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Drug Development Research Jun 2024Hepatic ischemia/reperfusion injury (IRI) remains a severe threat during liver surgery and transplantation, accounting for unfavorable clinical outcomes. Modafinil...
Hepatic ischemia/reperfusion injury (IRI) remains a severe threat during liver surgery and transplantation, accounting for unfavorable clinical outcomes. Modafinil (MOD), a wakefulness-inducing compound, is increasingly disclosed to protect against IRI. However, the specific literatures covering the association between MOD and hepatic IRI are few. Here, this paper is committed to unraveling the role and response mechanism of MOD in hepatic IRI. After the establishment of hepatic IRI mice model and cell model, relevant assay kits measured the concentrations of biochemical indicators of hepatotoxicity and hematoxylin and eosin staining estimated liver morphology. Enzyme-linked immunosorbent assay, reverse-transcription quantitative polymerase chain reaction, and western blot evaluated inflammatory levels. Terminal-deoxynucleoitidyl transferase-mediated nick end labeling assay and western blot appraised apoptosis. Western blot also analyzed the expression of Toll-like receptor 9 (TLR9)/myeloid differentiation primary response gene 88 (MyD88)/p38 signaling-associated proteins. Cell counting kit-8 method judged cell viability. MOD was discovered to mitigate liver dysfunction and morphological damage, inflammatory response, apoptosis in vivo and improve cell viability, suppress inflammatory response and apoptosis in vitro. In addition, MOD inactivated TLR9/Myd88/p38 signaling both in vitro and in vivo. Further, TLR9 elevation reversed the inhibitory role of MOD in inflammatory response and cell apoptosis in vitro. Anyway, MOD blocked TLR9/Myd88/p38 signaling to exhibit anti-inflammatory and anti-apoptotic properties in hepatic IRI.
Topics: Animals; Reperfusion Injury; Toll-Like Receptor 9; Myeloid Differentiation Factor 88; Apoptosis; Mice; Male; Liver; Signal Transduction; Mice, Inbred C57BL; p38 Mitogen-Activated Protein Kinases; Inflammation; Benzhydryl Compounds
PubMed: 38812444
DOI: 10.1002/ddr.22210 -
ACS Chemical Neuroscience Aug 2023Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many...
Understanding the neurochemistry underlying sex differences in psychostimulant use disorders (PSUD) is essential for developing related therapeutics. Many psychostimulants, like cocaine, inhibit the dopamine transporter (DAT), which is largely thought to account for actions related to their misuse and dependence. Cocaine-like, typical DAT inhibitors preferentially bind DAT in an outward-facing conformation, while atypical DAT inhibitors, like modafinil, prefer a more inward-facing DAT conformation. Modafinil and -modafinil have emerged as potential therapeutic options for selected populations of individuals affected by PSUD. In addition, analogs of modafinil (JJC8-088 and JJC8-091) with different pharmacological profiles have been explored as potential PSUD medications in preclinical models. In this work, we employ fast scan cyclic voltammetry (FSCV) to probe nucleus accumbens shell (NAS) dopamine (DA) dynamics in C57BL/6 male and female mice. We find that cocaine slowed DA clearance in both male and female mice but produced more robust increases in evoked NAS DA in female mice. -Modafinil produced mild increases in evoked NAS DA and slowed DA clearance across the sexes. The modafinil analog JJC8-088, a typical DAT inhibitor, produced increases in evoked NAS DA in female and male mice. Finally, JJC8-091, an atypical DAT inhibitor, produced limited increases in evoked NAS DA and slowed DA clearance in both sexes. In this work we begin to tease out how sex differences may alter the effects of DAT targeting and highlight how this may help focus research toward effective treatment options for PSUD.
Topics: Female; Mice; Male; Animals; Modafinil; Dopamine Plasma Membrane Transport Proteins; Dopamine; Nucleus Accumbens; Mice, Inbred C57BL; Central Nervous System Stimulants; Cocaine; Dopamine Uptake Inhibitors
PubMed: 37466616
DOI: 10.1021/acschemneuro.3c00354 -
Neuropsychopharmacology : Official... Mar 2024People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of...
People with depression and other neuropsychiatric disorders can experience motivational dysfunctions such as fatigue and anergia, which involve reduced exertion of effort in goal-directed activity. To model effort-related motivational dysfunction, effort-based choice tasks can be used, in which rats can select between obtaining a preferred reinforcer by high exertion of effort vs. a low effort/less preferred option. Preclinical data indicate that dopamine transport (DAT) inhibitors can reverse pharmacologically-induced low-effort biases and increase selection of high-effort options in effort-based choice tasks. Although classical DAT blockers like cocaine can produce undesirable effects such as liability for misuse and psychotic reactions, not all DAT inhibitors have the same neurochemical profile. The current study characterized the effort-related effects of novel DAT inhibitors that are modafinil analogs and have a range of binding profiles and neurochemical actions (JJC8-088, JJC8-089, RDS3-094, and JJC8-091) by using two different effort-related choice behavior tasks in male Sprague-Dawley rats. JJC8-088, JJC8-089, and RDS3-094 significantly reversed the low-effort bias induced by the VMAT-2 inhibitor tetrabenazine, increasing selection of high-effort fixed ratio 5 lever pressing vs. chow intake. In addition, JJC8-089 reversed the effects of tetrabenazine in female rats. JJC8-088 and JJC8-089 also increased selection of high-effort progressive ratio responding in a choice task. However, JJC8-091 failed to produce these outcomes, potentially due to its unique pharmacological profile (i.e., binding to an occluded conformation of DAT). Assessment of a broad range of DAT inhibitors with different neurochemical characteristics may lead to the identification of compounds that are useful for treating motivational dysfunction in humans.
PubMed: 38429498
DOI: 10.1038/s41386-024-01826-1 -
Journal of Psychopharmacology (Oxford,... Jul 2023
PubMed: 37458280
DOI: 10.1177/02698811231187127 -
Attention, Perception & Psychophysics Nov 2023When human monitors are required to detect infrequent signals among noise, they typically exhibit a decline in correct detections over time. Researchers have attributed...
When human monitors are required to detect infrequent signals among noise, they typically exhibit a decline in correct detections over time. Researchers have attributed this vigilance decrement to three alternative mechanisms: shifts in response bias, losses of sensitivity, and attentional lapses. The current study examined the extent to which changes in these mechanisms contributed to the vigilance decrement in an online monitoring task. Participants in two experiments (N = 102, N = 192) completed an online signal detection task, judging whether the separation between two probes each trial exceeded a criterion value. Separation was varied across trials and data were fit with logistic psychometric curves using Bayesian hierarchical parameter estimation. Parameters representing sensitivity, response bias, attentional lapse rate, and guess rate were compared across the first and last 4 minutes of the vigil. Data gave decisive evidence of conservative bias shifts, an increased attentional lapse rate, and a decreased positive guess rate over time on task, but no strong evidence for or against an effect of sensitivity. Sensitivity decrements appear less robust than criterion shifts or attention lapses as causes of the vigilance loss.
Topics: Humans; Psychomotor Performance; Psychometrics; Bayes Theorem; Attention; Modafinil; Reaction Time
PubMed: 37115493
DOI: 10.3758/s13414-023-02652-1 -
Sleep Medicine Jul 2024Patients with narcolepsy often experience disturbed nighttime sleep. Modafinil is commonly prescribed for hypersomnolence, but its impacts on nocturnal sleep remain...
BACKGROUND
Patients with narcolepsy often experience disturbed nighttime sleep. Modafinil is commonly prescribed for hypersomnolence, but its impacts on nocturnal sleep remain unclear. This study uses actigraphy to examine the effect of modafinil on both hypersomnolence and nocturnal sleep patterns in patients with narcolepsy.
METHODS
Prior to treatment, 87 patients with narcolepsy wore an actigraphy for 7-14 days to assess their nighttime sleep. After evaluation, they received a daily dose of 200-400 mg of modafinil in the morning and wore an actigraphy again six months after initiating treatment. Questionnaires, including the Epworth-Sleepiness-Scale (ESS), the Visual-Analogue-for-Hypersomnolence (VAS), and the Short-Form-36-Health-Survey (SF-36), were used to evaluate hypersomnolence and quality of life both before and after treatment. Paired t-tests and independent samples t-tests were used for pre- and post-treatment comparisons and subgroup analysis. We used the Pearson's correlation test to measure the correlations between the sleep parameters of the actigraphy and data of the questionnaires.
RESULTS
Improvements in hypersomnolence were noted following modafinil treatment, and we observed no significant deterioration in nocturnal sleep parameters by the actigraphy. The total number of awakenings by actigraphy significantly decreased (p = 0.005), especially in females (p = 0.008), while sleep onset latency significantly increased in children/adolescents (p = 0.014). Correlations were found between the sleep parameters of the actigraphy and ESS, VAS, and SF-36 scores.
CONCLUSION
Modafinil treatment may not worsen nighttime sleep in patients with narcolepsy. However, it should be administered with care in children and adolescents.
Topics: Humans; Modafinil; Narcolepsy; Female; Male; Actigraphy; Benzhydryl Compounds; Adult; Wakefulness-Promoting Agents; Adolescent; Cohort Studies; Quality of Life; Surveys and Questionnaires; Middle Aged; Young Adult; Sleep; Central Nervous System Stimulants; Child; Treatment Outcome
PubMed: 38669836
DOI: 10.1016/j.sleep.2024.04.024 -
Aerospace Medicine and Human Performance Jun 2024Modafinil is used as a countermeasure to limit the effects of fatigue in military aviation. However, literature is conflicting about its negative effects on subsequent... (Randomized Controlled Trial)
Randomized Controlled Trial
Modafinil is used as a countermeasure to limit the effects of fatigue in military aviation. However, literature is conflicting about its negative effects on subsequent sleep. This randomized placebo-controlled trial conducted by the Center of Man in Aviation of the Royal Netherlands Airforce is part of a larger study. It included 32 subjects (mean age 35 yr old, 84% male) who followed a normal daily routine and stayed awake the subsequent night. At midnight, all subjects received either 300 mg caffeine, 200 mg modafinil, or placebo. At the end of the test night, subjects were awake for a median period of 26 h. Afterwards, sleep questionnaires containing qualitative (Groningen Sleep Quality Scale) and quantitative parameters of sleep for the subsequent day (recovery sleep) and consecutive night (post-test sleep) were completed and statistically analyzed using Friedman and Wilcoxon signed rank tests. A statistically significant difference in the reported recovery sleep was observed. The modafinil group slept 30% shorter than placebo, but sleep efficiency was not statistically different. Quantitatively post-test sleep did not vary statistically significantly between the three groups. However, Groningen Sleep Quality Scale scores were lower post-test than pre-test in the modafinil group, while this was not the case in the caffeine and placebo group.This study found that modafinil subjectively does not negatively impact recovery sleep or subsequent nighttime sleep after an extended period of wakefulness and suggests it may decrease the need for recovery sleep compared to placebo or caffeine.
Topics: Humans; Modafinil; Male; Adult; Wakefulness; Wakefulness-Promoting Agents; Caffeine; Female; Military Personnel; Sleep; Double-Blind Method; Pilots; Aerospace Medicine; Sleep Quality; Benzhydryl Compounds; Fatigue
PubMed: 38790126
DOI: 10.3357/AMHP.6390.2024 -
World Neurosurgery May 2024Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating...
BACKGROUND
Disorders of consciousness impair early recovery after aneurysmal subarachnoid hemorrhage (aSAH). Modafinil, a wakefulness-promoting agent, is efficacious for treating fatigue in stroke survivors, but data pertaining to its use in the acute setting are scarce. This study sought to assess the effects of modafinil use on mental status after aSAH.
METHODS
Modafinil timing and dosage, neurological examination, intubation status, and physical and occupational therapy participation were documented. Repeated-measures paired tests were used for a before-after analysis of modafinil recipients. Propensity score matching (1:1 nearest neighbor) for modafinil and no-modafinil cohorts was used to compare outcomes.
RESULTS
Modafinil (100-200 mg/day) was administered to 21% (88/422) of aSAH patients for a median (IQR) duration of 10.5 (4-16) days and initiated 14 (7-17) days after aSAH. Improvement in mentation (alertness, orientation, or Glasgow Coma Scale score) was documented in 87.5% (77/88) of modafinil recipients within 72 hours and 86.4% (76/88) at discharge. Of 37 intubated patients, 10 (27%) were extubated within 72 hours after modafinil initiation. Physical and occupational therapy teams noted increased alertness or participation in 47 of 56 modafinil patients (83.9%). After propensity score matching for baseline covariates, the modafinil cohort had a greater mean (SD) change in Glasgow Coma Scale score than the no-modafinil cohort at discharge (2.2 [4.0] vs. -0.2 [6.32], P = 0.003).
CONCLUSIONS
A temporal relationship with improvement in mental status was noted for most patients administered modafinil after aSAH. These findings, a favorable adverse-effect profile, and implications for goals-of-care decisions favor a low threshold for modafinil initiation in aSAH patients in the acute-care setting.
Topics: Humans; Modafinil; Male; Subarachnoid Hemorrhage; Female; Middle Aged; Wakefulness-Promoting Agents; Aged; Adult; Treatment Outcome; Benzhydryl Compounds; Glasgow Coma Scale; Stroke
PubMed: 38367859
DOI: 10.1016/j.wneu.2024.02.056 -
Cureus Apr 2024The management of Narcolepsy, from the initial presentation to the long-term management and follow-up, remains a challenging endeavor, especially in developing climes....
The management of Narcolepsy, from the initial presentation to the long-term management and follow-up, remains a challenging endeavor, especially in developing climes. Worldwide, it has been recognized as a medical condition that is frequently associated with initial misdiagnoses, and delays in definitive management, further highlighted, in resource-limited settings like Nigeria where issues are further compounded by social, cultural, and political factors. In this report, we aim to shed some light on the peculiar challenges encountered by clinicians in Nigeria, and in other similar settings, in the process of diagnosis and management of narcolepsy. We present a case of a 17-year-old male teenager with Narcolepsy Type 1 (NT1) who had been previously managed as a case of Juvenile Absence Epilepsy in various centers prior to presentation at our facility. The symptoms began two years prior to presentation at our outpatient clinic, and they were excessive daytime sleepiness, cataplexy, and sleep paralysis. The symptoms were corroborated by laboratory parameters - reduced mean sleep latency (conducted in an improvised sleep laboratory), and a low cerebrospinal fluid (CSF) hypocretin level. The patient was initially placed on Modafinil for excessive daytime sleepiness and a trial of Fluoxetine for the Cataplexy. However, due to the scarcity of Modafinil, behavioral modifications - scheduled sleep naps and sleep hygiene - were eventually employed. Narcolepsy is a debilitating illness, and consequently, the far-reaching effects of these challenges must be understood. It is important that concerted efforts be made towards improving the overall quality of care received by patients from the early identification to the treatment of narcolepsy in the Nigerian healthcare system.
PubMed: 38738054
DOI: 10.7759/cureus.58143 -
Frontiers in Neurology 2024Traumatic brain injury (TBI), in any form and severity, can pose risks for developing chronic symptoms that can profoundly hinder patients' work/academic, social, and...
Traumatic brain injury (TBI), in any form and severity, can pose risks for developing chronic symptoms that can profoundly hinder patients' work/academic, social, and personal lives. In the past 3 decades, a multitude of pharmacological, stimulation, and exercise-based interventions have been proposed to ameliorate symptoms, memory impairment, mental fatigue, and/or sleep disturbances. However, most research is preliminary, thus limited influence on clinical practice. This review aims to systematically appraise the evidence derived from randomized controlled trials (RCT) regarding the effectiveness of pharmacological, stimulation, and exercise-based interventions in treating chronic symptoms due to TBI. Our search results indicate that despite the largest volume of literature, pharmacological interventions, especially using neurostimulant medications to treat physical, cognitive, and mental fatigue, as well as daytime sleepiness, have yielded inconsistent results, such that some studies found improvements in fatigue (e.g., Modafinil, Armodafinil) while others failed to yield the improvements after the intervention. Conversely, brain stimulation techniques (e.g., transcranial magnetic stimulation, blue light therapy) and exercise interventions were effective in ameliorating mental health symptoms and cognition. However, given that most RCTs are equipped with small sample sizes, more high-quality, larger-scale RCTs is needed.
PubMed: 38562423
DOI: 10.3389/fneur.2024.1321239