adjuvants, Anesthesia; Antidepressive Agents; Antidepressive Agents, Tricyclic; Cataplexy; Central Nervous System Stimulants; Drug Therapy; Humans; Immunogenetics; Intracellular Signaling Peptides and Proteins; Modafinil; Narcolepsy; Neurobiology; Sodium Oxybate
PubMed: 30503715
DOI: 10.1016/j.smrv.2018.09.006