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1.
Pharmacol Biochem Behav ; 186: 172765, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31470022

RESUMO

The present study investigated the influence of Vyvanse (lisdexamfetamine), a psychomotor stimulant, on spatial working memory, body weight, and adiposity in rats. Control and experimental rats were placed in individual cages equipped with a running wheel, and food and water were provided ad-libitum. The study was divided into three periods: 1) habituation, 2) experimental, and 3) withdrawal. Control rats received a placebo in periods 1, 2 and 3, while experimental rats received a placebo in periods 1 and 3. Experimental rats received a treatment of Vyvanse in place of the placebo during period 2. Spatial working memory was examined by utilizing the methodology of the Morris Water Maze. Rats were evaluated by performance in the maze each day during the experimental and withdrawal periods. Each assessment consisted of two trials. The first was a sample trial in which an escape platform was discovered by trial and error. The second was a test trial in which the platform location was recalled using working memory. Platform placement and start location of the rats were changed every session. It was hypothesized that Vyvanse would effectively enhance spatial working memory, and significantly decrease body weight and adiposity without side effects on activity level and anxiety in rats. Results supported the hypothesis. Compared to control rats, Vyvanse treated rats had significant improvement in working memory and significantly lowered body weight, as well as significantly decreased mesenteric, renal, and epididymal adiposity. No significant effects on activity level and task specific anxiety were noted in experimental animals. When compared to placebo treatment, Vyvanse treatment produced no significant influence on food and water intake. It was concluded that Vyvanse treatment in rats can enhance spatial working memory, and decrease adiposity without suppressing normal appetite.


Assuntos
Adiposidade/efeitos dos fármacos , Estimulantes do Sistema Nervoso Central/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Memória de Curto Prazo/efeitos dos fármacos , Pró-Fármacos/farmacologia , Animais , Peso Corporal/efeitos dos fármacos , Aprendizagem em Labirinto , Ratos
3.
Psychiatry Res Neuroimaging ; 286: 53-59, 2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-30903953

RESUMO

We examined the effects of lisdexamfetamine (LDX) treatment on ventral prefrontal cortex (VPFC) and striatal brain activation in binge eating disorder (BED). We hypothesized that participants with BED have an abnormal brain response to palatable food cues, and that VPFC and striatal regions would respond to such cues after LDX treatment. Twenty women with moderate to severe BED consented to a 12-week, open-label trial of LDX with fMRI before and after treatment. Twenty obese women without BED served as healthy controls and received one fMRI. LDX was started at 30 mg/d with a target of 70 mg/d at week 12. At baseline, women with BED showed greater activation in ventrolateral prefrontal cortex (VLPFC), striatum, and globus pallidus to food pictures and brain activation to food pictures predicted clinical outcome at 12 weeks. After 12 weeks of LDX treatment, BED women showed significant reductions in globus pallidus activation. Reductions in ventromedial prefrontal cortex (VMPFC) and thalamus activation specifically correlated with binge eating and obsessive-compulsive symptom reductions, respectively. Results suggest that BED is characterized by an abnormally large VPFC-subcortical brain response to palatable foods that LDX treatment helps modify. Moreover, VPFC-subcortical activation at baseline is a potential biomarker of LDX response.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Encéfalo/efeitos dos fármacos , Inibidores da Captação de Dopamina/uso terapêutico , Dimesilato de Lisdexanfetamina/uso terapêutico , Rede Nervosa/efeitos dos fármacos , Obesidade/tratamento farmacológico , Adulto , Transtorno da Compulsão Alimentar/diagnóstico por imagem , Transtorno da Compulsão Alimentar/fisiopatologia , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Corpo Estriado/diagnóstico por imagem , Corpo Estriado/efeitos dos fármacos , Corpo Estriado/fisiologia , Inibidores da Captação de Dopamina/farmacologia , Feminino , Humanos , Dimesilato de Lisdexanfetamina/farmacologia , Pessoa de Meia-Idade , Rede Nervosa/diagnóstico por imagem , Rede Nervosa/fisiologia , Obesidade/diagnóstico por imagem , Obesidade/fisiopatologia , Projetos Piloto , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiologia , Resultado do Tratamento
4.
J Steroid Biochem Mol Biol ; 186: 212-225, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30381248

RESUMO

The novel d-amphetamine prodrug lisdexamfetamine is applied to treat attention-deficit/hyperactivity disorder (ADHD). d-Amphetamine releases dopamine and norepinephrine and stimulates the hypothalamic-pituitary-adrenal (HPA) axis, which may contribute to its reinforcing effects and risk of abuse. However, no data is currently available on the effects of lisdexamfetamine on circulating steroids. This randomized, double-blind, placebo-controlled, cross-over study evaluated the effects of equimolar doses of d-amphetamine (40 mg) and lisdexamfetamine (100 mg) and placebo on circulating steroids in 24 healthy subjects. Plasma steroid and d-amphetamine levels were determined up to 24 h. Delayed increase and peak levels of plasma d-amphetamine concentrations were observed following lisdexamfetamine treatment compared with d-amphetamine administration, however the maximal concentrations and total exposure (area under the curve [AUC]) were similar. Lisdexamfetamine and d-amphetamine significantly enhanced plasma levels of adrenocorticotropic hormone, glucocorticoids (cortisol, cortisone, corticosterone, 11-dehydrocorticosterone, and 11-deoxycortisol), androgens (dehydroepiandrosterone, dehydroepiandrosterone sulfate, and Δ4-androstene-3,17-dione [androstenedione]), and progesterone (only in men) compared with placebo. Steroid concentration-time curves were shifted to later time points due to a non-significantly later onset following lisdexamfetamine administration than after d-amphetamine, however maximal plasma steroid concentrations and AUCs did not differ between the active treatments. None of the active treatments altered plasma levels of the mineralocorticoids aldosterone and 11-deoxycorticosterone or the androgen testosterone compared with placebo. The effects of the amphetamines on glucocorticoid production were similar to those that were previously reported for methylphenidate (60 mg) but weaker than those for the serotonin releaser 3,4-methylenedioxymethamphetamine (MDMA; 125 mg) or direct serotonin receptor agonist lysergic acid diethylamide (LSD; 0.2 mg). Lisdexamfetamine produced comparable HPA axis activation and had similar pharmacokinetics than d-amphetamine, except for a delayed time of onset. Thus, serotonin (MDMA, LSD) may more effectively stimulate the HPA axis than dopamine and norepinephrine (D-amphetamine).


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dextroanfetamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Esteroides/sangue , Hormônio Adrenocorticotrópico/sangue , Adulto , Estudos Cross-Over , Método Duplo-Cego , Feminino , Humanos , Masculino , Efeito Placebo , Adulto Jovem
5.
Artigo em Inglês | MEDLINE | ID: mdl-29661516

RESUMO

BACKGROUND: Prefrontal-limbic circuits that form the neural architecture for emotion to influence behavior have been implicated in the pathophysiology of attention-deficit/hyperactivity disorder (ADHD) and represent a potentially important target of medication treatment that has not been substantively evaluated. This study tested the effect of the psychostimulant prodrug lisdexamfetamine dimesylate on amygdala activation and connectivity during the emotional bias of response execution and inhibition. METHODS: Twenty-five adults with ADHD were scanned twice with event-related functional magnetic resonance imaging while performing an emotional go/no-go task after 3 to 4 weeks of lisdexamfetamine treatment and 3 weeks off medication in a randomized, counterbalanced, hybrid crossover design. Drug, trial type, and face emotion (happy, sad, or neutral) were included as within-subjects factors in repeated measures analyses of activation and connectivity. RESULTS: Lisdexamfetamine was associated with increased right amygdala activation and reduced psychophysiological interactions with the orbital aspect of the left inferior frontal gyrus specifically for responses to sad faces compared with placebo, but there was no effect on the accuracy of response execution or inhibition. The relative gain in right amygdala activation in response to sad faces for lisdexamfetamine was correlated with a reduction in symptoms of ADHD. CONCLUSIONS: Treatment with lisdexamfetamine potentiates affective encoding in amygdala, purportedly via catecholaminergic mechanisms, but functionally disconnects the amygdala from inferior frontal regions that encode behavioral significance-resulting in reduced emotional bias of cognitive control. Pinpointing the neurophysiologic underpinnings of therapeutic improvement with lisdexamfetamine represents a first step in developing targeted approaches to treatment of ADHD.


Assuntos
Tonsila do Cerebelo , Transtorno do Deficit de Atenção com Hiperatividade , Estimulantes do Sistema Nervoso Central/farmacologia , Emoções , Função Executiva , Neuroimagem Funcional/métodos , Dimesilato de Lisdexanfetamina/farmacologia , Córtex Pré-Frontal , Adulto , Tonsila do Cerebelo/diagnóstico por imagem , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/fisiopatologia , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico por imagem , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Transtorno do Deficit de Atenção com Hiperatividade/fisiopatologia , Estudos Cross-Over , Emoções/efeitos dos fármacos , Emoções/fisiologia , Função Executiva/efeitos dos fármacos , Função Executiva/fisiologia , Expressão Facial , Feminino , Humanos , Inibição Psicológica , Imagem por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Córtex Pré-Frontal/diagnóstico por imagem , Córtex Pré-Frontal/efeitos dos fármacos , Córtex Pré-Frontal/fisiopatologia , Adulto Jovem
6.
Psychopharmacology (Berl) ; 235(5): 1389-1402, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29511807

RESUMO

RATIONALE: Amphetamines are used as medications but are also misused as cognitive enhancers by healthy subjects and may have additional effects on social cognition. METHODS: We investigated the acute effects of single, high, equimolar doses of D-amphetamine (40 mg) and lisdexamfetamine (100 mg) on social cognition and cognitive performance using a randomized, placebo-controlled, double-blind, cross-over design in 24 healthy volunteers. Effects on social cognition were assessed using the Facial Emotion Recognition Task (FERT), Multifaceted Empathy Test (MET), and Sexual Arousal Task (SAT). Cognitive performance was measured using the Digit Symbol Substitution Test (DSST), Digit Span (DS), Stop-Signal Task (SST), and Mackworth Clock Test (MCT). RESULTS: D-Amphetamine and lisdexamfetamine had small effects on measures of social cognition. There were no effects on emotion recognition on the FERT. D-Amphetamine increased direct empathy on the MET, but only for positive stimuli. Both amphetamines increased ratings of pleasantness and attractiveness on the SAT in response to sexual but also to neutral stimuli. D-Amphetamine and lisdexamfetamine increased cognitive performance (go-accuracy and vigilance on the SST and MCT, respectively). Lisdexamfetamine increased processing speed on the DSST. Neither drug had an effect on the DS. CONCLUSION: Single, high, equimolar doses of D-amphetamine and lisdexamfetamine enhanced certain aspects of cognitive performance in healthy non-sleep-deprived subjects. Both amphetamines also slightly altered aspects of social cognition. Whether these small effects also influence social interaction behavior in amphetamine users remains to be investigated. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT02668926).


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Cognição/efeitos dos fármacos , Dextroanfetamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Testes Neuropsicológicos , Comportamento Social , Adulto , Cognição/fisiologia , Estudos Cross-Over , Método Duplo-Cego , Emoções/efeitos dos fármacos , Emoções/fisiologia , Feminino , Voluntários Saudáveis , Humanos , Masculino , Comportamento Sexual/efeitos dos fármacos , Comportamento Sexual/fisiologia , Comportamento Sexual/psicologia , Adulto Jovem
7.
Int J Eat Disord ; 50(8): 884-892, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28481434

RESUMO

OBJECTIVE: This study examined the time course of efficacy-related endpoints for lisdexamfetamine dimesylate (LDX) versus placebo in adults with protocol-defined moderate to severe binge-eating disorder (BED). METHODS: In two 12-week, double-blind, placebo-controlled studies, adults meeting DSM-IV-TR BED criteria were randomized 1:1 to receive placebo or dose-optimized LDX (50 or 70 mg). Analyses across visits used mixed-effects models for repeated measures (binge eating days/week, binge eating episodes/week, Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE] scores, percentage body weight change) and chi-square tests (Clinical Global Impressions-Improvement [CGI-I; from the perspective of BED symptoms] scale dichotomized as improved or not improved). These analyses were not part of the prespecified testing strategy, so reported p values are nominal (unadjusted and descriptive only). RESULTS: Least squares mean treatment differences for change from baseline in both studies favored LDX over placebo (all nominal p values < .001) starting at Week 1 for binge eating days/week, binge-eating episodes/week, and percentage weight change and at the first posttreatment assessment (Week 4) for Y-BOCS-BE total and domain scores. On the CGI-I, more participants on LDX than placebo were categorized as improved starting at Week 1 in both studies (both nominal p values < .001). Across these efficacy-related endpoints, the superiority of LDX over placebo was maintained at each posttreatment assessment in both studies (all nominal p values < .001). DISCUSSION: In adults with BED, LDX treatment appeared to be associated with improvement on efficacy measures as early as 1 week, which was maintained throughout the 12-week studies.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/uso terapêutico , Dimesilato de Lisdexanfetamina/uso terapêutico , Adulto , Estimulantes do Sistema Nervoso Central/farmacologia , Método Duplo-Cego , Feminino , Humanos , Dimesilato de Lisdexanfetamina/farmacologia , Masculino , Resultado do Tratamento
8.
J Clin Psychopharmacol ; 37(3): 315-322, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28383364

RESUMO

BACKGROUND: A 12-month, open-label extension study assessed the long-term safety and tolerability of lisdexamfetamine dimesylate (LDX) in adults with binge eating disorder (BED). METHODS: Adults (aged 18-55 y) with BED who completed 1 of 3 antecedent studies were enrolled in a 52-week, open-label extension study (dose optimization, 4 weeks [initial titration dose, 30-mg LDX; target doses, 50- or 70-mg LDX]; dose maintenance, 48 weeks). Safety evaluations included the occurrence of treatment-emergent adverse events (TEAEs), vital sign and weight assessments, and Columbia-Suicide Severity Rating Scale responses. RESULTS: Of the 604 enrolled participants, 599 (521 women and 78 men) comprised the safety analysis set, and 369 completed the study. Mean (SD) LDX exposure was 284.3 (118.84) days; cumulative LDX exposure duration was 12 months or longer in 344 participants (57.4%). A total of 506 participants (84.5%) reported TEAEs (TEAEs leading to treatment discontinuation, 54 [9.0%]; severe TEAEs, 42 [7.0%]; serious TEAEs, 17 [2.8%]). Treatment-emergent adverse events reported in greater than or equal to 10% of participants were dry mouth (27.2%), headache (13.2%), insomnia (12.4%), and upper respiratory tract infection (11.4%). Mean (SD) changes from antecedent study baseline in systolic and diastolic blood pressure, pulse, and weight at week 52/early termination (n = 597) were 2.19 (11.043) and 1.77 (7.848) mm Hg, 6.58 (10.572) beats per minute, and -7.04 (7.534) kg, respectively. On the Columbia-Suicide Severity Rating Scale, there were 2 positive responses for any active suicidal ideations; there were no positive responses for suicidal behavior or completed suicides. CONCLUSIONS: In this 12-month, open-label, extension study, the long-term safety and tolerability of LDX in adults with BED were generally consistent with its established profile for attention-deficit/hyperactivity disorder.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Inibidores da Captação de Dopamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Avaliação de Resultados em Cuidados de Saúde , Adolescente , Adulto , Inibidores da Captação de Dopamina/administração & dosagem , Inibidores da Captação de Dopamina/efeitos adversos , Esquema de Medicação , Feminino , Humanos , Dimesilato de Lisdexanfetamina/administração & dosagem , Dimesilato de Lisdexanfetamina/efeitos adversos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
9.
J Psychopharmacol ; 31(6): 784-797, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28372478

RESUMO

Freely-fed, female, rats were trained in a two-lever, delay-discounting task: one lever delivered a single chocolate-flavoured pellet immediately and the other a three-pellet reward after increasing delay (0, 4, 8, 16, 32 s). Rats were divided into two groups (i.e. binge-eating rats given irregular, limited access to chocolate in addition to normal chow and controls maintained on normal chow). Both groups exhibited increased preference for the immediate reward as the delay interval was lengthened. The discounting rate was significantly greater in binge-eating rats than non-binge-eating controls, especially as the behaviour became more established indicating that increased impulsivity and intolerance of delayed reward are part of the psychopathology of binge-eating. Lisdexamfetamine (0.8 mg/kg, orally ( d-amphetamine base)) reversed the reduced preference of binge-eating rats for larger rewards at delay intervals of 4 s, 8 s and 32 s and across all sessions. Lisdexamfetamine-treated binge-eating rats consumed the same number of pellets as vehicle-treated, binge-eating rats and non-binge-eating controls eliminating the possibility lisdexamfetamine's actions on appetite or satiety mediated its effects on operant responding for food pellets in delay-discounting. In summary, binge-eating rats showed increased impulsive choice compared with non-binge-eating controls that was reversed by lisdexamfetamine, complementing results showing lisdexamfetamine reduced impulsiveness scores in patients with binge-eating disorder.


Assuntos
Bulimia/tratamento farmacológico , Dextroanfetamina/farmacologia , Comportamento Impulsivo/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Pró-Fármacos/farmacologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Feminino , Alimentos , Masculino , Ratos , Ratos Wistar , Recompensa
10.
J Atten Disord ; 21(14): 1198-1207, 2017 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24464328

RESUMO

OBJECTIVE: To examine the level of agreement between self- and observer-reported ratings of ADHD symptoms and executive function (EF) behaviors in adults with moderate to severe ADHD and EF deficits. METHOD: During a 10-week, randomized, double-blind, placebo-controlled study, the effect of lisdexamfetamine dimesylate (LDX) on EF was assessed by self-report and informant report (Behavior Rating Inventory of Executive Function-Adult Version), and ADHD symptoms were assessed by clinician- and informant-rated scales (ADHD Rating Scale IV with adult prompts and Conners' Adult ADHD Rating Scales-Observer Report: Short Version, respectively). Post hoc analysis used Pearson correlations to assess relationships between self- and informant-rated EF and clinician- and informant-rated ADHD symptoms. RESULTS: Correlations between self-ratings versus informant ratings and clinician versus informant ratings were greater at Week 10/early termination (EF: placebo [0.5231-0.6085], LDX [0.3543-0.5167]; ADHD symptoms: placebo [0.4169], LDX [0.4004]) versus baseline (EF: placebo [0.3208-0.5023], LDX [0.2852-0.3439]; ADHD symptoms: placebo [0.1511], LDX [-0.0408]). CONCLUSION: LDX improved EF and ADHD symptoms, based on participant, informant, and clinician ratings. Increased rater agreement over time may reflect improved symptom awareness.


Assuntos
Estimulantes do Sistema Nervoso Central/uso terapêutico , Função Executiva/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/uso terapêutico , Adulto , Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Conscientização , Estimulantes do Sistema Nervoso Central/farmacologia , Método Duplo-Cego , Função Executiva/fisiologia , Feminino , Humanos , Dimesilato de Lisdexanfetamina/farmacologia , Masculino , Autorrelato , Resultado do Tratamento , Adulto Jovem
11.
Eur Neuropsychopharmacol ; 26(12): 1900-1908, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27842942

RESUMO

Drug-induced hyperlocomotion in rodents is frequently used as a behavioral model for mania. However, the use of locomotor activity as the single parameter in these animal models of mania may pose some limitations for developing new pharmacological treatments. Thus, alternative behavioral markers are required. Fifty-kHz ultrasonic vocalizations (USV), which are thought to represent positive affect, are increased by the administration of the psychostimulant d-amphetamine, an effect that can be prevented by lithium treatment, the gold standard antimanic drug for treating bipolar disorder. The aim of this study was to evaluate 50-kHz USV in two other pharmacological-induced animal models of mania: ketamine (KET)- and lisdexamfetamine (LDX)-induced hyperlocomotion. After systemic injection of LDX (10mg/kg, ip), racemic-ketamine (25mg/kg, ip) or S-ketamine (25mg/kg, ip), locomotor activity and 50-kHz USV emission were evaluated in rats. Furthermore, the effects of an antimanic treatment, namely lithium carbonate (100mg/kg, ip), on LDX-induced 50-kHz USV and hyperlocomotion were tested. Rats treated with racemic KET and S-KET showed increased locomotor activity, but these drug treatments did not significantly affect 50-kHz USV emission rates. On the other hand, LDX administration increased both locomotor activity and 50-kHz USV with both effects being reversed by lithium administration. The present findings suggest that 50-kHz USV can differentiate between drug-induced models of mania, which may represent different types of manic episodes. Thus, measuring 50-kHz USV might serve as an additional valuable behavioral variable to assess mania-like phenotypes in rat models.


Assuntos
Transtorno Bipolar/induzido quimicamente , Transtorno Bipolar/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/farmacologia , Antagonistas de Aminoácidos Excitatórios/farmacologia , Hipercinese/induzido quimicamente , Hipercinese/tratamento farmacológico , Ketamina/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Vocalização Animal/efeitos dos fármacos , Animais , Antimaníacos/farmacologia , Antimaníacos/uso terapêutico , Transtorno Bipolar/psicologia , Modelos Animais de Doenças , Hipercinese/psicologia , Carbonato de Lítio/farmacologia , Carbonato de Lítio/uso terapêutico , Masculino , Atividade Motora/efeitos dos fármacos , Ratos , Ratos Wistar
12.
Transl Psychiatry ; 6(9): e884, 2016 09 06.
Artigo em Inglês | MEDLINE | ID: mdl-27598968

RESUMO

Stimulant treatment is highly effective in mitigating symptoms associated with attention-deficit/hyperactivity disorder (ADHD), though the neurobiological underpinnings of this effect have not been established. Studies using anatomical magnetic resonance imaging (MRI) in children with ADHD have suggested that long-term stimulant treatment may improve symptoms of ADHD in part by stimulating striatal hypertrophy. This conclusion is limited, however, as these studies have either used cross-sectional sampling or did not assess the impact of treatment length on their dependent measures. We therefore used longitudinal anatomical MRI in a vehicle-controlled study design to confirm causality regarding stimulant effects on striatal morphology in a rodent model of clinically relevant long-term stimulant treatment. Sprague Dawley rats were orally administered either lisdexamfetamine (LDX, 'Vyvanse') or vehicle (N=12 per group) from postnatal day 25 (PD25, young juvenile) until PD95 (young adult), and imaged one day before and one day after the 70-day course of treatment. Our LDX dosing regimen yielded blood levels of dextroamphetamine comparable to those documented in patients. Longitudinal analysis of striatal volume revealed significant hypertrophy in LDX-treated animals when compared to vehicle-treated controls, with a significant treatment by time point interaction. These findings confirm a causal link between long-term stimulant treatment and striatal hypertrophy, and support utility of longitudinal MRI in rodents as a translational approach for bridging preclinical and clinical research. Having demonstrated comparable morphological effects in both humans and rodents using the same imaging technology, future studies may now use this rodent model to identify the underlying cellular mechanisms and behavioral consequences of stimulant-induced striatal hypertrophy.


Assuntos
Estimulantes do Sistema Nervoso Central/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Neostriado/efeitos dos fármacos , Animais , Peso Corporal/efeitos dos fármacos , Dextroanfetamina/sangue , Hipertrofia , Estudos Longitudinais , Imagem por Ressonância Magnética , Masculino , Neostriado/diagnóstico por imagem , Neostriado/patologia , Tamanho do Órgão , Ratos , Ratos Sprague-Dawley
13.
Drug Alcohol Depend ; 165: 103-10, 2016 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-27264165

RESUMO

BACKGROUND: Homologous cocaine self-administration procedures in laboratory animals and humans may facilitate translational research for medications development to treat cocaine dependence. This study, therefore, sought to establish choice between cocaine and an alternative reinforcer in rhesus monkeys responding under a procedure back-translated from previous human studies and homologous to a human laboratory procedure described in a companion paper. METHODS: Four rhesus monkeys with chronic indwelling intravenous catheters had access to cocaine injections (0, 0.043, 0.14, or 0.43mg/kg/injection) and food (0, 1, 3, or 10 1g banana-flavored food pellets). During daily 5h sessions, a single cocaine dose and a single food-reinforcer magnitude were available in 10 30-min trials. During the initial "sample" trial, the available cocaine and food reinforcer were delivered non-contingently. During each of the subsequent nine "choice" trials, responding could produce either the cocaine or food reinforcer under an independent concurrent progressive-ratio schedule. RESULTS: Preference was governed by the cocaine dose and food-reinforcer magnitude, and increasing cocaine doses produced dose-dependent increases in cocaine choice at all food-reinforcer magnitudes. Effects of the candidate medication lisdexamfetamine (0.32-3.2mg/kg/day) were then examined on choice between 0.14mg/kg/injection cocaine and 10 pellets. Under baseline conditions, this reinforcer pair maintained an average of approximately 6 cocaine and 3 food choices. Lisdexamfetamine dose-dependently decreased cocaine choice in all monkeys, but food choice was not significantly altered. CONCLUSIONS: These results support utility of this procedure in rhesus monkeys as one component of a platform for translational research on medications development to treat cocaine use disorder.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Cocaína/farmacologia , Alimentos , Pesquisa Médica Translacional/métodos , Animais , Cocaína/antagonistas & inibidores , Relação Dose-Resposta a Droga , Dimesilato de Lisdexanfetamina/farmacologia , Macaca mulatta , Masculino , Esquema de Reforço , Autoadministração
14.
J Psychopharmacol ; 30(7): 662-75, 2016 07.
Artigo em Inglês | MEDLINE | ID: mdl-27170676

RESUMO

Compulsive and perseverative behaviour in binge-eating, female, Wistar rats was investigated in a novel food reward/punished responding conflict model. Rats were trained to perform the conditioned avoidance response task. When proficient, the paradigm was altered to a food-associated conflict test by placing a chocolate-filled jar (empty jar for controls) in one compartment of the shuttle box. Entry into the compartment with the jar triggered the conditioning stimulus after a variable interval, and foot-shock 10 seconds later if the rat did not leave. Residence in the 'safe' compartment with no jar did not initiate trials or foot-shocks. By frequently entering the chocolate-paired compartment, binge-eating rats completed their 10 trials more quickly than non-binge controls. Binge-eating rats spent a greater percentage of the session in the chocolate-paired compartment, received foot-shocks more frequently, and tolerated foot-shocks for longer periods; all consistent with compulsive and perseverative behaviour. The d-amphetamine prodrug, lisdexamfetamine, has recently received US approval for the treatment of moderate to severe binge-eating disorder in adults. Lisdexamfetamine (0.8 mg/kg po [d-amphetamine base]) decreased chocolate consumption by binge-eating rats by 55% and markedly reduced compulsive and perseverative responding in the model. These findings complement clinical results showing lisdexamfetamine reduced compulsiveness scores in subjects with binge-eating disorder.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Bulimia/tratamento farmacológico , Comportamento Compulsivo/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Animais , Condicionamento Operante/efeitos dos fármacos , Feminino , Ratos , Ratos Wistar , Recompensa
15.
CNS Drugs ; 30(4): 343-54, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-27048350

RESUMO

Lisdexamfetamine dimesylate (lisdexamfetamine) is a long-acting amfetamine prodrug with a convenient once-daily oral regimen that offers the potential for improved adherence and reduced abuse compared with short-acting preparations of amfetamines. Lisdexamfetamine (as Elvanse Adult(®); Tyvense Adult™) has been approved for use in adults with attention-deficit hyperactivity disorder (ADHD) under the EU decentralization procedure, with the first approvals in the UK, Sweden and Denmark. This approval reflects the results of three short-term trials in adults with ADHD in which fixed- or flexible-dose lisdexamfetamine produced significantly greater improvements than placebo in ADHD symptoms, overall functioning, executive functioning (including in patients with significant pre-existing impairment) and quality of life. Of note, a post hoc analysis of one of these studies suggested that the response to lisdexamfetamine was generally similar in treatment-naïve patients and those who had already received-and not responded satisfactorily to-previous ADHD therapies, including methylphenidate (MPH). Two further studies demonstrated the longer-term effectiveness of flexible-dose lisdexamfetamine in reducing ADHD symptoms, albeit maintenance of efficacy required ongoing treatment with the drug. Lisdexamfetamine was generally well tolerated in clinical trials, with an adverse event profile typical of that reported for other long-acting stimulants. Head-to-head comparisons with other long-acting agents, notably MPH and atomoxetine, are lacking. Nonetheless, on the basis of the available data, lisdexamfetamine provides a useful alternative option for the treatment of adults with ADHD, including those who have not responded adequately to previous ADHD therapies, including MPH.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade/tratamento farmacológico , Estimulantes do Sistema Nervoso Central/administração & dosagem , Dimesilato de Lisdexanfetamina/administração & dosagem , Adulto , Estimulantes do Sistema Nervoso Central/efeitos adversos , Estimulantes do Sistema Nervoso Central/farmacologia , Humanos , Dimesilato de Lisdexanfetamina/efeitos adversos , Dimesilato de Lisdexanfetamina/farmacologia
16.
Eur Eat Disord Rev ; 24(3): 223-31, 2016 May.
Artigo em Inglês | MEDLINE | ID: mdl-26621156

RESUMO

In a published 11-week, placebo-controlled trial, 50 and 70 mg/d lisdexamfetamine dimesylate (LDX), but not 30 mg/d LDX, significantly reduced binge eating days (primary endpoint) in adults with binge eating disorder (BED). This report provides descriptions of LDX effects on secondary endpoints (Binge Eating Scale [BES]; Three-Factor Eating Questionnaire [TFEQ]; Yale-Brown Obsessive Compulsive Scale modified for Binge Eating [Y-BOCS-BE]; and the Barratt Impulsiveness Scale, version 11 [BIS-11]) from that study. Week 11 least squares mean treatment differences favoured all LDX doses over placebo on the BES (p ≤ 0.03), TFEQ Disinhibition and Hunger subscales (all p < 0.05), and Y-BOCS-BE total, obsessive, and compulsive scales (all p ≤ 0.02) and on BIS-11 total score at 70 mg/d LDX (p = 0.015) and the TFEQ Cognitive Restraint subscale at 30 and 70 mg/d LDX (both p < 0.05). These findings indicate that LDX decreased global binge eating severity and obsessive-compulsive and impulsive features of BED in addition to binge eating days.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Dimesilato de Lisdexanfetamina/uso terapêutico , Adolescente , Adulto , Bulimia/psicologia , Comportamento Compulsivo , Método Duplo-Cego , Feminino , Humanos , Comportamento Impulsivo/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Comportamento Obsessivo , Índice de Gravidade de Doença , Inquéritos e Questionários , Resultado do Tratamento , Adulto Jovem
17.
Psychopharmacology (Berl) ; 233(6): 949-60, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26694811

RESUMO

RATIONALE: Effort-related motivational symptoms, such as anergia, psychomotor retardation, and fatigue, are an important aspect of depression and other disorders. Motivational symptoms are resistant to some treatments, including serotonin transport (SERT) inhibitors. OBJECTIVES: Tests of effort-based choice using operant behavior tasks (e.g., concurrent lever pressing/ chow feeding tasks) can be used as animal models of motivational symptoms. Tests of effort-related choice allow animals to choose between high-effort actions that lead to more highly valued rewards vs. low-effort alternatives that lead to less valued rewards (i.e., less preferred or lower magnitude). Rats treated with the vesicular monoamine transport inhibitor tetrabenazine, or the cytokine interleukin-1ß (IL-1ß), which are associated with depressive symptoms in humans, can alter effort-related choice, reducing selection of the high effort alternative (lever pressing) while increasing intake of freely available chow. METHODS: The present studies focused upon the ability of lisdexamfetamine (LDX) to increase exertion of effort in rats responding on effort-based choice tasks under several different conditions. RESULTS: LDX attenuated the shift from fixed ratio 5 lever pressing to chow intake induced by tetrabenazine and IL-1ß. In contrast, the SERT inhibitor s-citalopram failed to reverse the effects of tetrabenazine. When given in combination with tetrabenazine+s-citalopram, LDX significantly increased lever pressing output compared to tetrabenaine+citalopram alone. LDX also increased work output in rats responding on a progressive ratio/chow feeding choice task. CONCLUSIONS: LDX can increase work output in rats responding on effort-based choice tasks, which may have implications for understanding the neurochemistry of motivational symptoms in humans.


Assuntos
Comportamento Animal/efeitos dos fármacos , Comportamento de Escolha/efeitos dos fármacos , Citalopram/farmacologia , Dimesilato de Lisdexanfetamina/farmacologia , Recompensa , Inibidores de Captação de Serotonina/farmacologia , Animais , Interações Medicamentosas , Comportamento Alimentar/efeitos dos fármacos , Masculino , Motivação/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley
18.
Neuropharmacology ; 101: 24-35, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26384654

RESUMO

The etiology of schizophrenia is poorly understood and two principle hypotheses have dominated the field. Firstly, that subcortical dopamine function is enhanced while cortical dopamine function is reduced and secondly, that cortical glutamate systems are dysfunctional. It is also widely accepted that currently used antipsychotics have essentially no impact on cognitive deficits and persistent negative symptoms in schizophrenia. Reduced dopamine transmission via dopamine D1 receptors in the prefrontal cortex has been hypothesized to be involved in the aetiology of these symptom domains and enhancing cortical dopamine transmission within an optimal window has been suggested to be potentially beneficial. In these pre-clinical studies we have determined that combined administration of the d-amphetamine pro-drug, lisdexamfetamine and the atypical antipsychotic olanzapine increased dopamine efflux in the rat prefrontal cortex and nucleus accumbens to an extent greater than either drug given separately without affecting olanzapine's ability to block striatal dopamine D2 receptors which is important for its antipsychotic activity. Furthermore, in an established rodent model used to compare the subjective effects of novel compounds the ability of lisdexamfetamine to generalize to a d-amphetamine cue was dose-dependently attenuated when co-administered with olanzapine suggesting that lisdexamfetamine may produce less marked subjective effects when administered adjunctively with olanzapine.


Assuntos
Anfetamina/farmacologia , Benzodiazepinas/farmacologia , Corpo Estriado/metabolismo , Dopamina/metabolismo , Sistema Límbico/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Receptores de Dopamina D2/metabolismo , Análise de Variância , Animais , Estimulantes do Sistema Nervoso Central/farmacologia , Cromatografia Líquida de Alta Pressão , Corpo Estriado/efeitos dos fármacos , Sinais (Psicologia) , Antagonistas de Dopamina/farmacologia , Generalização do Estímulo , Masculino , Olanzapina , Racloprida/farmacologia , Ratos , Ratos Sprague-Dawley , Espectrometria de Massas em Tandem , Fatores de Tempo
19.
J Psychopharmacol ; 29(12): 1290-307, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26589243

RESUMO

Binge-eating disorder is a common psychiatric disorder affecting ~2% of adults. Binge-eating was initiated in freely-fed, lean, adult, female rats by giving unpredictable, intermittent access to ground, milk chocolate over four weeks. The rats avidly consumed chocolate during 2 hr binge sessions, with compensatory reductions of normal chow intake in these sessions and the days thereafter. Bodyweights of binge-eating rats were normal. The model's predictive validity was explored using nalmefene (0.1-1.0mg/kg), R-baclofen (1.0-10mg/kg) and SB-334867 (3.0-30 mg/kg) (orexin-1 antagonist), which all selectively decreased chocolate bingeing without reducing chow intake. Sibutramine (0.3-5.0mg/kg) non-selectively reduced chocolate and chow consumption. Olanzapine (0.3-3.0mg/kg) was without effect and rolipram (1.0-10mg/kg) abolished all ingestive behaviour. The pro-drug, lisdexamfetamine (LDX; 0.1-1.5mg/kg), dose-dependently reduced chocolate bingeing by ⩽ 71% without significantly decreasing normal chow intake. Its metabolite, D-amphetamine (0.1-1.0mg/kg), dose-dependently and preferentially decreased chocolate bingeing ⩽ 56%. Using selective antagonists to characterize LDX's actions revealed the reduction of chocolate bingeing was partially blocked by prazosin (α1-adrenoceptor; 0.3 and 1.0mg/kg) and possibly by SCH-23390 (D1; 0.1mg/kg). RX821002 (α2-adrenoceptor; 0.1 and 0.3mg/kg) and raclopride (D2; 0.3 and 0.5mg/kg) were without effect. The results indicate that LDX, via its metabolite, d-amphetamine, reduces chocolate bingeing, partly by indirect activation of α1-adrenoceptors and perhaps D1 receptors.


Assuntos
Comportamento Animal/efeitos dos fármacos , Bulimia/tratamento farmacológico , Comportamento Alimentar/efeitos dos fármacos , Dimesilato de Lisdexanfetamina/farmacologia , Animais , Baclofeno/farmacologia , Benzazepinas/farmacologia , Benzodiazepinas/farmacologia , Peso Corporal/efeitos dos fármacos , Modelos Animais de Doenças , Ingestão de Alimentos/efeitos dos fármacos , Feminino , Idazoxano/análogos & derivados , Idazoxano/farmacologia , Naltrexona/análogos & derivados , Naltrexona/farmacologia , Olanzapina , Prazosina/farmacologia , Pró-Fármacos/farmacologia , Racloprida/farmacologia , Ratos , Ratos Wistar , Rolipram/farmacologia
20.
Drugs R D ; 15(2): 175-85, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25862215

RESUMO

INTRODUCTION: This open-label, randomized, two-period drug interaction study assessed lisdexamfetamine dimesylate (LDX) effects on cytochrome P450 (CYP) enzyme (CYP1A2, CYP2D6, CYP2C19, and CYP3A) activity. METHODS: Thirty healthy volunteers were administered the Cooperstown cocktail (CYP1A2 [caffeine 200 mg], CYP2D6 [dextromethorphan 30 mg], CYP2C19 [omeprazole 40 mg], and CYP3A [midazolam 0.025 mg/kg] substrates) or Cooperstown cocktail + oral LDX 70 mg. Blood samples for pharmacokinetic analysis were collected pre-dose and serially for 72 h post-dose. Treatment differences in the primary endpoints, maximum plasma concentration (C max) and area under the plasma concentration versus time curve from 0 to infinity (AUC0-∞), were assessed using geometric mean ratios with 90 % CIs. RESULTS: Geometric least squares (LS) means (without versus with LDX) for C max (ng/mL) were 5370 versus 5246 for caffeine, 2.43 versus 2.87 for dextromethorphan, 35.23 versus 35.11 for midazolam, and 677.9 versus 466.9 for omeprazole; and for AUC0-∞ (ng · h/mL) were 56,207 versus 56,688 for caffeine, 34.85 versus 37.27 for dextromethorphan, 92.07 versus 93.04 for midazolam, and 1428 versus 1499 for omeprazole. Geometric LS mean ratios were within the standard bioequivalence testing range, except for omeprazole and dextromethorphan C max. Parent/metabolite C max and AUC0-∞ ratios were similar between treatments except for dextromethorphan/dextrorphan AUC0-∞ ratio, which was lower with LDX. No serious or severe treatment-emergent adverse events were reported. CONCLUSIONS: LDX did not alter CYP1A2, CYP2D6, or CYP3A activity. A small C max reduction for omeprazole and its metabolite was observed, possibly reflecting an effect either on the activity of CYP2C19 or omeprazole absorption.


Assuntos
Sistema Enzimático do Citocromo P-450/metabolismo , Dimesilato de Lisdexanfetamina/farmacologia , Adulto , Área Sob a Curva , Cafeína/farmacocinética , Estudos Cross-Over , Dextrometorfano/farmacocinética , Interações Medicamentosas , Feminino , Humanos , Masculino , Midazolam/farmacocinética , Omeprazol/farmacocinética
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