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1.
Turk Psikiyatri Derg ; 33(3): 206-210, 2022.
Artigo em Inglês, Turco | MEDLINE | ID: mdl-36148571

RESUMO

Antidepressants are known to cause sexual dysfunctions. Sexual side effects due to antidepressants negatively affect compliance with treatment. Modafinil is a stimulant drug used for narcolepsy and some other sleep disorders. It is also used in treatment of resistant depression, chronic fatigue syndrome, attention deficit hyperactivity disorder, and cocaine addiction syndrome. In this article, two female patients whose depressive complaints improved with antidepressant treatment, but who applied to the psychiatry outpatient clinic with complaints of sexual dysfunction and daytime sleepiness, will be presented. Both patients had loss of sexual desire, arousal and orgasm difficulties. The sexual histories obtained from the patients suggested that there was no sexual dysfunction in the period before they started using antidepressants. Both patients stated that they did not want to change the current antidepressant treatment. Modafinil 100 mg/day was prescribed to the patients for daytime sleepiness. One month after the initiation of modafinil 100 mg/day in the 39-yearold patient, there was a marked decrease in the complaints of loss of sexual desire, decreased sexual arousal and orgasm difficulties. In the other patient, 43 years old, a slight improvement in sexual functions was observed after the initiation of modafinil. In this case, after the modafinil dose was increased to 200 mg/day, there was a significant improvement in sexual dysfunctions. In both cases, the improvement in sexual dysfunctions and possible mechanisms as a result of the addition of modafinil to the treatment will be discussed. Keywords: Antidepressant, woman, sexual dysfunction, modafinil.


Assuntos
Estimulantes do Sistema Nervoso Central , Distúrbios do Sono por Sonolência Excessiva , Adulto , Antidepressivos/efeitos adversos , Compostos Benzidrílicos/efeitos adversos , Estimulantes do Sistema Nervoso Central/uso terapêutico , Distúrbios do Sono por Sonolência Excessiva/induzido quimicamente , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Feminino , Humanos , Modafinila/efeitos adversos
2.
Sleep Med Clin ; 17(3): 379-398, 2022 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-36150801

RESUMO

Idiopathic hypersomnia (IH) includes a clinical phenotype resembling narcolepsy (with repeated, short restorative naps), and a phenotype with an excess of sleep, sleep drunkenness, drowsiness, and infrequent long, nonrestorative naps. Sleep tests reflect this heterogeneity. MSLTs are greater than 8 min in 2/3 of the cases and poorly repeatable. Sleep excess is better captured by extended monitoring identifying 11 to 16h of sleep/24 h. Patients with IH are young and more often female. Possible mechanisms of IH include deficiencies in arousal systems, inappropriate stimulation of sleep-inducing systems, and long biological night. Treatments now include robust studies of modafinil, clarithromycin, and sodium oxybate.


Assuntos
Distúrbios do Sono por Sonolência Excessiva , Hipersonia Idiopática , Narcolepsia , Oxibato de Sódio , Claritromicina , Distúrbios do Sono por Sonolência Excessiva/diagnóstico , Distúrbios do Sono por Sonolência Excessiva/tratamento farmacológico , Feminino , Humanos , Hipersonia Idiopática/diagnóstico , Hipersonia Idiopática/tratamento farmacológico , Modafinila , Medicina de Precisão , Espiperona/análogos & derivados
3.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S303-S304, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36163942

RESUMO

CONTEXT: A novel genomically defined subset of higher-risk myelodysplastic syndrome (HR-MDS) patients with an actionable target characterized by overexpression of RARA has been identified (McKeown 2017). Approximately 30% of HR-MDS patients are RARA-positive by a blood-based biomarker test (Vigil 2017). Tamibarotene is an oral selective RARα agonist with potential for clinical benefit in RARA-positive HR-MDS patients, irrespective of mutation or cytogenetic risk. Initial clinical data in RARA-positive relapsed/refractory HR-MDS showed myeloid differentiation, improved blood counts, and reduced bone marrow blasts, including one patient who achieved marrow complete remission with hematologic improvement (Jurcic 2017). Tamibarotene/azacitidine led to a CR/CRi rate of 61% with rapid onset of response in RARA-positive newly diagnosed (ND) unfit AML patients, including those with low blast count (≤30%) AML, and a majority of patients achieved or maintained transfusion independence (de Botton 2020). Tamibarotene/azacitidine was generally well tolerated with no increase in myelosuppression compared with azacitidine alone (de Botton 2020). Historical precedent demonstrating similar clinical outcomes in HR-MDS and low blast count AML (Estey 2022) supports further development of tamibarotene/azacitidine in HR-MDS to improve clinical outcomes of standard of care treatment with hypomethylating agents (HMAs). OBJECTIVE: To characterize and compare the CR rate of tamibarotene/azacitidine to placebo/azacitidine in RARA-positive ND HR-MDS patients. Secondary objectives include comparisons of overall response rate, event-free survival, overall survival, transfusion independence, and safety. DESIGN: Global, Phase 3, randomized, double-blind, placebo-controlled trial (NCT04797780). Approximately 190 patients will be randomized 2:1, providing 90% power to detect the difference in CR rates between the experimental and control arms. PATIENTS: The included patients will be RARA-positive based on investigational assay and ND with HR-MDS by WHO classification (Arber 2016) with an IPSS-R risk category of very high, high, or intermediate and a blast count >5% at baseline. Patients with prior treatment for MDS with any HMA, chemotherapy, or transplant are excluded. INTERVENTION: Azacitidine will be administered at 75 mg/m2 IV/SC daily on days 1-7 (or 1-5, 8-9) followed by tamibarotene/placebo at 6 mg BID orally on days 8-28 of each 28-day cycle. MAIN OUTCOME MEASURES: Response is assessed per the modified IWG MDS criteria (Cheson 2006).


Assuntos
Leucemia Mieloide Aguda , Síndromes Mielodisplásicas , Adulto , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Benzoatos , Humanos , Modafinila/uso terapêutico , Síndromes Mielodisplásicas/diagnóstico , Tetra-Hidronaftalenos , Resultado do Tratamento
4.
Int J Mol Sci ; 23(18)2022 Sep 06.
Artigo em Inglês | MEDLINE | ID: mdl-36142172

RESUMO

Attention deficit hyperactivity disorder (ADHD) is one of the most common worldwide mental disorders in children, young and adults. If left untreated, the disorder can continue into adulthood. The abuse of ADHD-related drugs to improve mental performance for studying, working and everyday life is also rising. The potentially high number of subjects with controlled or uncontrolled use of such substances increases the impact of possible side effects. It has been shown before that the early ADHD drug methylphenidate influences bone metabolism negatively. This study focused on the influence of three more recent cognitive enhancers, modafinil, atomoxetine and guanfacine, on the differentiation of mesenchymal stem cells to osteoblasts and on their cell functions, including migration. Human mesenchymal stem cells (hMSCs) were incubated with a therapeutic plasma dosage of modafinil, atomoxetine and guanfacine. Gene expression analyses revealed a high beta-2 adrenoreceptor expression in hMSC, suggesting it as a possible pathway to stimulate action. In bone formation assays, all three cognitive enhancers caused a significant decrease in the mineralized matrix and an early slight reduction of cell viability without triggering apoptosis or necrosis. While there was no effect of the three substances on early differentiation, they showed differing effects on the expression of osterix (OSX), receptor activator of NF-κB ligand (RANKL) and osteoprotegerin (OPG) in the later stages of osteoblast development, suggesting alternative modes of action. All three substances significantly inhibited hMSC migration. This effect could be rescued by a selective beta-blocker (Imperial Chemical Industries ICI-118,551) in modafinil and atomoxetine, suggesting mediation via beta-2 receptor stimulation. In conclusion, modafinil, atomoxetine and guanfacine negatively influence hMSC differentiation to bone-forming osteoblasts and cell migration through different intracellular pathways.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central , Metilfenidato , Nootrópicos , Adulto , Cloridrato de Atomoxetina/farmacologia , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Diferenciação Celular , Estimulantes do Sistema Nervoso Central/farmacologia , Criança , Guanfacina/farmacologia , Humanos , Ligantes , Metilfenidato/uso terapêutico , Modafinila/farmacologia , Modafinila/uso terapêutico , Nootrópicos/uso terapêutico , Osteoprotegerina/uso terapêutico , Receptor Ativador de Fator Nuclear kappa-B
5.
Clin Lymphoma Myeloma Leuk ; 22 Suppl 2: S213, 2022 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-36163766

RESUMO

CONTEXT: RARA-positive AML is a novel, genomically defined subset with an actionable target for treatment with tamibarotene, an oral and selective RARα agonist (McKeown 2017). In a previous trial in RARA-positive newly diagnosed (ND) AML patients ineligible for standard induction therapy, tamibarotene/azacitidine led to a CR/CRi rate of 61% with a rapid onset of response. The combination was generally well tolerated with no increase in myelosuppression compared to azacitidine alone (de Botton 2020). Responses were observed irrespective of mutations or cytogenetic risk. Approximately one-third of ND unfit AML patients do not respond to venetoclax, and nearly all patients eventually relapse (DiNardo 2020). Translational data suggest that RARA positivity, found in approximately 30% of patients in this AML subset (Vigil 2017), enriches for monocytic features reported to be associated with venetoclax resistance (Fiore 2020, Pei 2019). This suggests that the blood-based RARA biomarker selects for patients who may respond to tamibarotene and may be less likely to respond to venetoclax/azacitidine. OBJECTIVES: The primary objectives are to characterize the safety of the combination and to compare the CR/CRi rate of tamibarotene/venetoclax/azacitidine versus venetoclax/azacitidine; the secondary objectives are to compare the CR rate, CR/CRh rate, duration of response, time to response, and overall survival. DESIGN: A phase 2, open-label, multi-center trial comparing the activity of tamibarotene/venetoclax/azacitidine with that of venetoclax/azacitidine in treatment-naive RARA+ unfit AML patients. This 3-part trial includes a safety lead-in, randomized efficacy study, and salvage arm. Following the safety lead-in, patients will be randomized 1:1 to receive tamibarotene/venetoclax/azacitidine or venetoclax/azacitidine. Clinical activity will be characterized by European LeukemiaNet criteria. Response rates and 95% exact binomial confidence intervals will be calculated by treatment group. In the salvage arm, tamibarotene will be added for patients randomized to venetoclax/azacitidine who experience progressive disease, treatment failure, or relapse. INTERVENTION: Patients will be treated with azacitidine at 75 mg/m2 IV/SC daily on days 1-7, venetoclax on days 1-28 per VENCLEXTA® (venetoclax) USPI, and tamibarotene 6 mg twice per day by mouth on days 8-28 of each 28-day cycle. SELECT-AML-1 (NCT04905407) opened in July 2021 with ongoing enrollment. SETTING: U.S. and France.


Assuntos
Azacitidina , Leucemia Mieloide Aguda , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Azacitidina/farmacologia , Azacitidina/uso terapêutico , Benzoatos , Compostos Bicíclicos Heterocíclicos com Pontes/farmacologia , Compostos Bicíclicos Heterocíclicos com Pontes/uso terapêutico , Humanos , Quimioterapia de Indução , Modafinila/uso terapêutico , Recidiva Local de Neoplasia/tratamento farmacológico , Sulfonamidas , Tetra-Hidronaftalenos
6.
Cochrane Database Syst Rev ; 9: CD011376, 2022 09 12.
Artigo em Inglês | MEDLINE | ID: mdl-36094728

RESUMO

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.


Assuntos
Neoplasias Encefálicas , Glioma , Adulto , Neoplasias Encefálicas/complicações , Dextroanfetamina/uso terapêutico , Fadiga/etiologia , Fadiga/terapia , Humanos , Modafinila/uso terapêutico
7.
Psychiatry Res ; 316: 114776, 2022 10.
Artigo em Inglês | MEDLINE | ID: mdl-35964417

RESUMO

Novelty seeking is a tendency to approach new situations, putatively driven by the brain's catecholaminergic system. It is traditionally measured via self-report, but a laboratory-based paradigm, the human Behavioral Pattern Monitor (hBPM), quantifies behavior in a novel environment and has utility in cross-species studies of neuropsychiatric disorders. Our primary aim assessed whether self-reported novelty-seeking traits were associated with novelty-seeking behavior in the hBPM. An existing sample of 106 volunteers were categorized as high vs. low novelty seekers using the Temperament and Character Inventory (TCI). Subjects had been randomized to one dose of amphetamine (10 or 20 mg) or modafinil (200 or 400 mg), allowing us to explore whether a pharmacological catecholamine challenge further enhanced novelty-seeking behavior. High TCI novelty-seekers had more hBPM motor activity and novel object interactions. The exploratory analyses, although limited by low power, suggested that amphetamine and modafinil did not markedly moderate novelty-seeking traits. The hBPM demonstrates construct validity as a lab-based measure of novelty seeking and thus useful in translational studies of neuropsychiatric conditions and treatment options. Further research may illuminate whether a biological predisposition towards higher catecholaminergic activity, combined with the novelty-seeking trait, may increase propensity for risky and addictive behaviors.


Assuntos
Caráter , Comportamento Exploratório , Humanos , Modafinila , Temperamento
8.
Org Biomol Chem ; 20(29): 5836-5844, 2022 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-35838682

RESUMO

Sulfoxide-containing molecules are an important class of compounds in the pharmaceutical industry and many efforts have been made to develop new and green protocols, targeting the chemoselective transformation of sulfides into sulfoxides. Photochemistry is a rapidly expanding research field employing light as the energy source. Photochemical aerobic processes possess additional advantages to photochemistry and may find applications in the chemical industries. Herein, a 370 nm catalyst-free aerobic protocol was developed, using 2-Me-THF as the green solvent. At the same time, two low-catalyst-loading anthraquinone-based processes (under a CFL lamp or 427 nm irradiation) in 2-Me-THF were developed. Furthermore, a broad range of substrates was tested. We also implemented our protocols towards the synthesis of the pharmaceutical active ingredients (APIs) sulforaphane and modafinil.


Assuntos
Sulfetos , Sulfóxidos , Isotiocianatos , Modafinila , Oxirredução , Sulfetos/química , Sulfóxidos/química
9.
Int J Mol Sci ; 23(12)2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35743046

RESUMO

The misuse of psychostimulants is an increasing behavior among young people, highlighting in some countries the abuse of modafinil (MOD) as a neuropotentiator. However, several clinical trials are investigating MOD as an alternative pharmacological treatment for attentional deficit and hyperactivity disorder (ADHD) in children and adolescents. On the other hand, the early use of psychostimulants and the misdiagnosis rates in ADHD make it crucial to investigate the brain effects of this type of drug in young healthy individuals. The aim of this work was to evaluate the effects of chronic MOD treatment on neurochemicals (γ-aminobutyric acid and glutamate), dopamine receptor 2 (D2) expression and behavior (non-selective attention "NSA") in the mesocorticolimbic system of young healthy Sprague-Dawley rats. Preadolescent male rats were injected with MOD (75 mg/kg, i.p.) or a vehicle for 14 days (from postnatal day 22 to 35). At postnatal day 36, we measured the GLU and GABA contents and their extracellular levels in the nucleus accumbens (NAc). In addition, the GLU and GABA contents were measured in the ventral tegmental area (VTA) and D2 protein levels in the prefrontal cortex (PFC). Chronic use of MOD during adolescence induces behavioral and neurochemical changes associated with the mesocorticolimbic system, such as a reduction in PFC D2 expression, VTA GABA levels and NSA. These results contribute to the understanding of the neurological effects of chronic MOD use on a young healthy brain.


Assuntos
Estimulantes do Sistema Nervoso Central , Área Tegmentar Ventral , Adolescente , Animais , Atenção , Estimulantes do Sistema Nervoso Central/farmacologia , Ácido Glutâmico/metabolismo , Humanos , Masculino , Modafinila/metabolismo , Modafinila/farmacologia , Núcleo Accumbens/metabolismo , Córtex Pré-Frontal/metabolismo , Ratos , Ratos Sprague-Dawley , Área Tegmentar Ventral/metabolismo , Ácido gama-Aminobutírico/metabolismo
10.
Aerosp Med Hum Perform ; 93(6): 487-492, 2022 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-35729759

RESUMO

BACKGROUND: Modafinil, as a wake-promoting agent, is commonly used to relieve fatigue during military operations. However, there is a lack of clarity regarding the effects of modafinil on the equilibrium and vestibular organs, especially when prescribing this drug to flight crewmembers. The objective of this study was to evaluate the equilibrium- and vestibular-related safety effects of modafinil.METHODS: In a randomized, double-blind, placebo-controlled, crossover study, 10 healthy male volunteers received a single 200-mg oral dose of modafinil or placebo. Equilibrium and vestibular functions were assessed 2 h after oral administration by the sensory organization test (SOT), adaptation test (ADT), and video head impulse test (v-HIT).RESULTS: There was no change in the equilibrium scores of the six SOT conditions or the composite scores between the modafinil and placebo groups. Statistically significant differences were not observed for the sway energy score (SES) in the toe-down test. In the toe-up test, the SES decreased by 16.7% in the modafinil group relative to the placebo group in trial 2, while the differences in other trials were not statistically significant. In the v-HIT, there was no significant difference in the gain of each semicircular canal between the two groups.DISCUSSION: A single 200-mg dose of modafinil did not cause any impairment to vestibular function, equilibrium ability, or adaptive balance response; in fact, modafinil might have a positive effect on adaptation function in healthy volunteers. These findings preliminarily suggest that there is no hidden risk of vestibular dysfunction among aviation employees using modafinil.Liu F, Zhang M, Chen T, Zhai L, Zhang Z, Xue J. Equilibrium and vestibular safety of modafinil in healthy volunteers. Aerosp Med Hum Perform. 2022; 93(6):487-492.


Assuntos
Estimulantes do Sistema Nervoso Central , Vestíbulo do Labirinto , Compostos Benzidrílicos/efeitos adversos , Estimulantes do Sistema Nervoso Central/farmacologia , Estudos Cross-Over , Método Duplo-Cego , Voluntários Saudáveis , Humanos , Masculino , Modafinila/efeitos adversos
11.
Hum Brain Mapp ; 43(14): 4225-4238, 2022 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-35670369

RESUMO

Stimulants like methylphenidate, modafinil, and caffeine have repeatedly shown to enhance cognitive processes such as attention and memory. However, brain-functional mechanisms underlying such cognitive enhancing effects of stimulants are still poorly characterized. Here, we utilized behavioral and resting-state fMRI data from a double-blind randomized placebocontrolled study of methylphenidate, modafinil, and caffeine in 48 healthy male adults. The results show that performance in different memory tasks is enhanced, and functional connectivity (FC) specifically between the frontoparietal network (FPN) and default mode network (DMN) is modulated by the stimulants in comparison to placebo. Decreased negative connectivity between right prefrontal and medial parietal but also between medial temporal lobe and visual brain regions predicted stimulant-induced latent memory enhancement. We discuss dopamine's role in attention and memory as well as its ability to modulate FC between large-scale neural networks (e.g., FPN and DMN) as a potential cognitive enhancement mechanism.


Assuntos
Estimulantes do Sistema Nervoso Central , Metilfenidato , Adulto , Encéfalo/diagnóstico por imagem , Mapeamento Encefálico/métodos , Cafeína/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Cognição , Método Duplo-Cego , Humanos , Imageamento por Ressonância Magnética/métodos , Masculino , Metilfenidato/farmacologia , Modafinila/farmacologia , Vias Neurais/diagnóstico por imagem
12.
Neurobiol Learn Mem ; 192: 107625, 2022 07.
Artigo em Inglês | MEDLINE | ID: mdl-35504555

RESUMO

We aimed to explore whether modafinil mitigates the working memory decline induced by 36 h of acute total sleep deprivation (36-h TSD). Sixteen healthy male participants were enrolled in a randomized double-blind crossover control study involving three sleep-deprivation sessions. Participants were administered 400 mg of placebo, caffeine, or modafinil during these sessions. Behavior and EEG data were recorded while participants performed pronunciation-related working memory tasks. Behavioral indicators showed that, compared with placebo, modafinil improved the accuracy of pronunciation-related working memory tasks and reduced the response time. Compared with before sleep deprivation, the amplitudes of the event-related potentials (ERPs) increased in the N2 component and decreased in the P3 component after sleep deprivation in the placebo condition. In the caffeine condition, the amplitude of the P3 component decreased, the latency of the N2 component was prolonged, and the N2 amplitude remained unchanged. In the modafinil condition, the P3 latency was shortened, and no significant difference was found in the amplitude of the N2 or P3 ERPs; no significant difference was recorded in the N2 latency. Modafinil (400 mg) effectively ameliorated the decline in pronunciation-related working memory after 36-h TSD, suggesting that it may effectively counteract cognitive decline caused by acute sleep deprivation.


Assuntos
Estimulantes do Sistema Nervoso Central , Privação do Sono , Compostos Benzidrílicos/farmacologia , Cafeína , Estimulantes do Sistema Nervoso Central/farmacologia , Humanos , Masculino , Memória de Curto Prazo , Modafinila , Privação do Sono/tratamento farmacológico
13.
Pharmacol Biochem Behav ; 217: 173407, 2022 06.
Artigo em Inglês | MEDLINE | ID: mdl-35605783

RESUMO

Modafinil (MOD) is a wakefulness promoter used to treat sleep disorders such as narcolepsy and obstructive sleep apnea. Its action mechanism consists in inhibiting dopamine (DAT) and norepinephrine (NET) transporters, but it has no affinity for the serotonin transporter (SERT). Modafinil's addictive potential is not yet clear, but one feature that differentiates it from potentially addictive drugs like cocaine revolves around affinity for SERT. The aims of the present study were to determine whether co-administration of MOD with the selective serotonin reuptake inhibitor citalopram (CIT) can increase MOD's psychostimulant effects on motor activity (MA), verify the effects of subsequent self-administration of MOD mixed with CIT, and document the presence of any symptoms of withdrawal. At 60 postnatal days (PD), male Wistar rats were treated chronically (16 days) with MOD at 30 or 60 mg/kg, with MOD+CIT at four dosage combinations administered to four groups (30MOD + CIT3, 30MOD + CIT5, 60MOD + CIT3, 60MOD + CIT5 mg/kg), or with a vehicle. After 40 min of daily drug administration, MA was measured on the open field test. MA increased only in the 60MOD group. The rats co-administered with 30MOD + 3CIT and 60MOD + 3CIT showed a decrease in the motivation to seek a pleasurable stimulus (lower consumption of sweet solution) after treatment concluded. The 60MOD and 60MOD + 3CIT groups showed MA sensitization after MOD intake. Additionally, higher self-administration of the mixture was observed in the groups pre-treated with 30MOD + 3CIT and 60MOD + 3CIT. Results suggest that serotonergic activity enhances modafinil's psychostimulant effects.


Assuntos
Estimulantes do Sistema Nervoso Central , Citalopram , Animais , Compostos Benzidrílicos/farmacologia , Estimulantes do Sistema Nervoso Central/farmacologia , Citalopram/farmacologia , Proteínas da Membrana Plasmática de Transporte de Dopamina , Masculino , Modafinila/farmacologia , Ratos , Ratos Wistar , Proteínas da Membrana Plasmática de Transporte de Serotonina
14.
Ann Behav Med ; 56(10): 989-1001, 2022 Oct 03.
Artigo em Inglês | MEDLINE | ID: mdl-35512392

RESUMO

BACKGROUND: Patients receiving placebo in clinical trials often report side-effects (nocebo effects), but contributing factors are still poorly understood. PURPOSE: Using a sham trial of the cognition-enhancing "smart pill" Modafinil we tested whether medication beliefs and other psychological factors predicted detection and attribution of symptoms as side-effects to placebo. METHODS: Healthy students (n = 201) completed measures assessing beliefs about medication, perceived sensitivity to medicines, negative affectivity, somatization, and body awareness; 66 were then randomized to receive Deceptive Placebo (told Modafinil-given placebo, 67 to Open Placebo (told placebo-given placebo, and 68 to No Placebo. Memory and attention tasks assessed cognitive enhancement. Nocebo effects were assessed by symptom checklist. RESULTS: More symptoms were reported in the Deceptive Placebo condition (M = 2.65; SD = 2.27) than Open Placebo (M = 1.92; SD = 2.24; Mann-Whitney U = 1,654, z = 2.30, p = .022) or No Placebo (M = 1.68; SD = 1.75, Mann-Whitney U = 1,640, z = 2.74, p = .006). Participants were more likely to attribute symptoms to Modafinil side-effects if they believed pharmaceuticals to be generally harmful (incidence rate ratio [IRR] = 1.70, p = .019), had higher perceived sensitivity to medicines (IRR = 1.68, p = .011), stronger concerns about Modafinil (IRR = 2.10, p < .001), and higher negative affectivity (IRR = 2.37, p < .001). CONCLUSIONS: Beliefs about medication are potentially modifiable predictors of the nocebo effect. These findings provide insight into side-effect reports to placebo and, potentially, active treatment.


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Cognição , Humanos , Modafinila/efeitos adversos , Efeito Nocebo , Preparações Farmacêuticas
15.
Psychopharmacology (Berl) ; 239(8): 2573-2584, 2022 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-35471613

RESUMO

RATIONALE: Modafinil has been proposed as a potentially effective clinical treatment for neuropsychiatric disorders characterized by cognitive control deficits. However, the precise effects of modafinil, particularly on brain network functions, are not completely understood. OBJECTIVES: To address this gap, we examined the effects of modafinil on resting-state brain activity in 30 healthy adults using microstate analysis. Electroencephalographic (EEG) microstates are discrete voltage topographies generated from resting-state network activity. METHODS: Using a placebo-controlled, within-subjects design, we examined changes to microstate parameters following placebo (0 mg), low (100 mg), and high (200 mg) modafinil doses. We also examined the functional significance of these microstates via associations between microstate parameters and event-related potential indexes of conflict monitoring and automatic error processing (N2 and error-related negativity) and behavioral responses (accuracy and RT) from a subsequent flanker interference task. RESULTS: Five microstates emerged following each treatment condition, including four canonical microstates (A-D). Modafinil increased microstate C proportion and occurrence regardless of dose, relative to placebo. Modafinil also decreased microstate A proportion and microstate B proportion and occurrence relative to placebo. These modafinil-related changes in microstate parameters were not associated with similar changes in flanker ERPs or behavior. Finally, modafinil made transitions between microstates A and B less likely and transitions from A and B to C more likely. CONCLUSIONS: Previous fMRI work has correlated microstates A and B with auditory and visual networks and microstate C with a salience network. Thus, our results suggest modafinil may deactivate large-scale sensory networks in favor of a higher order functional network during resting-state in healthy adults.


Assuntos
Transtornos Cognitivos , Disfunção Cognitiva , Adulto , Encéfalo/fisiologia , Eletroencefalografia , Humanos , Modafinila/farmacologia
16.
Drugs ; 82(6): 633-647, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-35366192

RESUMO

'Smart drugs' (also known as 'nootropics' and 'cognitive enhancers' [CEs]) are being used by healthy subjects (i.e. students and workers) typically to improve memory, attention, learning, executive functions and vigilance, hence the reference to a 'pharmaceutical cognitive doping behaviour'. While the efficacy of known CEs in individuals with memory or learning deficits is well known, their effect on non-impaired brains is still to be fully assessed. This paper aims to provide an overview on the prevalence of use; putative neuroenhancement benefits and possible harms relating to the intake of the most popular CEs (e.g. amphetamine-type stimulants, methylphenidate, donepezil, selegiline, modafinil, piracetam, benzodiazepine inverse agonists, and unifiram analogues) in healthy individuals. CEs are generally perceived by the users as effective, with related enthusiastic anecdotal reports; however, their efficacy in healthy individuals is uncertain and any reported improvement temporary. Conversely, since most CEs are stimulants, the related modulation of central noradrenaline, glutamate, and dopamine levels may lead to cardiovascular, neurological and psychopathological complications. Furthermore, use of CEs can be associated with paradoxical short- and long-term cognitive decline; decreased potential for plastic learning; and addictive behaviour. Finally, the non-medical use of any potent psychotropic raises serious ethical and legal issues, with nootropics having the potential to become a major public health concern. Further studies investigating CE-associated social, psychological, and biological outcomes are urgently needed to allow firm conclusions to be drawn on the appropriateness of CE use in healthy individuals.


Assuntos
Estimulantes do Sistema Nervoso Central , Metilfenidato , Nootrópicos , Encéfalo , Estimulantes do Sistema Nervoso Central/efeitos adversos , Cognição , Humanos , Metilfenidato/farmacologia , Modafinila/farmacologia , Nootrópicos/efeitos adversos
17.
Biomolecules ; 12(4)2022 03 27.
Artigo em Inglês | MEDLINE | ID: mdl-35454095

RESUMO

Previous studies have shown that atypical dopamine-transporter-inhibitors such as modafinil and its analogues modify behavioral and cognitive functions in rodents. Here, we tested potential promnestic effects of the novel, more dopamine-transporter selective modafinil analogue CE-158 in the social discrimination memory task in male mice. Systemic administration of CE-158 1 h before the social learning event prevented the impairment of social-recognition memory following retroactive interference 3 h after the learning session of a juvenile conspecific. This effect was dose-dependent, as mice treated with 10 mg/kg, but not with 1 mg/kg CE-158, were able to discriminate between the novel and familiar conspecific despite the presentation of an interference stimulus, both 3 h and 6 h post learning. However, when 10 mg/kg of the drug was administered after learning, CE-158 failed to prevent social memory from interference. Paralleling these behavioral effects, the systemic administration of 10 mg/kg CE-158 caused a rapid and sustained elevation of extracellular dopamine in the nucleus accumbens, a brain area where dopaminergic signaling plays a key role in learning and memory function, of freely moving mice, while 1 mg/kg was not sufficient for altering dopamine levels. Taken together, our findings suggest promnestic effects of the novel dopamine-transporter-inhibitor CE-158 in a social recognition memory test that may be in part mediated via increased dopamine-neurotransmission in the nucleus accumbens. Thus, selective-dopamine-transporter-inhibitors such as CE-158 may represent interesting drug candidates for the treatment of memory complaints observed in humans with cognitive impairments and dementia.


Assuntos
Dopamina , Núcleo Accumbens , Animais , Aprendizagem , Masculino , Camundongos , Modafinila/farmacologia , Reconhecimento Psicológico
18.
Epilepsy Behav ; 130: 108649, 2022 05.
Artigo em Inglês | MEDLINE | ID: mdl-35344809

RESUMO

BACKGROUND: Status epilepticus (SE) is a continuous episode of seizures which leads to hippocampal neurodegeneration, severe systemic inflammation, and extreme damage to the brain. Modafinil, a psychostimulant and wake-promoting agent, has exerted neuroprotective and anti-inflammatory effects in previous preclinical studies. The aim of this study was to assess effects of modafinil on the lithium-pilocarpine-induced SE rat model and to explore possible involvement of tumor necrosis factor-α (TNF-α) and nitric oxide (NO) pathways in this regard. METHODS: Status epilepticus was provoked by injection of lithium chloride (127 mg/kg, intraperitoneally [i.p]) and pilocarpine (60 mg/kg, i.p.) in rats. Animals received different modafinil doses (50, 75, 100, and 150 mg/kg, i.p.) and SE scores were documented over 3 hours of duration. Moreover, the role of the nitrergic pathway in the effects of modafinil was evaluated by injection of the non-selective NO synthase (NOS) inhibitor L-NG-Nitro arginine methyl ester (L-NAME, 10 mg/kg, i.p.), the selective neuronal NOS inhibitor 7-nitroindazole (30 mg/kg, i.p.), and the selective inducible NOS inhibitor aminoguanidine (100 mg/kg, i.p.) 15 min before saline/vehicle or modafinil. The ELISA method was used to quantify TNF-α and NO metabolite levels in the isolated hippocampus. RESULTS: Modafinil at 100 mg/kg significantly decreased SE scores (P < 0.01). Pre-treatment with L-NAME, 7-nitroindazole, and aminoguanidine significantly reversed the anticonvulsive effects of modafinil. Status epilepticus-induced animals showed significantly higher NO metabolite and TNF-α levels in their hippocampal tissues, an effect that was reversed by modafinil (100 mg/kg, i.p.) treatment. Administration of NOS inhibitors resulted in excessive NO level reduction but an escalation of TNF-α level in modafinil-treated SE-animals. CONCLUSION: Our study revealed anticonvulsive effects of modafinil in the lithium-pilocarpine-induced SE rat model via possible involvement of TNF-α and nitrergic pathways.


Assuntos
Pilocarpina , Estado Epiléptico , Animais , Humanos , Lítio/efeitos adversos , Modafinila/efeitos adversos , NG-Nitroarginina Metil Éster/farmacologia , Óxido Nítrico/metabolismo , Pilocarpina/farmacologia , Ratos , Estado Epiléptico/induzido quimicamente , Estado Epiléptico/tratamento farmacológico , Estado Epiléptico/patologia , Fator de Necrose Tumoral alfa
19.
Brain ; 145(5): 1854-1865, 2022 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-35150243

RESUMO

Option generation is a critical process in decision making, but previous studies have largely focused on choices between options given by a researcher. Consequently, how we self-generate options for behaviour remain poorly understood. Here, we investigated option generation in major depressive disorder and how dopamine might modulate this process, as well as the effects of modafinil (a putative cognitive enhancer) on option generation in healthy individuals. We first compared differences in self-generated options between healthy non-depressed adults [n = 44, age = 26.3 years (SD 5.9)] and patients with major depressive disorder [n = 54, age = 24.8 years (SD 7.4)]. In the second study, a subset of depressed individuals [n = 22, age = 25.6 years (SD 7.8)] underwent PET scans with 11C-raclopride to examine the relationships between dopamine D2/D3 receptor availability and individual differences in option generation. Finally, a randomized, double-blind, placebo-controlled, three-way crossover study of modafinil (100 mg and 200 mg), was conducted in an independent sample of healthy people [n = 19, age = 23.2 years (SD 4.8)] to compare option generation under different doses of this drug. The first study revealed that patients with major depressive disorder produced significantly fewer options [t(96) = 2.68, P = 0.009, Cohen's d = 0.54], albeit with greater uniqueness [t(96) = -2.54, P = 0.01, Cohen's d = 0.52], on the option generation task compared to healthy controls. In the second study, we found that 11C-raclopride binding potential in the putamen was negatively correlated with fluency (r = -0.69, P = 0.001) but positively associated with uniqueness (r = 0.59, P = 0.007). Hence, depressed individuals with higher densities of unoccupied putamen D2/D3 receptors in the putamen generated fewer but more unique options, whereas patients with lower D2/D3 receptor availability were likely to produce a larger number of similar options. Finally, healthy participants were less unique [F(2,36) = 3.32, P = 0.048, partial η2 = 0.16] and diverse [F(2,36) = 4.31, P = 0.021, partial η2 = 0.19] after taking 200 mg versus 100 mg and 0 mg of modafinil, while fluency increased linearly with dosage at a trend level [F(1,18) = 4.11, P = 0.058, partial η2 = 0.19]. Our results show, for the first time, that option generation is affected in clinical depression and that dopaminergic activity in the putamen of patients with major depressive disorder may play a key role in the self-generation of options. Modafinil was also found to influence option generation in healthy people by reducing the creativity of options produced.


Assuntos
Transtorno Depressivo Maior , Dopamina , Adulto , Estudos Cross-Over , Depressão , Transtorno Depressivo Maior/diagnóstico por imagem , Transtorno Depressivo Maior/tratamento farmacológico , Dopamina/metabolismo , Humanos , Modafinila/uso terapêutico , Tomografia por Emissão de Pósitrons/métodos , Racloprida , Receptores de Dopamina D3 , Adulto Jovem
20.
J Cogn Neurosci ; 34(5): 864-876, 2022 03 31.
Artigo em Inglês | MEDLINE | ID: mdl-35195725

RESUMO

Errors in performance trigger cognitive and neural changes that are implemented to adaptively adjust to fluctuating demands. Error-related alpha suppression (ERAS)-which refers to decreased power in the alpha frequency band after an incorrect response-is thought to reflect cognitive arousal after errors. Much of this work has been correlational, however, and there are no direct investigations into its pharmacological sensitivity. In Study 1 (n = 61), we evaluated the presence and scalp distribution of ERAS in a novel flanker task specifically developed for cross-species assessments. Using this same task in Study 2 (n = 26), which had a placebo-controlled within-subject design, we evaluated the sensitivity of ERAS to placebo (0 mg), low (100 mg), and high (200 mg) doses of modafinil, a wakefulness promoting agent. Consistent with previous work, ERAS was maximal at parieto-occipital recording sites in both studies. In Study 2, modafinil did not have strong effects on ERAS (a significant Accuracy × Dose interaction emerged, but drug-placebo differences did not reach statistical significance after correction for multiple comparisons and was absent after controlling for accuracy rate). ERAS was correlated with accuracy rates in both studies. Thus, modafinil did not impact ERAS as hypothesized, and findings indicate ERAS may reflect an orienting response to infrequent events.


Assuntos
Compostos Benzidrílicos , Couro Cabeludo , Nível de Alerta , Compostos Benzidrílicos/farmacologia , Compostos Benzidrílicos/uso terapêutico , Método Duplo-Cego , Humanos , Modafinila/farmacologia , Modafinila/uso terapêutico , Vigília
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