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[PMID]:29338466
[Au] Autor:Sarva H; Henchcliffe C
[Ad] Endereço:a Parkinson's Disease and Movement Disorders Institute , Weill Cornell Medicine/New York Presbyterian Hospital , New York , NY , USA.
[Ti] Título:Valbenazine as the first and only approved treatment for adults with tardive dyskinesia.
[So] Source:Expert Rev Clin Pharmacol;11(3):209-217, 2018 Mar.
[Is] ISSN:1751-2441
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Valbenazine is a selective VMAT2 inhibitor that the FDA approved in April 2017 for the specific treatment of tardive dyskinesia (TD), a movement disorder commonly caused by dopamine blocking agents. Valbenazine acts to decrease dopamine release, reducing excessive movement found in TD. Areas covered: This drug profile reviews the development of valbenazine and the clinical trials that led to its approval as the first treatment specific to TD. The literature search was performed with the PubMed online database. Expert commentary: Two clinical trials assessing the efficacy of valbenazine have shown the reduction of antipsychotic-induced involuntary movement. No life threatening adverse effects were found. Data from a 42-week extension study demonstrated sustained response.
[Mh] Termos MeSH primário: Dopamina/metabolismo
Discinesia Tardia/tratamento farmacológico
Tetrabenazina/análogos & derivados
Valina/análogos & derivados
[Mh] Termos MeSH secundário: Adulto
Animais
Antipsicóticos/administração & dosagem
Antipsicóticos/efeitos adversos
Antipsicóticos/farmacologia
Aprovação de Drogas
Seres Humanos
Discinesia Tardia/induzido quimicamente
Tetrabenazina/efeitos adversos
Tetrabenazina/farmacologia
Tetrabenazina/uso terapêutico
Valina/efeitos adversos
Valina/farmacologia
Valina/uso terapêutico
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (SLC18A2 protein, human); 0 (Vesicular Monoamine Transport Proteins); 54K37P50KH (valbenazine); HG18B9YRS7 (Valine); VTD58H1Z2X (Dopamine); Z9O08YRN8O (Tetrabenazine)
[Em] Mês de entrada:1803
[Cu] Atualização por classe:180301
[Lr] Data última revisão:
180301
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:180118
[St] Status:MEDLINE
[do] DOI:10.1080/17512433.2018.1429264


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[PMID]:28982631
[Au] Autor:Litim N; Morissette M; Caruso D; Melcangi RC; Di Paolo T
[Ad] Endereço:Neuroscience Research Unit, Centre Hospitalier Universitaire de Québec, CHUL, Quebec City, Canada; Faculty of Pharmacy, Laval University, Quebec City, Canada.
[Ti] Título:Effect of the 5α-reductase enzyme inhibitor dutasteride in the brain of intact and parkinsonian mice.
[So] Source:J Steroid Biochem Mol Biol;174:242-256, 2017 Nov.
[Is] ISSN:1879-1220
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Dutasteride is a 5alpha-reductase inhibitor in clinical use to treat endocrine conditions. The present study investigated the neuroprotective mechanisms of action of dutasteride in intact and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned mice using a low dose of MPTP not affecting motor activity modeling early stages of Parkinson's disease (PD). We hypothesized that dutasteride neuroprotection is due to altered steroids levels. Dutasteride pre-treatment prevented loss of striatal dopamine (DA) and its metabolite DOPAC. Dutasteride decreased effects of MPTP on striatal dopamine transporter (DAT), vesicular monoamine transporter 2 (VMAT2) and D2 DA receptor specific binding while D1 receptor specific binding remained unchanged. Dutasteride enhanced DAT specific binding and the glycosylated form of DAT in intact mice. MPTP-lesioned mice had plasma and brain testosterone and dihydrotestosterone levels lower than control mice whereas progesterone and its metabolites (dihydroprogesterone, isopregnanolone and tetrahydroprogesterone) pathway showed increases. Dutasteride treatment by inhibiting transformation of progesterone and testosterone to its metabolites elevated plasma and brain concentrations of testosterone compared to MPTP mice and decreased DHT levels in intact mice. Plasma and brain estradiol levels were low and remained unchanged by MPTP and/or dutasteride treatment. Dutasteride treatment did not affect striatal phosphorylation of Akt and its downstream substrate GSK3ß as well as phosphorylation of ERK1/2 in intact and MPTP lesioned MPTP mice. Striatal glial fibrillary acidic protein (GFAP) levels were markedly elevated in MPTP compared to control mice and dutasteride reduced GFAP levels in MPTP mice. Treatment with dutasteride post-lesion left unchanged striatal DA levels. These results suggest dutasteride as promising drug for PD neuroprotection.
[Mh] Termos MeSH primário: Inibidores de 5-alfa Redutase/farmacologia
Encéfalo/efeitos dos fármacos
Dutasterida/farmacologia
Intoxicação por MPTP/metabolismo
Fármacos Neuroprotetores/farmacologia
[Mh] Termos MeSH secundário: Inibidores de 5-alfa Redutase/uso terapêutico
Androgênios/sangue
Androgênios/metabolismo
Animais
Comportamento Animal/efeitos dos fármacos
Encéfalo/metabolismo
Dopamina/metabolismo
Proteínas da Membrana Plasmática de Transporte de Dopamina/genética
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo
Dutasterida/uso terapêutico
Proteína Glial Fibrilar Ácida/metabolismo
Intoxicação por MPTP/tratamento farmacológico
Intoxicação por MPTP/fisiopatologia
Masculino
Camundongos Endogâmicos C57BL
Fármacos Neuroprotetores/uso terapêutico
Desempenho Psicomotor/efeitos dos fármacos
Receptores de Dopamina D1/metabolismo
Receptores de Dopamina D2/metabolismo
Congêneres da Testosterona/sangue
Congêneres da Testosterona/metabolismo
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (5-alpha Reductase Inhibitors); 0 (Androgens); 0 (Dopamine Plasma Membrane Transport Proteins); 0 (Glial Fibrillary Acidic Protein); 0 (Neuroprotective Agents); 0 (Receptors, Dopamine D1); 0 (Receptors, Dopamine D2); 0 (Slc18a2 protein, mouse); 0 (Testosterone Congeners); 0 (Vesicular Monoamine Transport Proteins); 0 (glial fibrillary astrocytic protein, mouse); O0J6XJN02I (Dutasteride); VTD58H1Z2X (Dopamine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171113
[Lr] Data última revisão:
171113
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171007
[St] Status:MEDLINE


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[PMID]:28968818
[Au] Autor:Zhang D; Li Z; Xu X; Zhou D; Tang S; Yin X; Xu F; Li H; Zhou Y; Zhu T; Deng H; Zhang S; Huang Q; Wang J; Yin W; Zhu Y; Lai M
[Ad] Endereço:Department of Pathology, Zhejiang University School of Medicine, Hangzhou 310058, China.
[Ti] Título:Deletions at SLC18A1 increased the risk of CRC and lower SLC18A1 expression associated with poor CRC outcome.
[So] Source:Carcinogenesis;38(11):1057-1062, 2017 Oct 26.
[Is] ISSN:1460-2180
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:Copy number variations (CNVs) contribute to the development of colorectal cancer (CRC). We conducted a two-stage association study to identify CNV risk loci for CRC. We performed a gene-based rare CNV study on 694 sporadic CRC and 1641 controls using Illumina Human-OmniExpress-12v1.0 BeadChips, and further replicated in 934 CRC cases and 2680 controls for risk CNVs by using TaqMan Copy Number Assay. Tumor buddings, cancer cells in the center of primary tumor and normal intestinal epithelial cells were captured using laser capture microdissection (LCM) and were assayed using AffymetrixGeneChip® Human Genome U133 Plus 2.0 Array. In addition, The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus data were assessed for the effects of risk CNVs. We found that germline deletions affecting the last six exons of SLC18A1 significantly associated with CRC with a combined P value of 6.4 × 10-5 by a two-stage analysis. Both in TCGA CRC RNA seq dataset and GDS4382, SLC18A1 was significantly down regulated in CRC tissues than in paired normal tissues (N = 32 and 17 pairs, P = 0.004 and 0.009, respectively). In LCM samples, similar observations were obtained that the expression levels of SLC18A1 in the tumor buddings, cancer cells in the center of primary tumor, and stroma of both tumor budding and cancer cells were lower than normal intestinal epithelial and stromal cells (fold change = 0.17-0.62, 0.12-0.57 and 0.37-0.68, respectively). In summary, the germline deletions at SLC18A1 contributed to the development of CRC. The role of SLC18A1 required further exploration.
[Mh] Termos MeSH primário: Neoplasias Colorretais/genética
Deleção de Sequência/genética
Proteínas Vesiculares de Transporte de Monoamina/genética
[Mh] Termos MeSH secundário: Adulto
Estudos de Casos e Controles
China
Variações do Número de Cópias de DNA/genética
Regulação para Baixo/genética
Células Epiteliais/metabolismo
Éxons/genética
Feminino
Regulação Neoplásica da Expressão Gênica/genética
Genoma Humano/genética
Estudo de Associação Genômica Ampla/métodos
Seres Humanos
Mucosa Intestinal/metabolismo
Masculino
Meia-Idade
Fatores de Risco
Células Estromais/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SLC18A1 protein, human); 0 (Vesicular Monoamine Transport Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171108
[Lr] Data última revisão:
171108
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:171003
[St] Status:MEDLINE
[do] DOI:10.1093/carcin/bgx088


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[PMID]:28699794
[Au] Autor:Seeberger LC; Hauser RA
[Ad] Endereço:a Department of Neurology , University of Colorado , Denver , CO , USA.
[Ti] Título:Valbenazine for the treatment of tardive dyskinesia.
[So] Source:Expert Opin Pharmacother;18(12):1279-1287, 2017 Aug.
[Is] ISSN:1744-7666
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:INTRODUCTION: Tardive dyskinesia (TD) is a hyperkinetic movement disorder that may result from treatment with antipsychotics or other dopamine receptor blocking agents. Underlying pathophysiology is incompletely understood but since the 1970s dopamine depleting agents have been used to reduce involuntary movements. The search for safe, effective treatments for TD is ongoing. Valbenazine, a novel VMAT2 inhibitor, has recently been FDA approved for treatment of TD. Areas covered: An overview of TD, unmet medical needs and current treatment guidelines are presented. The background, chemistry and clinical development of valbenazine to treat TD is detailed. A competitive market is developing as the treatment gap is identified and potential therapies are discussed in context of a broader market overview. Expert opinion: Antipsychotic use is growing among adults and children in the U.S. Consequently, prevalence of TD is expected to rise. Cessation of antipsychotics is often not possible as the psychiatric condition may deteriorate. Increasing doses of an antipsychotic to suppress involuntary movements is not sustainable long term as underlying TD worsens and movements typically recur. There were no FDA approved treatments for TD. The approval of valbenazine to treat TD is a critical step in addressing this gap in neurologic care.
[Mh] Termos MeSH primário: Discinesia Tardia/tratamento farmacológico
Tetrabenazina/análogos & derivados
Valina/análogos & derivados
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antipsicóticos/efeitos adversos
Ensaios Clínicos como Assunto
Seres Humanos
Transtornos Mentais/tratamento farmacológico
Discinesia Tardia/induzido quimicamente
Discinesia Tardia/psicologia
Tetrabenazina/uso terapêutico
Resultado do Tratamento
Valina/uso terapêutico
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (SLC18A2 protein, human); 0 (Vesicular Monoamine Transport Proteins); 54K37P50KH (valbenazine); HG18B9YRS7 (Valine); Z9O08YRN8O (Tetrabenazine)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171106
[Lr] Data última revisão:
171106
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170713
[St] Status:MEDLINE
[do] DOI:10.1080/14656566.2017.1353078


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[PMID]:28578484
[Au] Autor:Kim ES
[Ad] Endereço:Springer, Private Bag 65901, Mairangi Bay 0754, Auckland, New Zealand. dru@adis.com.
[Ti] Título:Valbenazine: First Global Approval.
[So] Source:Drugs;77(10):1123-1129, 2017 Jul.
[Is] ISSN:1179-1950
[Cp] País de publicação:New Zealand
[La] Idioma:eng
[Ab] Resumo:Valbenazine (Ingrezza™) is an orally bioavailable, selective, vesicular monoamine transporter 2 (VMAT2) inhibitor being developed by Neurocrine Biosciences for the treatment of various central nervous system disorders. Valbenazine has been approved in the USA for the treatment of adults with tardive dyskinesia (TD), is at various stages of development in other countries for TD and is in phase 2 development in the USA for Tourette syndrome. This article summarizes the milestones in the development of valbenazine leading to its first global approval in the USA for the treatment of adults with TD.
[Mh] Termos MeSH primário: Aprovação de Drogas
Discinesia Tardia/tratamento farmacológico
Tetrabenazina/análogos & derivados
Valina/análogos & derivados
[Mh] Termos MeSH secundário: Adulto
Ensaios Clínicos como Assunto
Seres Humanos
Tetrabenazina/efeitos adversos
Tetrabenazina/química
Tetrabenazina/farmacocinética
Tetrabenazina/uso terapêutico
Síndrome de Tourette/tratamento farmacológico
Estados Unidos
United States Food and Drug Administration
Valina/efeitos adversos
Valina/química
Valina/farmacocinética
Valina/uso terapêutico
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Vesicular Monoamine Transport Proteins); 54K37P50KH (valbenazine); HG18B9YRS7 (Valine); Z9O08YRN8O (Tetrabenazine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:171114
[Lr] Data última revisão:
171114
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170605
[St] Status:MEDLINE
[do] DOI:10.1007/s40265-017-0770-9


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[PMID]:28523547
[Au] Autor:Pishva E; Rutten BPF; van den Hove D
[Ad] Endereço:Complex Disease Epigenetic Group, University of Exeter Medical School, RILD Building, RD&E Hospital Wonford, Barrack Road, Exeter, EX2 5DW, UK. e.pishva@exeter.ac.uk.
[Ti] Título:DNA Methylation in Major Depressive Disorder.
[So] Source:Adv Exp Med Biol;978:185-196, 2017.
[Is] ISSN:0065-2598
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:Epigenetic mechanisms regulate gene expression, influencing protein levels and ultimately shaping phenotypes during life. However, both stochastic epigenetic variations and environmental reprogramming of the epigenome might influence neurodevelopment and ageing, and this may contribute to the origins of mental ill-health. Studying the role of epigenetic mechanisms is challenging, as genotype-, tissue- and cell type-dependent epigenetic changes have to be taken into account, while the nature of mental disorders also poses significant challenges for linking them with biological profiles. In this chapter, we summarise the current evidence suggesting the role of DNA methylation as a key epigenetic mechanism in major depressive disorder.
[Mh] Termos MeSH primário: Metilação de DNA/genética
Transtorno Depressivo Maior/genética
Epigênese Genética/genética
[Mh] Termos MeSH secundário: Antidepressivos/farmacologia
Antidepressivos/uso terapêutico
Encéfalo/metabolismo
Encéfalo/patologia
Fator Neurotrófico Derivado do Encéfalo/genética
Fator Neurotrófico Derivado do Encéfalo/fisiologia
Metilação de DNA/efeitos dos fármacos
Metilação de DNA/fisiologia
Transtorno Depressivo Maior/tratamento farmacológico
Transtorno Depressivo Maior/metabolismo
Transtorno Depressivo Maior/fisiopatologia
Doenças em Gêmeos/genética
Regulação da Expressão Gênica
Predisposição Genética para Doença
Seres Humanos
Sistema Hipotálamo-Hipofisário/fisiopatologia
Proteínas do Tecido Nervoso/genética
Proteínas do Tecido Nervoso/metabolismo
Sistema Hipófise-Suprarrenal/fisiopatologia
Estresse Fisiológico/genética
Estresse Fisiológico/fisiologia
Estresse Psicológico/genética
Estresse Psicológico/metabolismo
Estudos em Gêmeos como Assunto
Proteínas Vesiculares de Transporte de Monoamina/genética
Proteínas Vesiculares de Transporte de Monoamina/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE; REVIEW
[Nm] Nome de substância:
0 (Antidepressive Agents); 0 (Brain-Derived Neurotrophic Factor); 0 (Nerve Tissue Proteins); 0 (Vesicular Monoamine Transport Proteins); 0 (brain-derived neurotrophic factor, human)
[Em] Mês de entrada:1709
[Cu] Atualização por classe:170927
[Lr] Data última revisão:
170927
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170520
[St] Status:MEDLINE
[do] DOI:10.1007/978-3-319-53889-1_10


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[PMID]:28489481
[Au] Autor:Davis MC; Miller BJ; Kalsi JK; Birkner T; Mathis MV
[Ad] Endereço:From the Division of Psychiatry Products (M.C.D., B.J.M., J.K.K., M.V.M.) and the Division of Biometrics I (T.B.), Center for Drug Evaluation and Research, Silver Spring, MD; and the University of North Carolina Kenan-Flagler School of Business, Chapel Hill (B.J.M.).
[Ti] Título:Efficient Trial Design - FDA Approval of Valbenazine for Tardive Dyskinesia.
[So] Source:N Engl J Med;376(26):2503-2506, 2017 Jun 29.
[Is] ISSN:1533-4406
[Cp] País de publicação:United States
[La] Idioma:eng
[Mh] Termos MeSH primário: Aprovação de Drogas/métodos
Discinesia Tardia/tratamento farmacológico
Tetrabenazina/análogos & derivados
Valina/análogos & derivados
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
[Mh] Termos MeSH secundário: Antipsicóticos/efeitos adversos
Antipsicóticos/uso terapêutico
Ensaios Clínicos Fase III como Assunto
Dopamina/secreção
Seres Humanos
Transmissão Sináptica/efeitos dos fármacos
Transmissão Sináptica/fisiologia
Discinesia Tardia/induzido quimicamente
Tetrabenazina/uso terapêutico
Estados Unidos
United States Food and Drug Administration
Valina/uso terapêutico
Proteínas Vesiculares de Transporte de Monoamina/fisiologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Antipsychotic Agents); 0 (SLC18A2 protein, human); 0 (Vesicular Monoamine Transport Proteins); 54K37P50KH (valbenazine); HG18B9YRS7 (Valine); VTD58H1Z2X (Dopamine); Z9O08YRN8O (Tetrabenazine)
[Em] Mês de entrada:1707
[Cu] Atualização por classe:170718
[Lr] Data última revisão:
170718
[Sb] Subgrupo de revista:AIM; IM
[Da] Data de entrada para processamento:170511
[St] Status:MEDLINE
[do] DOI:10.1056/NEJMp1704898


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[PMID]:28476685
[Au] Autor:Noroozi R; Ghafouri-Fard S; Omrani MD; Habibi M; Sayad A; Taheri M
[Ad] Endereço:Young Researchers and Elite Club, Ahvaz Branch, Islamic Azad University, Ahvaz, Iran.
[Ti] Título:Association study of the vesicular monoamine transporter 1 (VMAT1) gene with autism in an Iranian population.
[So] Source:Gene;625:10-14, 2017 Aug 20.
[Is] ISSN:1879-0038
[Cp] País de publicação:Netherlands
[La] Idioma:eng
[Ab] Resumo:Autism Spectrum Disorders (ASD) (MIM 209850) are a group of neurodevelopmental disorders distinguished by destructed social interaction and communication abilities along with peculiar repetitive behavior. Several genetic loci have been linked to this disorder. Vesicular monoamine transporter 1 (VMAT1/SLC18A1) is an attractive candidate gene for psychiatric disorders because of its participation in regulation monoamines. In the present case-control study, we evaluated the link between three non-synonymous single nucleotide polymorphisms (SNPs) (rs2270641 [Pro4Thr], rs2270637 [Thr98Ser] and rs1390938 [Thr136Ile]) and one intronic SNP (rs2279709) across the VMAT1 gene and ASD in a group of Iranian patients. Allele frequency analyses showed significant over-presentation of rs1390938-G allele in cases compared with controls (P<0.001). The analysis under different genetic models showed that the AA genotype of the rs1390938 was protective against ASD under dominant and recessive models. The rs2270641 SNP was associated with ASD risk only in over-dominant model. Other SNPs showed no significant difference in allele or genotype frequencies between two groups. Haplotype analysis revealed that C A T T and C A T G haplotypes (rs2270637, rs1390938, rs2279709 and rs2270641 respectively) have a protective effect against ASD. Consequently, the functional rs1390938 SNP in VMAT1 is associated with ASD in Iranian population. Considering the role of VMAT1 in regulation of monoamines, the dysregulated expression of this protein during early stages of brain development might be implicated in ASD.
[Mh] Termos MeSH primário: Transtorno do Espectro Autista/genética
Polimorfismo de Nucleotídeo Único
Proteínas Vesiculares de Transporte de Monoamina/genética
[Mh] Termos MeSH secundário: Adolescente
Estudos de Casos e Controles
Criança
Feminino
Frequência do Gene
Genes Dominantes
Genes Recessivos
Haplótipos
Seres Humanos
Irã (Geográfico)
Masculino
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (SLC18A1 protein, human); 0 (Vesicular Monoamine Transport Proteins)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170615
[Lr] Data última revisão:
170615
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170507
[St] Status:MEDLINE


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[PMID]:28404690
[Au] Autor:Grigoriadis DE; Smith E; Hoare SRJ; Madan A; Bozigian H
[Ad] Endereço:Neurocrine Biosciences Inc., San Diego, California (D.E.G., E.S., H.B.); Pharmechanics, Wayne, Pennsylvania (S.R.J.H.); and Crinetics Pharmaceuticals, San Diego, California (A.M.) dgrigoriadis@neurocrine.com.
[Ti] Título:Pharmacologic Characterization of Valbenazine (NBI-98854) and Its Metabolites.
[So] Source:J Pharmacol Exp Ther;361(3):454-461, 2017 Jun.
[Is] ISSN:1521-0103
[Cp] País de publicação:United States
[La] Idioma:eng
[Ab] Resumo:The vesicular monoamine transporter 2 (VMAT2) is an integral presynaptic protein that regulates the packaging and subsequent release of dopamine and other monoamines from neuronal vesicles into the synapse. Valbenazine (NBI-98854), a novel compound that selectively inhibits VMAT2, is approved for the treatment of tardive dyskinesia. Valbenazine is converted to two significant circulating metabolites in vivo, namely, (+)- -dihydrotetrabenazine (R,R,R-HTBZ) and a mono-oxy metabolite, NBI-136110. Radioligand-binding studies were conducted to assess and compare valbenazine, tetrabenazine, and their respective metabolites in their abilities to selectively and potently inhibit [ H]-HTBZ binding to VMAT2 in rat striatal, rat forebrain, and human platelet homogenates. A broad panel screen was conducted to evaluate possible off-target interactions of valbenazine, R,R,R-HTBZ, and NBI-136110 at >80 receptor, transporter, and ion channel sites. Radioligand binding showed R,R,R-HTBZ to be a potent VMAT2 inhibitor in homogenates of rat striatum (K = 1.0-2.8 nM), rat forebrain (K = 4.2 nM), and human platelets (K = 2.6-3.3 nM). Valbenazine (K = 110-190 nM) and NBI-136110 (K = 160-220 nM) also exhibited inhibitory effects on VMAT2, but with lower potency than R,R,R-HTBZ. Neither valbenazine, R,R,R-HTBZ, nor NBI-136110 had significant off-target interactions at serotonin (5-HT , 5-HT , 5-HT ) or dopamine (D or D ) receptor sites. In vivo studies measuring ptosis and prolactin secretion in the rat confirmed the specific and dose-dependent interactions of tetrabenazine and R,R,R-HTBZ with VMAT2. Evaluations of potency and selectivity of tetrabenazine and its pharmacologically active metabolites were also performed. Overall, the pharmacologic characteristics of valbenazine appear consistent with the favorable efficacy and tolerability findings of recent clinical studies [KINECT 2 (NCT01733121), KINECT 3 (NCT02274558)].
[Mh] Termos MeSH primário: Tetrabenazina/análogos & derivados
Valina/análogos & derivados
Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Mh] Termos MeSH secundário: Animais
Plaquetas/efeitos dos fármacos
Plaquetas/metabolismo
Células CHO
Corpo Estriado/efeitos dos fármacos
Corpo Estriado/metabolismo
Cricetinae
Cricetulus
Células HEK293
Seres Humanos
Ligação Proteica/efeitos dos fármacos
Ligação Proteica/fisiologia
Ratos
Tetrabenazina/metabolismo
Tetrabenazina/farmacologia
Valina/metabolismo
Valina/farmacologia
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Vesicular Monoamine Transport Proteins); 54K37P50KH (valbenazine); HG18B9YRS7 (Valine); Z9O08YRN8O (Tetrabenazine)
[Em] Mês de entrada:1706
[Cu] Atualização por classe:170613
[Lr] Data última revisão:
170613
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170414
[St] Status:MEDLINE
[do] DOI:10.1124/jpet.116.239160


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[PMID]:28318542
[Au] Autor:De Felice LJ
[Ad] Endereço:Department of Physiology and Biophysics, Virginia Commonwealth University, Richmond, VA 23284, USA.
[Ti] Título:Monoamine Transporters as Ionotropic Receptors.
[So] Source:Trends Neurosci;40(4):195-196, 2017 Apr.
[Is] ISSN:1878-108X
[Cp] País de publicação:England
[La] Idioma:eng
[Ab] Resumo:It is well established that glutamate and GABA signal through both ionotropic and metabotropic receptors. Conversely, it is thought that, with one exception, monoamines (dopamine, serotonin, and norepinephrine) signal via metabotropic receptors. Given their capacity to generate fast-acting currents, I suggest that the monoamine transporters should be considered as ionotropic receptors.
[Mh] Termos MeSH primário: Proteínas da Membrana Plasmática de Transporte de Neurotransmissores/metabolismo
Receptores Ionotrópicos de Glutamato/metabolismo
Proteínas Vesiculares de Transporte de Monoamina/metabolismo
[Mh] Termos MeSH secundário: Animais
Neurônios/metabolismo
[Pt] Tipo de publicação:JOURNAL ARTICLE
[Nm] Nome de substância:
0 (Plasma Membrane Neurotransmitter Transport Proteins); 0 (Receptors, Ionotropic Glutamate); 0 (Vesicular Monoamine Transport Proteins)
[Em] Mês de entrada:1711
[Cu] Atualização por classe:171103
[Lr] Data última revisão:
171103
[Sb] Subgrupo de revista:IM
[Da] Data de entrada para processamento:170321
[St] Status:MEDLINE



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