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.

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.

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.

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.

Consumo de modafinilo en profesionales de la salud mental: reporte de un caso y revisión bibliográfica / Modafinil use in mental health professionals: case report and bibliographic review

INTRODUCCIÓN El presente estudio busca comenzar un abordaje inicial del fenómeno del consumo de Modafinilo en profesionales de la Salud Mental en Chile y los factores precipitantes que promueven el consumo de esta sustancia psicoestimulante. OBJETIVOS: Realizar una revisión bibliográfica respecto del consumo de Psicoestimulantes en Profesionales de la Salud Mental; identificar el psicoestimulante de más fácil acceso; buscar y contactar a profesionales de la salud mental del SSMC que consuman activamente Modafinilo e Identificar los posibles factores precipitantes asociados al consumo de Modafinilo. MATERIAL Y MÉTODOS: Reporte de caso y análisis de discurso de una entrevista en profundidad, identificando las categorías centrales que estructuran la experiencia del profesional respecto de su consumo. RESULTADOS Y DISCUSIÓN: De acuerdo al análisis de la entrevista, podemos destacar cuatro factores que desencadenan el consumo habitual de la sustancia psicoestimulante: la narcolepsia, sobrecarga laboral, sobrecarga emocional y el fácil acceso al Modafinilo. CONCLUSIONES: La bibliografía existente es muy escasa; este estudio se constituye como una primera aproximación al abordaje de este tema a nivel nacional; la sobrecarga emocional cobra gran importancia ya que complementa la dependencia fisiológica; los estados emocionales que generan y mantienen el consumo en el profesional se ven asociados a eventos ambientales, y la dependencia psicológica es una realidad inseparable de la dependencia fisiológica.

BACKGROUND: The present study aims to start an initial approach to the phenomenon of Modafinil use in mental health professionals in Chile, and the precipitating factors that promote the consumption of this psychostimulant substance. OBJETIVES: To carry out a bibliographic review regarding the use of Psychostimulants in Mental Health Professionals; to identify the most easily accessible psychostimulant; to find and contact mental health professionals who actively consume Modafinil and to identify the possible precipitating factors associated with consumption of Modafinil. METHODS: Case report and discourse analysis of an in-depth interview, identifying the central categories that structure the professional's experience regarding their consumption. RESULTS AND DISCUSSION: According to the analysis of the interview, we can highlight four factors that trigger the habitual consumption of the psychostimulant substance: Narcolepsy, work overload, emotional overload and easy access to Modafinil. CONCLUSIONS: The existing literature is very scarce; this study constitutes a first approach of this topic at national level; emotional overload is of great importance since it complements the physiological dependence; the emotional states that generate and maintain consumption in the professional are seen associated with environmental factors, and psychological dependence is an inseparable reality of physiological dependence.