Chronic administration of caffeine, modafinil, AVL-3288 and CX516 induces time-dependent complex effects on cognition and mood in an animal model of sleep deprivation.

OBJECTIVE: Caffeine and modafinil are used to reverse effects of sleep deprivation. Nicotinic alpha-7 receptor and AMPA receptor positive allosteric modulators (PAM) are also potential substances in this context. Our objective is to evaluate the effects of caffeine, modafinil, AVL-3288 (nicotinic alpha-7 PAM) and CX516 (AMPA receptor PAM) on cognition and mood in a model of sleep deprivation. METHOD: Modified multiple platform model is used to sleep-deprive mice for 24 days, for 8 h/day. Vehicle, Modafinil (40 mg/kg), Caffeine (5 mg/kg), CX516 (10 mg/kg), and AVL3288 (1 mg/kg) were administered intraperitoneally daily. A cognitive test battery was applied every six days for four times. The battery that included elevated plus maze, novel object recognition, and sucrose preference tests was administered on consecutive days. RESULTS: Sleep deprivation decreased novel object recognition skill, but no significant difference was found in anxiety and depressive mood. Caffeine administration decreased anxiety-like behavior in short term, but this effect disappeared in chronic administration. Caffeine administration increased memory performance in chronic period. AVL group showed better memory performance in short term, but this effect disappeared in the rest of experiment. Although, in the modafinil group, no significant change in mood and memory was observed, anhedonia was observed in the chronic period in vehicle, caffeine and modafinil groups, but not in AVL-3288 and CX-516 groups. CONCLUSION: Caffeine has anxiolytic effect in acute administration. The improvement of memory in chronic period may be associated with the neuroprotective effects of caffeine. AVL-3288 had a short-term positive effect on memory, but tolerance to these effects developed over time. Furthermore, no anhedonia was observed in AVL-3288 and CX516 groups in contrast to vehicle, caffeine and modafinil groups. This indicates that AVL-3288 and CX516 may show protective effect against depression.

Collaborative rp-hplc method development for modafinil and scopolamine hydrobromide in sublingual tablets: involving key industry players

Objective: This research aims to develop and validate a collaborative RP-HPLC method, with input from key industry players, for the simultaneous determination of modafinil and scopolamine hydrobromide in compound sublingual tablets. The focus is on ensuring the safety and efficacy of these substances for enhancing the physical and cognitive fitness of athletes and players. Method: Utilizing a C18 chromatographic column (200mm×4.6mm, 5μm), the method employs a mobile phase of acetonitrile-water (25:75) with 0.02mol/L ammonium acetate and 0.02% triethylamine, pH adjusted to 6.0. The flow rate was set at 1 mL/min, detection at 225 nm wavelength, and an injection volume of 20 μL.Results: Scopolamine hydrobromide showed a linear range of 1-50 μg/mL, with a standard curve equation of A=0.2187C+0.0708 (R²=0.9993), and modafinil exhibited a range of 10-500 μg/mL, with A=0.6702C-1.6855 (R²=0.9993). Both substances demonstrated average recoveries of over 99%, within acceptable variance limits, signifying reliable quantification for fitness-related applications. Conclusion: The developed method is sensitive, precise, accurate, and reproducible, conforming to the standards of the Chinese Pharmacopoeia (2020 edition). It is particularly valuable for monitoring the quality of substances used by athletes and players to ensure their safe application in enhancing fitness and performance. The method benefits significantly from the collaboration with industry experts, addressing the specific needs of fitness and sports professionals (AU)

Leveraging Human Plasma-Derived Small Extracellular Vesicles as Liquid Biopsy to Study the Induction of Cytochrome P450 3A4 by Modafinil.

Preparations of plasma-derived small extracellular vesicles (sEVs) were deployed as liquid biopsy to study cytochrome P450 (CYP) 3A4 (CYP3A4) induction following modafinil 400 mg once daily × 14 days (young healthy volunteers, N = 10 subjects). Induction was confirmed using the 4ß-hydroxycholesterol-to-cholesterol (4ßHC/C) ratio, a plasma CYP3A4/5 biomarker, with a mean 2.1-fold increase (Day 15 vs. Day 1; 90% confidence interval (CI) = 1.8-2.3; P value = 0.0004). Proteomic analysis revealed the induction (mean Day 15 vs. Day 1 fold-increase (90% CI)) of both liver (1.3 (1.1-1.5), P value = 0.014) and nonliver (1.9 (1.6-2.2), P value = 0.04) sEV CYP3A4 protein expression. In CYP3A5 nonexpresser subjects, the baseline (pre-dose) 4ßHC/C plasma ratio was more highly correlated with liver sEVs (r = 0.937, P value = 0.001) than nonliver sEVs (r = 0.619, P value = 0.101) CYP3A4 protein expression. When CYP3A5 expressers (CYP3A5*1/*3) were included, the correlation with liver sEVs (r = 0.761, P value = 0.011) and nonliver sEVs (r = 0.391, P value = 0.264) CYP3A4 protein was weaker. Although modafinil-induced changes in plasma 4ßHC/C ratio did not correlate with sEVs CYP3A4 protein expression, the individual subject sEVs proteomic data were used successfully to predict victim drug (midazolam, triazolam, dextromethorphan, 17α-ethinylestradiol, and abemaciclib) area under the plasma concentration-time curve (AUC) ratios (AUCRs) following modafinil. Based on the AUCR values, modafinil was classified as a weak to moderate CYP3A4 inducer (vs. rifampicin). For the first time, it was possible to deploy plasma-derived sEVs to study CYP3A4 induction beyond rifampicin, a more potent CYP3A4 inducer.

Modafinil rescues repeated morphine-induced synaptic and behavioural impairments via activation of D1R-ERK-CREB pathway in medial prefrontal cortex.

Long-term opioid abuse causes a variety of long-lasting cognitive impairments such as attention, impulsivity and working memory. These cognitive impairments undermine behavioural treatment for drug abuse and lead to poor treatment retention and outcomes. Modafinil is a wake-promoting drug that shows potential in improving attention and memory in humans and animals. However, modafinil's effect on opioid-induced cognitive impairments remains unclear, and the underlying mechanism is poorly understood. This study showed that repeated morphine administration significantly impairs attention, increases impulsivity and reduces motivation to natural rewards in mice. Systemic modafinil treatment at low dose efficiently ameliorates morphine-induced attention dysfunction and improves motivation and working memory in mice. High dose of modafinil has adverse effects on impulsive action and attention. Local infusion of D1R antagonist SCH-23390 reverses the morphine-induced synaptic abnormalities and activation of the D1R-ERK-CREB pathway in medial prefrontal cortex (mPFC). This study demonstrated a protective effect of modafinil in mPFC neurons and offered a therapeutic potential for cognitive deficits in opioid abuse.

Application of armodafinil-loaded microneedle patches against the negative influence induced by sleep deprivation.

Cognition maintenance is essential for healthy and safe life if sleep deprivation happens. Armodafinil is a wake-promoting agent against sleep deprivation related disorders. However, only the tablet formulation is available, which may limit its potential in some circumstances. Here, we report the synthesis of a new formulation of armodafinil, microneedle patches, which can be conveniently used by any individual and removed in time if not wanted. To produce the needles of higher mechanical strength and higher drug loading, polyvinylpyrrolidone (PVP) K90 was used to fabricate armodafinil-loaded microneedles by applying the mold casting method after dissolving in methanol and drying. The higher mechanical strength was validated by COMSOL Multiphysics® software stimulation and universal mechanical testing machines. The obtained armodafinil microneedles can withstand a force of 70 N and penetrate the skin to a depth of 230 µm, and quickly released the drug within 1.5 h in vitro. The pharmacokinetic analysis showed that microneedle administration can maintain a more lasting and stable blood concentration as compared to oral administration. After the treatment of sleep deprived mice with microneedles, the in vivo pharmacodynamics study clearly demonstrated that armodafinil microneedles could eliminate the effects of sleep deprivation and improve the cognitive functions of sleep-deprived mice. A self-administered, high drug-loaded microneedle patch were prepared successfully, which appeared to be highly promising in preserving cognition by transdermal administration.

Nicotine and modafinil combination protects against the neurotoxicity induced by 3,4-Methylenedioxymethamphetamine in hippocampal neurons of male rats.

MDMA (3,4-Methylenedioxymethamphetamine) is a common recreational drug of abuse which causes neurodegeneration. Nicotine and modafinil provide antioxidant and neuroprotective properties and may be beneficial in the management of MDMA-induced neurotoxicity. The purpose of this study was to characterize how acute and chronic administration of nicotine and/or modafinil exert protective effects against the MDMA-induced impaired cognitive performance, oxidative stress, and neuronal loss. Adult male rats were divided into three groups, namely control, MDMA and treatment (modafinil and/or nicotine). MDMA (10 mg/kg) was administered intraperitoneally during a three-week schedule (two times/day for two consecutive days/week). The treated-groups were classified based on the acute or chronic status of treatment. In the groups which underwent acute treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected just prior to the MDMA administration (acute nicotine (NA), acute modafinil (MA), and acute nicotine and modafinil (NMA)). In the rats which received chronic treatments, nicotine (0.5 mg/kg) and/or modafinil (100 mg/kg) were injected every day during the three week-schedule administration of MDMA (chronic nicotine (NC), chronic modafinil (MC), and chronic nicotine and modafinil (NMC)). Learning and memory performance, as well as avoidance response, were assessed by Morris water maze and Shuttle box, respectively. Our findings indicate enhanced learning and memory and avoidance response in the NMC group. By TUNEL test and Cresyl Violet staining we evaluated neuronal loss and apoptosis in the hippocampal CA1 and found increased neuronal viability in the NMC group. On the other hand, chronic administration of modafinil and nicotine significantly down-regulated the caspase 3 and up-regulated both BDNF and TrkB levels in the MDMA-received rats. The serum levels of glutathione peroxidase (GPx) and total antioxidant capacity (TAC) were evaluated and we found that the alterations of serum levels of GPx and TAC were considerably prevented in the NMC group. The overall results indicate that nicotine and modafinil co-administration rescued brain from MDMA-induced neurotoxicity. We suggest that nicotine and modafinil combination therapy could be considered as a possible treatment to reduce the neurological disorders induced by MDMA.

Efficacy and safety of modafinil versus dexamethasone in cancer-related fatigue: a prospective randomized controlled study.

The aim of this study was to compare the efficacy and safety of modafinil and dexamethasone in the management of cancer-related fatigue and their effects on quality of life (QoL). A prospective randomized controlled study was conducted, enrolling 80 cancer patients experiencing moderate or severe fatigue following at least three cycles of chemotherapy or a course of palliative/curative radiotherapy. Patients received either oral modafinil 100 mg or dexamethasone 4 mg daily for 14 days. Levels of fatigue, QoL and symptom severity were compared after 14-21 days. Both drugs were efficacious and safe in the management of fatigue and QoL. However, modafinil performed marginally better. Although modafinil demonstrated marginal superiority, both modafinil and dexamethasone can improve fatigue and QoL in cancer patients. Clinical trials registry of India: CTRI/2018/05/014046 (www.ctri.nic.in).

Lay abstract Cancer-related fatigue is a common and nagging problem that needs best evidence-based management. Modafinil, a brain stimulant, and dexamethasone, a corticosteroid, have been shown in separate studies to provide benefit, but there are little data regarding which one is superior. The present study compared modafinil with dexamethasone in a randomized controlled trial. Modafinil was found to be marginally superior in treating cancer-related fatigue and several domains of quality of life, though dexamethasone also demonstrated significant improvement of fatigue. This study provides a valuable guide for future larger studies for implementation of the findings in the form of better patient care.

Treatment of unexplained coma and hypokinetic-rigid syndrome in a patient with COVID-19.

The COVID-19 pandemic has dealt a devastating blow to healthcare systems globally. Approximately 3.2% of patients infected with COVID-19 require invasive ventilation during the course of the illness. Within this population, 25% of patients are affected with neurological manifestations. Among those who are affected by severe neurological manifestations, some may have acute cerebrovascular complications (5%), impaired consciousness (15%) or exhibit skeletal muscle hypokinesis (20%). The cause of the severe cognitive impairment and hypokinesis is unknown at this time. Potential causes include COVID-19 viral encephalopathy, toxic metabolic encephalopathy, post-intensive care unit syndrome and cerebrovascular pathology. We present a case of a 60 year old patient who sustained a prolonged hospitalization with COVID-19, had a cerebrovascular event and developed a persistent unexplained encephalopathy along with a hypokinetic state. He was treated successfully with modafinil and carbidopa/levodopa showing clinical improvement within 3-7 days and ultimately was able to successfully discharge home.

Stimulating meditation: a pre-registered randomised controlled experiment combining a single dose of the cognitive enhancer, modafinil, with brief mindfulness training.

BACKGROUND: Mindfulness-meditation has a variety of benefits on well-being. However, individuals with primary attentional impairments (e.g. attention deficit disorder) or attentional symptoms secondary to anxiety, depression or addiction, may be less likely to benefit, and require additional mindfulness-augmenting strategies. AIMS: To determine whether a single dose of the cognitive enhancer, modafinil, acutely increases subjective and behavioural indices of mindfulness, and augments brief mindfulness training. METHODS: A randomised, double-blind, placebo-controlled, 2 (drug: placebo, modafinil) × 2 (strategy: mindfulness, relaxation control) experiment was conducted. Seventy-nine meditation-naïve participants were assigned to: placebo-relaxation, placebo-mindfulness, modafinil-relaxation or modafinil-mindfulness. Pre-drug, post-drug and post-strategy state mindfulness, affect and autonomic activity, along with post-strategy sustained attention and mind-wandering were assessed within a single lab session. After the session, participants were instructed to practice their assigned behavioural strategy daily for one week, with no further drug administration, after which, follow-up measures were taken. RESULTS: As predicted, modafinil acutely increased state mindfulness and improved sustained attention. Differential acute strategy effects were found following mindfulness on autonomic activity but not state mindfulness. There were no strategy or drug effects on mind-wandering. However, exploratory analyses indicated that participants receiving modafinil engaged in more strategy practice across strategy conditions during follow-up. CONCLUSIONS: Modafinil acutely mimicked the effects of brief mindfulness training on state mindfulness but did not enhance the effects of this training. Limitations of the current study, and recommendations for future research examining modafinil as an adjunct to mindfulness- (or relaxation-) based treatments are discussed.

Safety and efficacy of amantadine, modafinil, and methylphenidate for fatigue in multiple sclerosis: a randomised, placebo-controlled, crossover, double-blind trial.

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.

How effective are pharmaceuticals for cognitive enhancement in healthy adults? A series of meta-analyses of cognitive performance during acute administration of modafinil, methylphenidate and D-amphetamine.

Modafinil, methyphenidate (MPH) and d-amphetamine (d-amph) are putative cognitive enhancers. However, efficacy of cognitive enhancement has yet to be fully established. We examined cognitive performance in healthy non-sleep-deprived adults following modafinil, MPH, or d-amph vs placebo in 3 meta-analyses, using subgroup analysis by cognitive domain; executive functions (updating, switching, inhibitory control, access to semantic/long term memory), spatial working memory, recall, selective attention, and sustained attention. We adhered to PRISMA. We identified k = 47 studies for analysis; k = 14 studies (64 effect sizes) for modafinil, k = 24 studies (47 effect sizes) for Methylphenidate, and k = 10 (27 effect sizes) for d-amph. There was an overall effect of modafinil (SMD=0.12, p=.01). Modafinil improved memory updating (SMD=0.28, p=.03). There was an overall effect of MPH (SMD=0.21, p=.0004) driven by improvements in recall (SMD=0.43, p=.0002), sustained attention (SMD=0.42, p=.0004), and inhibitory control (SMD=0.27, p=.03). There were no effects for d-amph. MPH and modafinil show enhancing effects in specific sub-domains of cognition. However, data with these stimulants is far from positive if we consider that effects are small, in experiments that do not accurately reflect their actual use in the wider population. There is a user perception that these drugs are effective cognitive enhancers, but this is not supported by the evidence so far.

[Intrathecal baclofen therapy in brain injury and recovery of persistent vegetative state. Apropos of a case]. / Baclofeno intratecal en daño cerebral y recuperación de estado vegetativo persistente. A propósito de un caso.

Patients with brain injury and spasticity are candidates for intrathecal baclofen therapy (ITB) when maximal doses of oral antispastic drugs fail. Some authors have described an improvement in the level of consciousness in patients with brain injury and disorder of consciousness treated with ITB for spasticity. We present the case of a 43-year-old patient with brain injury, spasticity, and permanent vegetative state (PVS) who showed an improvement in the level of consciousness after ITB for spasticity. We performed an ITB infusion test, assessing the spasticity with the Modified Ashworth Scale (MAS) and level of consciousness with the Coma Recovery Scale-Revised (CRS-R) and observed an improvement in the spasticity and the level of consciousness. Consequently, the ITB pump was implanted and the patient recovered from PVS to minimal conscious state (MCS). We conclude that ITB is indicated in patients with brain injury and spasticity. We suggest the improvement in the level of consciousness as a possible additional benefit. There is a lack of evidence to recommend ITB in patients with altered level of consciousness.

Modafinil reduces choice impulsivity while increasing motor activity in preadolescent rats treated prenatally with alcohol.

Rats exposed prenatally to alcohol show a reduction in the spontaneous activity of dopaminergic neurons of the ventral tegmental area (VTA), as well as greater impulsive behavior and motor activity, behavioral alterations that have been related to dopaminergic dysfunction. Modafinil (MOD) is a dopamine (DA) reuptake blocker prescribed to treat sleep disorders; however, in recent years it has been used for the treatment of ADHD with positive results. Also, studies in humans and rodents show beneficial effects on learning and attention; however, studies evaluating MOD effects on impulsivity are few and show contradictory results. The purpose of this work was to evaluate the effect of a daily dose of MOD (60 mg/kg i.g.) on cognitive (or choice) impulsivity and motor activity in male preadolescent rats exposed prenatally to alcohol or sucrose (isocaloric control). MOD reduced the impulsive responses in a delay discounting task (DDT) at the same time that increased the motor activity, in both healthy and prenatal alcohol treated rats; however, MOD reduced the response latency in DDT only in prenatal alcohol treated rats. This differential effect of DA activation on impulsivity and motor activity show that the MOD dose that improves the impulse control, does not necessarily decrease motor activity, and suggests a possible differential neural mechanism underlying the expression of these behaviors. On the other hand, the changes in the response latency, only in prenatal alcohol treated groups, suggest that decision-making in animals with a dopaminergic dysfunction is more susceptible to be affected by MOD action.

Wake-Promoting and EEG Spectral Effects of Modafinil After Acute or Chronic Administration in the R6/2 Mouse Model of Huntington's Disease.

Huntington's disease (HD) is characterised by progressive symptoms including cognitive deficits and sleep/wake disturbances reflected in an abnormal electroencephalography (EEG). Modafinil, a wake-promoting and cognitive-enhancing drug, has been considered as a treatment for HD. We used HD (R6/2) mice to investigate the potential for using modafinil to treat sleep-wake disturbance in HD. R6/2 mice show sleep-wake and EEG changes similar to those seen in HD patients, with increased rapid eye movement sleep (REMS), decreased wakefulness/increased non-REMS (NREMS), and pathological changes in EEG spectra, particularly an increase in gamma power. We recorded EEG from R6/2 and wild-type mice treated with modafinil acutely (with single doses between 25 and 100 mg/kg; at 12 and 16 weeks of age), or chronically (64 mg/kg modafinil/day from 6 to 15 weeks). Acutely, modafinil increased wakefulness in R6/2 mice and restored NREMS to wild-type levels at 12 weeks. It also suppressed the pathologically increased REMS. This was accompanied by decreased delta power, increased peak frequency of theta, and increased gamma power. At 16 weeks, acute modafinil also restored wakefulness and NREMS to wild-type levels. However, whilst REMS decreased, it did not return to normal levels. By contrast, in the chronic treatment group, modafinil-induced wakefulness was maintained at 15 weeks (after 9 weeks of treatment). Interestingly, chronic modafinil also caused widespread suppression of power across the EEG spectra, including a reduction in gamma that increases pathologically in R6/2 mice. The complex EEG effects of modafinil in R6/2 mice should provide a baseline for further studies to investigate the translatability of these result to clinical practice.

Biochemical and histopathological evidence for the beneficial effects of modafinil on the rat model of inflammatory bowel disease: involvement of nitric oxide pathway.

BACKGROUND: Inflammatory bowel disease is an intestinal disorder presented by recurrent inflammation in the gastrointestinal tract. It has been reported that modafinil, also known as an awakening drug, has anti-inflammatory characteristics. The objective of this experiment is to investigate the protective effects of modafinil on colitis induced by acetic acid in rat and the involvement of nitric oxide pathway. METHODS: Colitis was induced by intra-rectal instillation of 1 ml acetic acid (4%). After one h of colitis induction (first day), intraperitoneal injection of dexamethasone (1 mg/kg), modafinil (50, 100, and 150 mg/kg), nitric oxide synthase inhibitors (NOS)-N (G)-nitro-L-arginine methyl ester (L-NAME) 10 mg/kg, 7-nitroindazole 40 mg/kg, and aminoguanidine 50 mg/kg-was performed and continued for 2 consecutive days. Ultimately, macroscopic, microscopic, and biochemical assessments were performed. RESULTS: While induction of colitis caused severe macroscopic lesions, administration of dexamethasone and modafinil (100 and 150 mg/kg) significantly improved macroscopic ulcers. Interestingly, the combination of modafinil with NOS inhibitors reversed the beneficial effects of modafinil on macroscopic destructions. In addition, the elevated level of interleukin-1beta (IL-1ß) and tumor necrosis factor-alpha (TNF-α) was decreased by modafinil. However, treatment with NOS inhibitors before modafinil neutralized the anti-inflammatory influence of modafinil. Additionally, histological disorders emerged by acetic acid in colon tissue remarkably were disappeared after treatment with modafinil. CONCLUSIONS: In conclusion, modafinil has a protective effect on injuries induced by acetic acid in the colon of rat, which is presumably via the inhibition of inflammatory cascade and mediation of NO pathway.

Returning to work after fatigue treatment and counseling in HIV/AIDS.

BACKGROUND: Employment rates for people with HIV/AIDS are low, compared to the general population. One widespread barrier is fatigue, accompanied by daytime sleepiness and a lack of stamina. Previous pharmacological studies have demonstrated improvement of fatigue-related symptoms without affecting work-related goal attainmentOBJECTIVE:In this pilot study, we sought to determine whether a pharmacologic-behavioral two-phase combined approach could facilitate returning to work. METHODS: HIV+ participants with fatigue were treated with armodafinil. If energy improved, 8 sessions of biweekly manualized Behavioral Activation (BA) counseling were added to medication maintenance. Outcome was assessed on a 3-point scale along with clinician and self-ratings. RESULTS: Of the 46 participants enrolled in BA, 15 (33%) did not complete all 8 sessions: 6 got jobs so they no longer needed counseling; 4 did not like BA, and 5 dropped out for reasons such as moving away or substance use relapse. Of the 46, 29 (63%) attained their vocational goal and showed significant changes on self-report scales. CONCLUSIONS: Our integrated treatment including armodafinil plus BA counseling significantly increased the success of achieving work-related goals. The two-phase medication plus counseling program was well-tolerated by participants and the manualized BA counseling was readily applied by counselors without advanced mental health training, making the method potentially feasible in community settings.

[Use of Modafinil in Co-existing Major Depression and ErectileDysfunction: A Case Report]. / Sertlesme Bozuklugunun Eslik Ettigi Majör Depresyonda Modafinil Kullanimi: Bir Olgu Sunumu.

Erectile dysfunction is a sexual dysfunction which is commonlycomorbid with major depression. Antidepressant treatment does notalways improve comorbid sexual dysfunctions in major depression. Infact, sexual dysfunction may worsen or get complicated following theintroduction of antidepressants. Modafinil is a drug with stimulanteffect on the central nervous system by binding to norepinephrineand dopamine transporters and consequently increasing synapticnorepinephrine and dopamine levels. Modafinil is primarily used inthe treatment of narcolepsy and chronic fatigue syndrome. In addition,it is known for its effectiveness in attention deficit hyperactivitydisorder and as an add-on option for major depression. In this paper,we report the case of a 39-year-old man with major depression whosecomorbid erectile dysfunction improved after addition of modafinilto antidepressant treatment. Fluoxetine 20 mg/day was initiatedand despite the improvement of most of the depressive symptomsand the sexual desire, his complaints of fatigue, weakness and erectiledysfunction continued. With the addition of modafinil (200 mg /day),improvement was observed not only in psychomotor symptoms but alsoin erectile dysfunction of the patient.

Protective effects of modafinil administration on testicular torsion/detorsion damage in rats.

Testicular torsion is a pathological condition which leads to sever scrotal pain and ischemia. After surgical reperfusion, oxidative stress factors cause to germ cell apoptosis. Thus, adjuvant therapy to surgery should be useful to decrease of ischemia/reperfusion (I/R) injury of testis. Modafinil, a drug to treat sleepiness, has been indicated to have anti-inflammatory effects. The aim was to evaluate the efficiency of modafinil administration after reperfusion surgery in a rat model of testicular torsion/detorsion (T/D). Male wistar rats were divided into three groups and each group contained 10 animals. To induce torsion right testis was rotated 720° clockwise and was left for 1 h. Modafinil group received modafinil (10 mg/kg) once daily intraperitoneally for 7 days after the surgery and the control group received physiologic saline once daily intraperitoneally for 7 days after the surgery. Thereafter, MDA, IL-1ß and TNF-α levels and histopathological changes were investigated. MDA, IL-1ß and TNF-α levels significantly increased in T/D group compared to the control group (⁎⁎P < .01 and ⁎⁎⁎P < .001, respectively). Moreover, modafinil administration significantly reduced these values compared to T/D group (#P < .05 and ##P < .01, respectively). Histopathological changes such as degeneration in germinal cells were detected in testis T/D group of rats whereas modafinil administration prevented degeneration in germinal cells, edema and hemorrhage compared with T/D group. In conclusion, administration of modafinil after reperfusion surgery had protective role on testicular torsion in rat and reduced ischemia/reperfusion cellular injury via anti-inflammatory and decrease of oxidative stress.

The Efficacy of Modafinil as a Cognitive Enhancer: A Systematic Review and Meta-Analysis.

BACKGROUND: Animal models and human studies have identified the potential of modafinil as a cognitive enhancing agent, independent of its effects on promoting wakefulness in sleep-deprived samples. Given that single-dose applications of other putative memory enhancers (eg, D-cycloserine, yohimbine, and methylene blue) have shown success in enhancing clinical outcomes for anxiety-related disorders, we conducted a meta-analytic review examining the potential for single-dose effects for modafinil on cognitive functioning in non-sleep-deprived adults. METHODS: A total of 19 placebo-controlled trials that examined the effects of single-dose modafinil versus placebo on the cognitive domains of attention, executive functioning, memory, or processing speed were identified, allowing for the calculation of 67 cognitive domain-specific effect sizes. RESULTS: The overall positive effect of modafinil over placebo across all cognitive domains was small and significant (g = 0.10; 95% confidence interval, 0.05-0.15; P < 0.001). No significant differences between cognitive domains were found. Likewise, no significant moderation was found for modafinil dose (100 mg vs 200 mg) or for the populations studied (psychiatric vs nonpsychiatric). CONCLUSIONS: In conclusion, the available evidence indicates only limited potential for modafinil to act as a cognitive enhancer outside sleep-deprived populations.

Differential effect of modafinil on impulsivity, attention and motor activity in preadolescent rats prenatally treated with alcohol.

The purpose of the present research was to study the effect of different doses of modafinil (0, 10, 30 and 60 mg/kg) on reactive impulsivity, attention and hyperactivity in male Wistar rats treated with prenatal alcohol (PA), treatment that produces an alteration in dopaminergic (DA) neurons. The control rats were treated prenatally with sucrose (PS). Animals with PA were less efficient, more impulsive, and inattentive compared to PSs, in a Go-Signal-Task paradigm. The results indicated that a dose of 30 mg/kg of modafinil increased the number of correct responses in the task; decreased impulsivity and did not affect the attention in the PA animals. In contrast, in the PS animals the doses of 30 and 60 mg/kg of modafinil decreased the number of correct responses and increased the impulsivity. Inattention was only increased with 30 mg/kg in PS animals. Hyperactivity increased with a dose-response effect of modafinil in the PS group; meanwhile, this behavior increased only with the dose of 60 mg/kg in the PA group. A moderate dose of modafinil had beneficial effects on behaviors that are altered in animals with a dysfunction of the dopaminergic system; on the other hand, it has a deleterious effect on these behaviors in healthy animals, which suggests that it is due to the predominance of the psychostimulant effect of this drug. The main target of modafinil is the DA system, thus, the data suggest that this system has an important role in impulsive behavior and hyperactivity.