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1.
Psychopharmacology (Berl) ; 224(4): 501-9, 2012 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-22752384

RESUMO

RATIONALE: Translational research implicates the mu opioid neurochemical system in hedonic processing, but its role in dissociable high-level cognitive functions is not well understood. Binge-eating represents a useful model of 'behavioural addiction' for exploring this issue. OBJECTIVE: The aim of this study was to objectively assess the cognitive effects of a mu opioid receptor antagonist in obese individuals with binge-eating symptoms. METHODS: Adults with moderate to severe binge-eating and body mass index ≥30 kg/m² received 4 weeks of treatment with a mu opioid receptor antagonist (GSK1521498) 2 or 5 mg per day, or placebo, in a double-blind randomised parallel design. Neuropsychological assessment was undertaken at baseline and endpoint to quantify processing bias for food stimuli (visual dot probe with 500- and 2,000-ms stimulus presentations and food Stroop tasks) and other distinct cognitive functions (N-back working memory, sustained attention, and power of attention tasks). RESULTS: GSK1521498 5 mg/day significantly reduced attentional bias for food cues on the visual dot probe task versus placebo (p = 0.042), with no effects detected on other cognitive tasks (all p > 0.10). The effect on attentional bias was limited to the longer stimulus duration condition in the higher dose cohort alone. CONCLUSIONS: These findings support a central role for mu opioid receptors in aspects of attentional processing of food cues but militate against the notion of major modulatory influences of mu opioid receptors in working memory and sustained attention. The findings have implications for novel therapeutic directions and suggest that the role of different opioid receptors in cognition merits further research.


Assuntos
Transtorno da Compulsão Alimentar/tratamento farmacológico , Indanos/farmacologia , Antagonistas de Entorpecentes/farmacologia , Receptores Opioides mu/antagonistas & inibidores , Triazóis/farmacologia , Adolescente , Adulto , Atenção , Transtorno da Compulsão Alimentar/psicologia , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Método Duplo-Cego , Feminino , Humanos , Indanos/administração & dosagem , Masculino , Pessoa de Meia-Idade , Antagonistas de Entorpecentes/administração & dosagem , Testes Neuropsicológicos , Índice de Gravidade de Doença , Fatores de Tempo , Triazóis/administração & dosagem , Adulto Jovem
2.
J Clin Pharmacol ; 52(4): 464-74, 2012 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21610207

RESUMO

Endogenous opioids and µ-opioid receptors have been linked to hedonic and rewarding aspects of palatable food intake. The authors examined the safety, pharmacokinetic, and pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being investigated primarily for the treatment of overeating behavior in obesity. In healthy participants, GSK1521498 oral solution and capsule formulations were well tolerated up to a dose of 100 mg. After single doses (10-150 mg), the maximum concentration (C(max)) and area under the curve (AUC) in plasma increased in a dose-proportional manner. GSK1521498 selectively reduced sensory hedonic ratings of high-sugar and high-fat dairy products and caloric intake of high-fat/high-sucrose snack foods. These findings provide encouraging data in support of the development of GSK1521498 for the treatment of disorders of maladaptive ingestive behavior or compulsive consumption.


Assuntos
Ingestão de Alimentos/efeitos dos fármacos , Preferências Alimentares/efeitos dos fármacos , Indanos/farmacologia , Receptores Opioides mu/agonistas , Triazóis/farmacologia , Administração Oral , Adulto , Área Sob a Curva , Estudos Cross-Over , Relação Dose-Resposta a Droga , Método Duplo-Cego , Agonismo Inverso de Drogas , Humanos , Indanos/efeitos adversos , Indanos/farmacocinética , Masculino , Método Simples-Cego , Triazóis/efeitos adversos , Triazóis/farmacocinética
3.
J Clin Pharmacol ; 52(10): 1456-67, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-22162534

RESUMO

The endogenous opioid system and µ-opioid receptors in particular have been demonstrated to play a fundamental role in hedonic and motivational behaviors reinforced by rewards. In healthy participants, the authors examined the multiple-dose safety, pharmacokinetic, and secondary pharmacodynamic profile of GSK1521498, a µ-opioid receptor inverse agonist that is being developed for treatment of disorders of compulsive consumption. Clinically relevant doses of GSK1521498 (2, 5, and 10 mg) following once-daily administration for 10 days, were well tolerated with no clinically relevant changes in vital signs, chemistry, or hematologic parameters and with a favorable neuropsychiatric profile. Following oral administration, median first time to reach maximum observed plasma concentration for GSK1521498 occurred 2 to 5 hours after dosing, with individual values ranging from 1 to 8 hours. Systemic exposure to GSK1521498 (area under the curve [0-∞] and maximum observed plasma concentration) increased in a slightly greater-than-dose-proportional manner, and steady-state plasma levels were reached within approximately 7 days. The secondary pharmacodynamic effects of GSK1521498 on cognition and pain threshold and tolerance were dose related, with mild to moderate impairments in measures of attention and reductions of pressure pain threshold and tolerance at the highest dose. These findings provide encouraging safety, tolerability, and pharmacokinetic data in support of the continued clinical development of GSK1521498.


Assuntos
Indanos/administração & dosagem , Receptores Opioides mu/agonistas , Triazóis/administração & dosagem , Adulto , Afeto/efeitos dos fármacos , Cognição/efeitos dos fármacos , Método Duplo-Cego , Esquema de Medicação , Feminino , Temperatura Alta , Humanos , Indanos/efeitos adversos , Indanos/farmacocinética , Masculino , Pessoa de Meia-Idade , Limiar da Dor/efeitos dos fármacos , Pressão , Triazóis/efeitos adversos , Triazóis/farmacocinética , Adulto Jovem
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