| [PMID]: | 26316187 |
| [Au] Autor: | Chiuccariello L; Cooke RG; Miler L; Levitan RD; Baker GB; Kish SJ; Kolla NJ; Rusjan PM; Houle S; Wilson AA; Meyer JH |
| [Ad] Endereço: | CAMH Research Imaging Centre and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health and Departments of Psychiatry, Pharmacology and Toxicology, and Institute of Medical Sciences, University of Toronto, Canada (Drs Chiuccariello, Cooke, Levitan, Kish, Kolla, Rusj |
| [Ti] Título: | Monoamine Oxidase-A Occupancy by Moclobemide and Phenelzine: Implications for the Development of Monoamine Oxidase Inhibitors. |
| [So] Source: | Int J Neuropsychopharmacol;19(1), 2015 Aug 27. |
| [Is] ISSN: | 1469-5111 |
| [Cp] País de publicação: | England |
| [La] Idioma: | eng |
| [Ab] Resumo: | BACKGROUND: Monoamine oxidase inhibitors (MAOIs) are being developed for major depressive disorder, Alzheimer's, and Parkinson's Disease. Newer MAOIs have minimal sensitivity to tyramine, but a key limitation for optimizing their development is that standards for in vivo monoamine oxidase-A (MAO-A) occupancy in humans are not well established. The objectives were to determine the dose-occupancy relationship of moclobemide and the occupancy of phenelzine at typical clinical dosing. METHODS: Major depressive episode (MDE) subjects underwent [(11)C]harmine positron emission tomography scanning prior to and following 6 weeks of treatment with moclobemide or phenelzine. RESULTS: Mean brain MAO-A occupancies were 74.23±8.32% for moclobemide at 300-600 mg daily (n = 11), 83.75±5.52% for moclobemide at 900-1200 mg daily (n = 9), and 86.82±6.89% for phenelzine at 45-60 mg daily (n = 4). The regional dose-occupancy relationship of moclobemide fit a hyperbolic function [F(x) = a(x/[b + x]); F(1,18) = 5.57 to 13.32, p = 0.002 to 0.03, mean 'a': 88.62±2.38%, mean 'b': 69.88±4.36 mg]. Multivariate analyses of variance showed significantly greater occupancy of phenelzine (45-60mg) and higher-dose moclobemide (900-1200 mg) compared to lower-dose moclobemide [300-600 mg; F(7,16) = 3.94, p = 0.01]. CONCLUSIONS: These findings suggest that for first-line MDE treatment, daily moclobemide doses of 300-600mg correspond to a MAO-A occupancy of 74%, whereas for treatment-resistant MDE, either phenelzine or higher doses of moclobemide correspond to a MAO-A occupancy of at least 84%. Therefore, novel MAO inhibitor development should aim for similar thresholds. The findings provide a rationale in treatment algorithm design to raise moclobemide doses to inhibit more MAO-A sites, but suggest switching from high-dose moclobemide to phenelzine is best justified by binding to additional targets. |
| [Mh] Termos MeSH primário: |
Encéfalo/efeitos dos fármacos
Moclobemida/farmacologia
Inibidores da Monoaminoxidase/farmacocinética
Monoaminoxidase/metabolismo
Fenelzina/farmacologia
|
| [Mh] Termos MeSH secundário: |
Adulto
Encéfalo/diagnóstico por imagem
Isótopos de Carbono/farmacocinética
Relação Dose-Resposta a Droga
Feminino
Harmina/farmacocinética
Voluntários Saudáveis
Seres Humanos
Masculino
Meia-Idade
Análise Multivariada
Tomografia por Emissão de Pósitrons
Ligação Proteica/efeitos dos fármacos
Adulto Jovem
|
| [Pt] Tipo de publicação: | JOURNAL ARTICLE; RESEARCH SUPPORT, NON-U.S. GOV'T |
[Nm] Nome de substância:
| 0 (Carbon Isotopes); 0 (Monoamine Oxidase Inhibitors); 4FHH5G48T7 (Harmine); EC 1.4.3.4 (Monoamine Oxidase); O408N561GF (Phenelzine); PJ0Y7AZB63 (Moclobemide) |
| [Em] Mês de entrada: | 1610 |
| [Cu] Atualização por classe: | 170220 |
[Lr] Data última revisão:
| 170220 |
| [Sb] Subgrupo de revista: | IM |
| [Da] Data de entrada para processamento: | 150829 |
| [St] Status: | MEDLINE |
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