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International Journal of Stroke :... Oct 2023
Topics: Humans; Stroke; Fatigue; Quality of Life
PubMed: 37898830
DOI: 10.1177/17474930231207695 -
European Neuropsychopharmacology : the... Jan 2024Growing evidence suggests an association between inflammatory processes and depressive disorders (DD). DD typically emerge during adolescence. Treatment effects of... (Meta-Analysis)
Meta-Analysis Review
Growing evidence suggests an association between inflammatory processes and depressive disorders (DD). DD typically emerge during adolescence. Treatment effects of agents with anti-inflammatory properties in youth DD have not been systematically reviewed. Here, the existing evidence on the use of anti-inflammatory drugs (including polyunsaturated fatty acids, nonsteroidal anti-inflammatory drugs, cytokine inhibitors, statins, pioglitazone, corticosteroids, and minocycline or modafinil) in children and adolescents with DD was synthesized using meta-analysis. The PROSPERO preregistered search yielded 22 records meeting search criteria. Of these, data from 19 primary studies (n = 1366 subjects) were subjected to meta-analysis. A significant but small effect in favor of anti-inflammatory agents in reducing depressive symptoms in youth with DD was found (SMD = -0.29, 95 % CI = -0.514; -0.063, p = 0.01). Post-hoc analyzes of drug subclasses found a significant effect of omega-3 fatty acids in reducing depressive symptoms. Results underline the importance to consider inflammatory pathways in the supplemental treatment of youth with DD. Further research is warranted, to clarify if anti-inflammatory agents are only effective in a subpopulation of patients (inflammatory biotype of depression in youth) and/or to alleviate specific symptom domains of depression (e.g., cognitive symptoms).
Topics: Child; Humans; Adolescent; Depression; Anti-Inflammatory Agents; Minocycline; Pioglitazone; Fatty Acids, Omega-3
PubMed: 37864981
DOI: 10.1016/j.euroneuro.2023.09.006 -
ACS Pharmacology & Translational Science Oct 2023Chronic stressful situations result in altered monoaminergic activity of neurotransmitters, resulting in various conditions characterized by deficits in learning, memory...
PURPOSE
Chronic stressful situations result in altered monoaminergic activity of neurotransmitters, resulting in various conditions characterized by deficits in learning, memory and attention. Stimulant effects can be visualized in terms of increased cognitive abilities through enhancement of dopamine (DA) release.
METHOD
This study examined cognitive responses and brain DA and 5-hydroxytryptamine (5HT) levels after prolonged methylphenidate (MPH) and modafinil administration, to demonstrate their effect on stress-induced cognitive deficits in rats. Effects on cognition were evaluated by passive avoidance and water maze tests. Furthermore brain levels of DA, homovanillic acid (HVA), dihydroxyphenylacetic acid (DOPAC), 5HT and 5-hydroxyindoleacetic acid (5HIAA) were analyzed by high-performance liquid chromatography coupled with electrochemical detection.
RESULTS
We found that both MPH and modafinil improved cognition in both restrained and unrestrained rats, as examined through water maze and passive avoidance tests. Furthermore, these substance were associated with increased brain DA and 5-HT levels. Notabily, we observed decrease in DOPAC and HVA levels, while 5-HIAA levels exhibited a slight increase.
CONCLUSIONS
The prevention of stress-induced cognitive deficits by MPH and modafinil could be elucidated through the interaction between 5HT and DA in regulating cognitive function.
PubMed: 37854618
DOI: 10.1021/acsptsci.3c00077 -
Analytical Methods : Advancing Methods... Nov 2023Modafinil (MOD) is a CNS stimulant used for the treatment of narcolepsy, shift work sleep disorder, excessive daytime sleepiness, and post-COVID 19 neurological...
Modafinil (MOD) is a CNS stimulant used for the treatment of narcolepsy, shift work sleep disorder, excessive daytime sleepiness, and post-COVID 19 neurological symptoms. In the literature, there is no report of square wave voltammetric (SWV) methods being used for the determination of MOD. This study describes, for the first time, the construction and evaluation of the analytical performance of a novel sensor for ultrasensitive SWV detection of MOD. The sensor was constructed by integration of silver nanoparticles (Ag) on Mesna (MSN) layers over a pencil graphite electrode (PGE) surface. The interface and morphological characteristics of the fabricated Ag@MSN/PGE sensor were investigated cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and scanning electron microscopy (SEM). This sensor was found to enhance the electro-oxidation of MOD. The combination of Ag@MSN/PGE with SWV enabled the determination of MOD in its bulk form and in pharmaceutical and biological matrices at the nanomolar scale (LOD = 28.59 nM) with excellent recoveries. This study represents the first report describing an electrochemical procedure for MOD detection in human plasma. The established SWV method was also validated, and the results were consistent with ICH criteria. Finally, the presented SWV procedure provides a facile, sensitive, rapid, and cost-effective approach compared to other existing methods.
Topics: Humans; Metal Nanoparticles; Modafinil; Mesna; Silver; Electrochemical Techniques; Graphite
PubMed: 37847517
DOI: 10.1039/d3ay01401k -
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 -
Neurocritical Care Jun 2024The limited representation from developing countries in the original COME TOGETHER survey gave us an impetus to conduct this survey in the Indian subcontinent.
BACKGROUND
The limited representation from developing countries in the original COME TOGETHER survey gave us an impetus to conduct this survey in the Indian subcontinent.
METHODS
This cross-sectional online survey was conducted from August through September 2022. Participants were health care physicians caring for patients with coma and disorders of consciousness. Fischer's exact test or the Mann-Whitney U-test was used to compare respondents who agreed or disagreed with the preestablished coma definition. Fleiss κ values were calculated to assess agreement among respondents. A p value less than 0.05 was considered statistically significant.
RESULTS
The survey was completed by 130 physicians. We found substantial interrater agreement on absence of wakefulness (71.54%; κ = 0.71), Glasgow Coma Score ≤ 8 (78.46%; κ = 0.78), and failure to respond purposefully to visual, verbal, or tactile stimuli (66.15%; κ = 0.66). Reported common etiologies of coma included traumatic brain injury (50.76%), ischemic stroke (30%), and intracerebral hemorrhage (29.23%). The most common clinical assessment tools used for coma included the Glasgow Coma Score (92.3%) and neurological examination (60.8%). Neurological examination was the most common diagnostic tool used (100%), followed by magnetic resonance imaging (89.2%), basic laboratory studies (88.5%), and head computed tomography/angiography (86.9%). Pharmacological interventions used to stimulate arousal in patients with coma were sedation vacation (91.5%), electrolyte/endocrine correction (65.4%), osmotic therapy with mannitol (60%), hypertonic saline (54.6%), modafinil (46.9%), and antidote for drugs (45.4%). Among the nonpharmacological interventions, sensory stimulation (57.7%) was the most commonly used modality. The most common discharge disposition for comatose patients who survived hospitalization were home with or without services (70.0%).
CONCLUSIONS
Differences from the global survey were noted regarding the following: traumatic brain injury being the most common etiology of coma in India, more frequent practice of sedation interruption, less frequent use of electroencephalography in India, rare use of pharmacological neurostimulants, and home being the most common discharge disposition in India.
Topics: Humans; India; Coma; Cross-Sectional Studies; Glasgow Coma Scale; Adult; Male; Female; Brain Injuries, Traumatic; Surveys and Questionnaires; Middle Aged; Cerebral Hemorrhage; Stroke
PubMed: 37821721
DOI: 10.1007/s12028-023-01852-9 -
PloS One 2023Methamphetamine use and related harms have risen at alarming rates. While several psychosocial and pharmacologic interventions have been described in the literature,... (Review)
Review
RATIONALE
Methamphetamine use and related harms have risen at alarming rates. While several psychosocial and pharmacologic interventions have been described in the literature, there is uncertainty regarding the best approach for the management of methamphetamine use disorder (MUD) and problematic methamphetamine use (PMU). We conducted a scoping review of recent systematic reviews (SR), clinical practice guidelines (CPG), and primary controlled studies of psychosocial and pharmacologic treatments for MUD/PMU.
METHODS
Guided by an a priori protocol, electronic database search updates (e.g., MEDLINE, Embase) were performed in February 2022. Screening was performed following a two-stage process, leveraging artificial intelligence to increase efficiency of title and abstract screening. Studies involving individuals who use methamphetamine, including key subgroups (e.g. those with mental health comorbidities; adolescents/youths; gay, bisexual, and other men who have sex with men) were sought. We examined evidence related to methamphetamine use, relapse, use of other substances, risk behaviors, mental health, harms, and retention. Figures, tables and descriptive synthesis were used to present findings from the identified literature.
RESULTS
We identified 2 SRs, one CPG, and 54 primary studies reported in 69 publications that met our eligibility criteria. Amongst SRs, one concluded that psychostimulants had no effect on methamphetamine abstinence or treatment retention while the other reported no effect of topiramate on cravings. The CPG strongly recommended psychosocial interventions as well as self-help and family support groups for post-acute management of methamphetamine-related disorders. Amongst primary studies, many interventions were assessed by only single studies; contingency management was the therapy most commonly associated with evidence of potential effectiveness, while bupropion and modafinil were analogously the most common pharmacologic interventions. Nearly all interventions showed signs of potential benefit on at least one methamphetamine-related outcome measure.
DISCUSSION
This scoping review provides an overview of available interventions for the treatment of MUD/PMU. As most interventions were reported by a single study, the effectiveness of available interventions remains uncertain. Primary studies with longer durations of treatment and follow-up, larger sample sizes, and of special populations are required for conclusive recommendations of best approaches for the treatment of MUD/PMU.
Topics: Male; Adolescent; Humans; Methamphetamine; Homosexuality, Male; Sexual and Gender Minorities; Artificial Intelligence; Central Nervous System Stimulants
PubMed: 37819931
DOI: 10.1371/journal.pone.0292745 -
Archivos de Bronconeumologia Dec 2023Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness...
INTRODUCTION
Obstructive sleep apnea (OSA) is a chronic condition characterized by intermittent hypoxia (IH) and sleep fragmentation (SF). OSA can induce excessive daytime sleepiness (EDS) and is associated with impaired cognition and anxiety. Solriamfetol (SOL) and modafinil (MOD) are widely used wake-promoting agents in OSA patients with EDS.
METHODS
Male C57Bl/6J mice were exposed to SF along with sleep controls (SC) or to IH and room air (RA) controls during the light (inactive) phase for 4 and 16 weeks, respectively. Both IH and SF exposures were then discontinued to mimic "ideal" continuous positive airway pressure (CPAP) adherence. All groups were then randomly assigned to receive once daily intraperitoneal injections of SOL, MOD, or vehicle (VEH) for 6 days. Sleep/wake activity was assessed along with tests of explicit memory, anxiety and depression were performed before and after treatments.
RESULTS
IH and SF exposures increased sleep percentage in the dark phase and reduced wake bouts lengths (i.e., EDS), and induced cognitive deficits and impulsivity in mice. Both SOL and MOD treatments effectively mitigated EDS when combined with recovery, while recovery alone did not improve EDS over the 6-day period. Furthermore, improvements explicit memory emerged only after SOL.
CONCLUSION
Chronic IH and SF induce EDS in young adult mice that is not ameliorated by recovery except when combined with either SOL or MOD. SOL, but not MOD, significantly improves IH-induced cognitive deficits. Thus, SOL emerges as a viable adjuvant medication for residual EDS in OSA along with its positive impact on cognition.
Topics: Humans; Male; Animals; Mice; Wakefulness; Wakefulness-Promoting Agents; Continuous Positive Airway Pressure; Disease Models, Animal; Sleep Apnea, Obstructive; Modafinil; Disorders of Excessive Somnolence; Hypoxia; Cognition
PubMed: 37783638
DOI: 10.1016/j.arbres.2023.09.007 -
Biomolecules Sep 2023The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal...
The high structural similarity, especially in transmembrane regions, of dopamine, norepinephrine, and serotonin transporters, as well as the lack of all crystal structures of human isoforms, make the specific targeting of individual transporters rather challenging. Ligand design itself is also rather limited, as many chemists, fully aware of the synthetic and analytical challenges, tend to modify lead compounds in a way that reduces the number of chiral centers and hence limits the potential chemical space of synthetic ligands. We have previously shown that increasing molecular complexity by introducing additional chiral centers ultimately leads to more selective and potent dopamine reuptake inhibitors. Herein, we significantly extend our structure-activity relationship of dopamine transporter-selective ligands and further demonstrate how stereoisomers of defined absolute configuration may fine-tune and direct the activity towards distinct targets. From the pool of active compounds, using the examples of stereoisomers and , we further showcase how in vitro activity significantly differs in in vivo drug efficacy experiments, calling for proper validation of individual stereoisomers in animal studies. Furthermore, by generating a large library of compounds with defined absolute configurations, we lay the groundwork for computational chemists to further optimize and rationally design specific monoamine transporter reuptake inhibitors.
Topics: Animals; Humans; Norepinephrine Plasma Membrane Transport Proteins; Serotonin Plasma Membrane Transport Proteins; Biological Transport; Structure-Activity Relationship; Norepinephrine; Ligands
PubMed: 37759815
DOI: 10.3390/biom13091415 -
Frontiers in Psychiatry 2023Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During...
INTRODUCTION
Despite advances in the treatment of bipolar disorder (BD), most patients do not achieve complete inter-episode recovery and functional disability is common. During periods of relative remission, many patients continue to experience neurocognitive dysfunction, reduced daytime activity levels, and sleep disturbances. This 8-week, randomized, placebo-controlled pilot study evaluated the feasibility, safety and preliminary efficacy of the wake-promoting drug, modafinil (Provigil), on neurocognitive functioning, daytime sleepiness, and sleep quality in affectively-stable BD patients.
METHODS
Twelve individuals with affectively-stable BD were recruited and randomized to a flexible dose of modafinil (100 to 200 mg/day) or placebo, adjunctive to a therapeutic dose of a mood stabilizer. Weekly in-person visits tracked sleep quality and daytime sleepiness as well as side effects and mood symptoms. Neurocognitive functioning was assessed at baseline, week 4, and week 8.
RESULTS
No serious adverse events were reported. Newly emergent side effects in the modafinil group included heart palpitations, itching, fatigue, and decreased energy. Two patients discontinued modafinil owing to side effects and one of these patients withdrew from the study. One patient discontinued placebo and was withdrawn from the study. Preliminary evaluations of clinical efficacy showed a marginally significant interaction between treatment group and time in two cognitive domains (speed of processing and verbal learning), indicating greater improvement in the modafinil group versus placebo. Additionally, there was a marginally significant effect of treatment group on daytime sleepiness, suggesting lower daytime sleepiness in the modafinil group versus placebo. Counterintuitively, we found a significant treatment group by time interaction effect on sleep quality, suggesting greater improvement in sleep quality in the placebo group versus the modafinil group.
DISCUSSION
Results suggest that modafinil is a relatively safe medication for affectively-stable BD patients when given with adjunctive mood stabilizers. Results are suggestive of cognitive benefit and improved daytime sleepiness, but worse sleep quality in those patients prescribed modafinil. A fully powered clinical trial is warranted with specific attention to the characteristics of patients who are most likely to benefit from treatment with modafinil and other methodological lessons learned from this pilot.
CLINICAL TRIAL REGISTRATION
ClinicalTrials.gov, identifier NCT01965925.
PubMed: 37732080
DOI: 10.3389/fpsyt.2023.1246149