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2.
Neuropharmacology ; 183: 108325, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-32956676

RESUMO

Depressed individuals suffer from effort-related motivational symptoms such as anergia and fatigue, which are resistant to treatment with many common antidepressants. While drugs that block dopamine transport (DAT) reportedly have positive motivational effects, DAT inhibitors such as cocaine and amphetamines produce undesirable side effects. Thus, there is a need to develop and characterize novel atypical DAT inhibitors with unique and selective binding profiles. Rodent effort-based choice tasks provide useful models of motivational dysfunctions. With these tasks, animals choose between a high-effort instrumental action leading to highly valued reinforcement vs. a low effort/low reward option. The present studies focused on the initial characterization of a novel atypical DAT inhibitor, CT-005404, which binds to DAT with high selectivity relative to serotonin and norepinephrine transport, and produces long-term elevations of extracellular DA. CT-005404 was assessed for its ability to attenuate the effort-related motivational effects of the DA depleting agent tetrabenazine and the pro-inflammatory cytokine interleukin-1ß (IL-1ß) using a fixed ratio 5/chow feeding choice test. Tetrabenazine (1.0 mg/kg i.p.) shifted choice behavior, decreasing lever pressing and increasing chow intake. IL-1ß (4.0 µg/kg i.p.) also decreased lever pressing. CT-005404 was co-administered (7.5-30.0 mg/kg p.o.) with either tetrabenazine or IL-1ß, and the 15.0 and 30.0 mg/kg doses significantly reversed the effects of tetrabenazine and IL-1ß. CT-005404 administered alone produced a dose-related increase in lever pressing in rats tested on a progressive ratio/chow feeding choice task. Atypical DAT inhibitors such as CT-005404 offer potential as a new avenue for drug treatment of motivational dysfunctions in humans.


Assuntos
Comportamento de Escolha/efeitos dos fármacos , Condicionamento Operante/efeitos dos fármacos , Depressão/tratamento farmacológico , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Alimentar/efeitos dos fármacos , Interleucina-1beta/farmacologia , Masculino , Núcleo Accumbens/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Recompensa
3.
J Clin Psychiatry ; 81(6)2020 11 03.
Artigo em Inglês | MEDLINE | ID: mdl-33147658

RESUMO

​​​​​​ Clinicians now have 2 effective and well-tolerated vesicular monoamine transporter 2 (VMAT2) inhibitors-valbenazine and deutetrabenazine-for the treatment of patients with tardive dyskinesia (TD), a severe and potentially irreversible side effect associated with dopamine receptor blocking agents. Clinicians should use measurement-based care, eg, the Abnormal Involuntary Movement Scale with activation maneuvers, to assess and document TD symptoms and treatment progress. Each follow-up visit should be personalized with questions related to patients' functioning and level of distress regarding their specific TD symptoms. Family members, if available, can provide information on symptom changes and assistance with medication adherence. With continued treatment and measurement-based care, patients can experience improvement in their TD symptoms.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Avaliação de Resultados em Cuidados de Saúde/métodos , Discinesia Tardia/diagnóstico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Adulto , Humanos , Psiquiatria/educação , Tetrabenazina/farmacologia , Valina/farmacologia
4.
Neuropharmacology ; 178: 108246, 2020 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-32771528

RESUMO

While neuropsychiatric drugs influence neural activity across multiple brain regions, the current understanding of their mechanism of action derives from studies that investigate an influence of a given drug onto a pre-selected and small number of brain regions. To understand how neuropsychiatric drugs affect coordinated activity across brain regions and to detect the brain regions most relevant to pharmacological action in an unbiased way, studies that assess brain-wide neuronal activity are paramount. Here, we used whole-brain immunostaining of the neuronal activity marker cFOS, and graph theory to generate brain-wide maps of neuronal activity upon pharmacological challenges. We generated brain-wide maps 2.5 h after treatment of the atypical dopamine transporter inhibitor modafinil (10, 30, and 100 mg/kg) or the vesicular monoamine transporter 2 inhibitor tetrabenazine (0.25, 0.5 and 1 mg/kg). Modafinil increased the number of cFOS positive neurons in a dose-dependent manner. Moreover, modafinil significantly reduced functional connectivity across the entire brain. Graph theory analysis revealed that modafinil decreased the node degree of cortical and subcortical regions at the three doses tested, followed by a reduction in global efficiency. Simultaneously, we identified highly interconnected hub regions that emerge exclusively upon modafinil treatment. These regions were the mediodorsal thalamus, periaqueductal gray, subiculum, and rhomboid nucleus. On the other hand, while tetrabenazine had mild effects on cFOS counts, it reduced functional connectivity across the entire brain, cortical node degree, and global efficiency. As hub regions, we identified the substantia innominata and ventral pallidum. Our results uncovered novel mechanisms of action at a brain-wide scale for modafinil and tetrabenazine. Our analytical approach offers a tool to characterize signatures of whole-brain functional connectivity for drug candidates and to identify potential undesired effects at a mesoscopic scale. Additionally, it offers a guide towards targeted experiments on newly identified hub regions.


Assuntos
Química Encefálica/fisiologia , Mapeamento Encefálico/métodos , Encéfalo/metabolismo , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Rede Nervosa/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Animais , Encéfalo/efeitos dos fármacos , Química Encefálica/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modafinila/farmacologia , Rede Nervosa/química , Rede Nervosa/efeitos dos fármacos , Tetrabenazina/farmacologia
5.
Psychopharmacology (Berl) ; 237(11): 3459-3470, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32770257

RESUMO

RATIONALE: Atypical dopamine (DA) transport blockers such as modafinil and its analogs may be useful for treating motivational symptoms of depression and other disorders. Previous research has shown that the DA depleting agent tetrabenazine can reliably induce motivational deficits in rats, as evidenced by a shift towards a low-effort bias in effort-based choice tasks. This is consistent with human studies showing that people with major depression show a bias towards low-effort activities. OBJECTIVES: Recent studies demonstrated that the atypical DA transport (DAT) inhibitor (S)-CE-123 reversed tetrabenazine-induced motivational deficits, increased progressive ratio (PROG) lever pressing, and increased extracellular DA in the nucleus accumbens. In the present studies, a recently synthesized modafinil analog, (S, S)-CE-158, was assessed in a series of neurochemical and behavioral studies in rats. RESULTS: (S, S)-CE-158 demonstrated the ability to reverse the effort-related effects of tetrabenazine and increase selection of high-effort PROG lever pressing in rats tested on PROG/chow feeding choice task. (S, S)-CE-158 showed a high selectivity for inhibiting DAT compared with other monoamine transporters, and systemic administration of (S, S)-CE-158 increased extracellular DA in the nucleus accumbens during the behaviorally active time course, which is consistent with the effects of (S)-CE-123 and other DAT inhibitors that enhance high-effort responding. CONCLUSIONS: These studies provide an initial neurochemical characterization of a novel atypical DAT inhibitor, and demonstrate that this compound is active in models of effort-related choice. This research could contribute to the development of novel compounds for the treatment of motivational dysfunctions in humans.


Assuntos
Comportamento de Escolha/fisiologia , Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Comportamento Alimentar/fisiologia , Modafinila/análogos & derivados , Modafinila/metabolismo , Motivação/fisiologia , Inibidores da Captação Adrenérgica/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Animais , Comportamento de Escolha/efeitos dos fármacos , Proteínas da Membrana Plasmática de Transporte de Dopamina/antagonistas & inibidores , Relação Dose-Resposta a Droga , Comportamento Alimentar/efeitos dos fármacos , Células HEK293 , Humanos , Masculino , Modafinila/farmacologia , Motivação/efeitos dos fármacos , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ligação Proteica/fisiologia , Ratos , Ratos Sprague-Dawley , Tetrabenazina/metabolismo , Tetrabenazina/farmacologia
6.
Psychopharmacology (Berl) ; 237(9): 2845-2854, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32561947

RESUMO

RATIONALE: Effort-based decision-making tasks allow animals to choose between preferred reinforcers that require high effort to obtain vs. low-effort/low reward options. Mesolimbic dopamine (DA) and related neural systems regulate effort-based choice. Tetrabenazine (TBZ) is a vesicular monoamine transport type-2 inhibitor that blocks DA storage and depletes DA. In humans, TBZ induces motivational dysfunction and depression. TBZ has been shown reliably to induce a low-effort bias in rats, but there are fewer mouse studies. OBJECTIVES: The present studies used touchscreen operant procedures (Bussey-Saksida chambers) to assess the effects of TBZ on effort-based choice in mice. METHODS: C57BL6 mice were trained to press an elevated lit panel on the touchscreen on a fixed ratio 1 schedule reinforced by strawberry milkshake, vs. approaching and consuming a concurrently available but less preferred food pellets (Bio-serv). RESULTS: TBZ (2.0-8.0 mg/kg IP) shifted choice, producing a dose-related decrease in panel pressing but an increase in pellet intake. In contrast, reinforcer devaluation by pre-feeding substantially decreased both panel pressing and pellet intake. In free-feeding choice tests, mice strongly preferred the milkshake vs. the pellets, and TBZ had no effect on milkshake intake or preference, indicating that the TBZ-induced low-effort bias was not due to changes in primary food motivation or preference. TBZ significantly decreased tissue levels of nucleus accumbens DA. CONCLUSION: The DA depleting agent TBZ induced an effort-related motivational dysfunction in mice, which may have clinical relevance for assessing novel drug targets for their potential use as therapeutic agents in patients with motivation impairments.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Comportamento de Escolha/efeitos dos fármacos , Dopamina/metabolismo , Motivação/efeitos dos fármacos , Reforço Psicológico , Tetrabenazina/farmacologia , Animais , Comportamento de Escolha/fisiologia , Condicionamento Operante/efeitos dos fármacos , Condicionamento Operante/fisiologia , Antagonistas de Dopamina/farmacologia , Relação Dose-Resposta a Droga , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Motivação/fisiologia , Núcleo Accumbens/efeitos dos fármacos , Núcleo Accumbens/metabolismo , Ratos Sprague-Dawley , Recompensa
7.
Chem Phys Lipids ; 230: 104917, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32439327

RESUMO

Tetrabenazine reduces chorea symptoms associated with Huntington's disease by depleting monoamines in pre-synaptic vesicles. It exhibits low aqueous solubility and undergoes first pass metabolism due to which it has low oral bioavailability. The aim of present work was to formulate intranasal tetrabenazine loaded nanoemulsion for better management and treatment of hyperkinesia related with Huntington's disease. A quality by design (QbD) technique was employed as statistical multivariate approach for formulation and optimization of nanoemulsion. Optimized formulation showed droplet size of 106.80 ±â€¯1.96 nm with polydispersity index (PDI) value of 0.198 ±â€¯0.005 and -9.63 ±â€¯0.63 mV zeta potential. Ex-vivo drug permeation studies were carried out and found that the formulation has an augmented permeation by 1.68 times as compared to tetrabenazine suspension. MTT assay on neuro-2a cell lines showed that tetrabenazine loaded nanoemulsion displayed better cell viability than placebo and aqueous drug solution at ½ × Cmax, Cmax and 2 × Cmax. Pharmacokinetic parameters in brain after intranasal administration of tetrabenazine nanoemulsion were found to be Cmax = 3.497 ±â€¯0.275 µg/mL, AUC0-12 = 29.196 ±â€¯0.870 µg h/mL and elimination rate constant (ke) = 0.097 ±â€¯0.012 h-1 where as in plasma the pharmacokinetic parameters were Cmax = 1.400 ±â€¯0.084 µg/mL, AUC0-12 = 12.925 ±â€¯0.340 µg h/mL and ke = 0.061 ±â€¯0.010 h-1. Histopathological studies of porcine nasal mucosa showed that nasal mucosa remains intact when treated with tetrabenazine loaded nanoemulsion. Thus it can be concluded from study that optimized nanoemulsion formulation of a tetrabenazine was robust and its delivery through nasal route is a viable alternative to other routes of administration for treatment of hyperkinesia associated with Huntington's disease.


Assuntos
Encéfalo/metabolismo , Doença de Huntington/complicações , Hipercinese/complicações , Hipercinese/tratamento farmacológico , Nanopartículas/química , Bulbo Olfatório , Tetrabenazina/farmacologia , Administração Intranasal , Animais , Linhagem Celular , Portadores de Fármacos/química , Emulsões , Hipercinese/metabolismo , Ratos , Suínos , Tetrabenazina/administração & dosagem , Tetrabenazina/farmacocinética , Tetrabenazina/uso terapêutico , Distribuição Tecidual
8.
J Huntingtons Dis ; 9(2): 185-197, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32250312

RESUMO

In this edition of the Huntington's Disease Clinical Trials Corner we expand on the UniQure AMT-130 and on the Neurocrine Biosciences KINECT-HD trials, and list all currently registered and ongoing clinical trials in Huntington's disease.


Assuntos
Ensaios Clínicos como Assunto , Doença de Huntington/terapia , Terapia Genética , Humanos , Doença de Huntington/tratamento farmacológico , Ensaios Clínicos Controlados Aleatórios como Assunto , Tetrabenazina/análogos & derivados , Tetrabenazina/farmacologia , Valina/análogos & derivados , Valina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
9.
Naunyn Schmiedebergs Arch Pharmacol ; 393(9): 1625-1634, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32291496

RESUMO

The aim of the present study was to explore the ameliorative role of imatinib and tetrabenazine in acute stress-induced behavioural and biochemical changes in mice. Cold-water immersion (5 min duration) was employed to induce acute stress and the resulting changes in the locomotor activity, exploratory behaviour, motor activity and social behaviour were assessed using the actophotometer, the hole board, the open field and the social interaction tests. The biochemical alterations were assessed by measuring the plasma corticosterone levels using ELISA kit. Cold-water immersion-induced acute stress diminished the locomotor activity, exploratory behaviour, motor activity and social behaviour along with increase in the plasma corticosterone levels. Administration of imatinib (50 and 100 mg/kg, i.p.), a tyrosine kinase inhibitor, significantly attenuated the cold-water immersion-induced behavioural alterations with normalization of the plasma corticosterone levels in a dose-dependent manner. Moreover, administration of tetrabenazine (1 and 2 mg/kg, i.p.), a vesicular monoamine transporter 2 (VMAT2) inhibitor, also abolished the acute stress-induced behavioural and biochemical changes in a dose-dependent manner. The beneficial effects of imatinib and tetrabenazine in normalizing acute stress-induced biochemical and behavioural changes make them promising therapeutic agents in the treatment of acute stress-related problems.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Comportamento Animal/efeitos dos fármacos , Encéfalo/efeitos dos fármacos , Mesilato de Imatinib/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Estresse Psicológico/prevenção & controle , Tetrabenazina/farmacologia , Doença Aguda , Animais , Encéfalo/metabolismo , Encéfalo/fisiopatologia , Temperatura Baixa , Corticosterona/sangue , Modelos Animais de Doenças , Comportamento Exploratório/efeitos dos fármacos , Feminino , Imersão , Locomoção/efeitos dos fármacos , Masculino , Camundongos , Atividade Motora/efeitos dos fármacos , Comportamento Social , Estresse Psicológico/metabolismo , Estresse Psicológico/fisiopatologia , Estresse Psicológico/psicologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
10.
Eur Neuropsychopharmacol ; 32: 136-141, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32029310

RESUMO

Rodent studies on effort-related responding provide a tool to analyze basal aspects of motivation and to model psychiatric motivational dysfunctions reflecting low exertion of effort or reduced behavioral activation. It turned out that dopamine (DA) signaling in brain areas such as nucleus accumbens are essential in regulating effort-related motivational function and could play a major role in motivational dysfunction in psychiatric disorders. Recent rodent studies revealed that the medial orbitofrontal cortex (mOFC) is another key component of the neural circuitry regulating effort-related motivational function. The mOFC receives prominent DA input, however, the behavioral role of mOFC DA signaling is unknown. Here, we investigated whether DA signaling in the mOFC supports effort-related responding in rats. Results demonstrate that an intra-mOFC D1 receptor blockade markedly reduced effort-related responding in a progressive ratio task. Notably, the magnitude of this effect was comparable to the one caused by a systemic DA depletion induced by the VMAT-2 inhibitor tetrabenazine or by a satiety-induced motivational downshift. Collectively, our data show for the first time that D1 receptor activity in the mOFC plays a critical role in high effort responding. These results support findings in humans pointing to a role of the mOFC in effort-related responding. It is well known that the mOFC becomes dysfunctional in depression and schizophrenia. Our data point to the possibility that reduced mOFC DA activity could contribute to effort-related motivational symptoms in these disorders and support the notion that the DA system may be a drug target to treat effort-related motivational symptoms.


Assuntos
Motivação/fisiologia , Córtex Pré-Frontal/metabolismo , Receptores de Dopamina D1/antagonistas & inibidores , Receptores de Dopamina D1/metabolismo , Inibidores da Captação Adrenérgica/farmacologia , Animais , Benzazepinas/farmacologia , Masculino , Motivação/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Ratos , Ratos Sprague-Dawley , Tetrabenazina/farmacologia
11.
J Clin Psychiatry ; 81(2)2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32078259

RESUMO

The use of second-generation antipsychotics has not eliminated tardive dyskinesia (TD), and the prevalence of the disorder is higher than commonly realized. The involuntary movements of TD can decrease patients' quality of life, cause embarrassment, and lead to social withdrawal. Clinicians must evaluate patients taking DRBAs for TD risk factors and regularly screen them for TD using a rating scale. Familiarity with tools and diagnostic criteria will enable clinicians to conduct a differential diagnosis. Once a diagnosis is made, medications approved by the US Food and Drug Administration can be used to treat the condition. These medications are effective, but clinicians should be aware of key differences. A baseline assessment and regular follow-up evaluations will allow the clinician to monitor the patient's progress and make adjustments to meet treatment goals.​.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Antipsicóticos/efeitos adversos , Antagonistas de Dopamina/efeitos adversos , Esquizofrenia/tratamento farmacológico , Discinesia Tardia/diagnóstico , Discinesia Tardia/tratamento farmacológico , Discinesia Tardia/etiologia , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Inibidores da Captação Adrenérgica/administração & dosagem , Adulto , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Discinesia Tardia/induzido quimicamente , Tetrabenazina/administração & dosagem , Tetrabenazina/farmacologia , Valina/administração & dosagem , Valina/farmacologia
12.
Pharmacol Biochem Behav ; 190: 172872, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32084491

RESUMO

Valbenazine, a vesicular monoamine transporter 2 (VMAT2, SLC18A2) inhibitor, is a newly approved treatment for tardive dyskinesia. VMAT2 is present in the membrane of secretory vesicles and transports dopamine (DA), norepinephrine (NE), serotonin (5-HT), histamine, glutamate (Glu), and GABA into vesicles for presynaptic release. We utilized microdialysis in awake, freely moving mice to determine the effect of NBI-98782, the active metabolite of valbenazine, alone, or in combination with several antipsychotic drugs (APDs), to influence neurotransmitter efflux in the medial prefrontal cortex (mPFC), dorsal striatum (dSTR), hippocampus and nucleus accumbens (NAC); we also compared it with tetrabenazine, the prototypical VMAT2 inhibitor. Acute NBI-98782 and tetrabenazine decreased mPFC, dSTR, hippocampus, and NAC DA, 5-HT, and NE efflux, while increasing that of DOPAC, HVA, and 5-HIAA. Sub-chronic NBI-98782 (7 days) decreased baseline DA and 5-HT efflux in both mPFC and dSTR. NBI-98782 elicited similar effects on neurotransmitter efflux in sub-chronic NBI-98782-treated mice but also enhanced ACh and GABA; the decrease in DA efflux in mPFC and dSTR was not significant in the sc-treated animals. NBI-98782 suppressed clozapine-, olanzapine- and risperidone-induced DA efflux in both mPFC and dSTR, and ACh efflux in mPFC. NBI-98782 suppressed the haloperidol-induced DA efflux in dSTR, with minimal effect on GABA efflux. NBI-98782 attenuated PCP-induced DA, 5-HT, NE and Glu efflux, and AMPH-induced DA and NE efflux, in both mPFC and dSTR, as well as PCP- and AMPH-induced hyperlocomotion, suggesting possible beneficial antipsychotic effects.


Assuntos
Antipsicóticos/farmacologia , Antipsicóticos/uso terapêutico , Locomoção/efeitos dos fármacos , Fenciclidina/farmacologia , Transmissão Sináptica/efeitos dos fármacos , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Animais , Dopamina/metabolismo , Hipocampo/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microdiálise , Núcleo Accumbens/efeitos dos fármacos , Córtex Pré-Frontal/efeitos dos fármacos , Serotonina/metabolismo , Tetrabenazina/farmacologia , Tetrabenazina/uso terapêutico , Valina/farmacologia , Valina/uso terapêutico
13.
Am J Health Syst Pharm ; 77(3): 167-174, 2020 Jan 24.
Artigo em Inglês | MEDLINE | ID: mdl-31974564

RESUMO

PURPOSE: The purpose of this review is to summarize the current evidence for valbenazine and deutetrabenazine use for the treatment of tardive dyskinesia (TD). SUMMARY: A literature search was conducted to gather relevant data regarding the use of valbenazine and deutetrabenazine for TD management. PubMed, MEDLINE, and ClinicalTrials.gov were searched using the following keywords and MeSH terms: valbenazine, deutetrabenazine, tardive dyskinesia, VMAT2 inhibitors, and vesicular monoamine transporter 2 inhibitors. Randomized, double-blind, placebo-controlled trials and meta-analyses published in English from April 2015 to August 2019 were included. Valbenazine 40-80 mg and deutetrabenazine 12-36 mg per day have been evaluated for the treatment of TD. Abnormal Involuntary Movement Scale (AIMS) scores decline similarly (by 2-5 points) with use of either agent. AIMS response rates, defined by a 50% decline in symptoms, range from 33% to 50%. Both agents are well tolerated, with somnolence and akathisia reported most frequently (at low rates). Agent selection may be guided by manufacturer labeling recommendations for special populations and cost considerations. CONCLUSIONS: Valbenazine and deutetrabenazine were demonstrated to be effective in decreasing AIMS scores and were well tolerated in randomized controlled trials. These treatments may be considered as a next-line option when traditional strategies are not feasible or are ineffective. Head-to-head studies are warranted to decipher if either agent is preferable in terms of efficacy or tolerability.


Assuntos
Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Humanos , Ensaios Clínicos Controlados Aleatórios como Assunto , Discinesia Tardia/fisiopatologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/farmacologia , Resultado do Tratamento , Valina/administração & dosagem , Valina/efeitos adversos , Valina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores
15.
J Ethnopharmacol ; 249: 112373, 2020 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-31689479

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: In Turkish folk medicine, infusions and decoctions prepared from the flowers, fruits and aerial parts of Centaurea kurdica Reichardt (Asteraceae) are used as sedative and antidepressant-like effects of various sedative plants have been identified in many studies. The present study was designed to evaluate the antidepressant activity of this plant. MATERIALS AND METHODS: n-Hexane, ethyl acetate (EtOAc), and methanol (MeOH) extracts were prepared from the branches with leaves and also flowers of the plant. Antidepressant potentials of these extracts were researched by using the forced swimming test, tail suspension test, and antagonism of tetrabenazine-induced ptosis, hypothermia, and suppression of locomotor activity. RESULTS: After determination of high antidepressant potentials of MeOH extract prepared from flowers and n-hexane extract prepared from branches with leaves, isolation studies were carried out on these two extracts and the main active components were determined as ß-amyrin, mixture of ß-sitosterol and stigmasterol and costunolide for the branches with leaves and quercitrin, isoquercetin and naringenin-7-O-glucopyranoside for the flowers. CONCLUSIONS: As a result of the mechanistic and toxicity studies planned on this plant, it is thought that C. kurdica may be a glimmer of hope for depressed patients.


Assuntos
Antidepressivos/química , Centaurea/química , Extratos Vegetais/química , Plantas Medicinais/química , Animais , Antidepressivos/farmacologia , Depressão/tratamento farmacológico , Flores/química , Elevação dos Membros Posteriores , Masculino , Medicina Tradicional/métodos , Metanol/química , Camundongos , Camundongos Endogâmicos BALB C , Fitoterapia/métodos , Componentes Aéreos da Planta/química , Extratos Vegetais/farmacologia , Folhas de Planta/química , Quercetina/análogos & derivados , Quercetina/química , Quercetina/farmacologia , Tetrabenazina/química , Tetrabenazina/farmacologia
16.
Handb Clin Neurol ; 165: 179-189, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31727211

RESUMO

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by an expanded cytosine-adenine-guanine triplet repeat in the huntingtin gene. The current diagnosis is based on the presence of typical motor signs in combination with a positive gene test. The motor onset of the disease is usually between 30 and 50 years of age, and the disease then progresses over around 20 more years. Nonmotor symptoms and signs such as cognitive decline, metabolic dysfunction, sleep disturbances, as well as psychiatric symptoms are common and can occur many years before motor onset. Psychiatric symptoms include irritability, apathy, depression, anxiety, and OCD. Although there exist no disease-modifying treatment, available pharmacologic drugs often offer significant symptom relief and improve quality of life. Today, there are only two drugs that are approved by the US Food and Drug Association for the treatment of HD. These are the dopamine-depleting drugs tetrabenazine and deutetrabenazine that both target motor symptoms. The current status of best clinical practice for HD is based on expert opinions as well as evidence and/or experience of treating similar symptoms in other conditions. In this chapter, we provide an overview of the complex clinical manifestations of HD and the commonly used psychopharmacologic treatments.


Assuntos
Inibidores da Captação Adrenérgica/uso terapêutico , Doença de Huntington/tratamento farmacológico , Doença de Huntington/metabolismo , Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Inibidores da Captação Adrenérgica/farmacologia , Humanos , Doença de Huntington/diagnóstico , Psicofarmacologia , Tetrabenazina/farmacologia , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Proteínas Vesiculares de Transporte de Monoamina/metabolismo
17.
J Clin Psychopharmacol ; 39(6): 620-627, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31688452

RESUMO

PURPOSE/BACKGROUND: Valbenazine is approved to treat tardive dyskinesia (TD) in adults. KINECT 4 (NCT02405091) was conducted to explore the long-term effects of once-daily valbenazine in patients with TD. METHODS/PROCEDURES: The study included a 48-week, open-label treatment period and 4-week washout. Dosing was initiated at 40 mg/d, with escalation to 80 mg/d at week 4 based on efficacy and tolerability. Standard safety methods were applied, including treatment-emergent adverse event (TEAE) reporting. Valbenazine effects on TD were assessed using the Abnormal Involuntary Movement Scale (AIMS), Clinical Global Impression of Change-TD, and Patient Global Impression of Change. FINDINGS/RESULTS: After week 4, <15% of all participants had a serious TEAE (13.7%) or TEAE leading to discontinuation (11.8%). Participants experienced TD improvements during long-term treatment as indicated by mean change from baseline to week 48 in AIMS total score (sum of items 1-7, evaluated by site raters) with valbenazine 40 mg/d (-10.2 [n = 45]) or 80 mg/d (-11.0 [n = 107]). At week 48, most participants had ≥50% improvement from baseline in AIMS total score (40 mg/d, 90.0%; 80 mg/d, 89.2%), Clinical Global Impression of Change-TD rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 95.9%), and Patient Global Impression of Change rating of much or very much improved (40 mg/d, 90.0%; 80 mg/d, 89.2%). No dose effects were apparent by week 36. Week 52 results indicated some loss of effect after washout. IMPLICATIONS/CONCLUSIONS: Valbenazine was generally well tolerated, and no new safety concerns were detected. Substantial clinician- and patient-reported improvements were observed in adults with TD who received once-daily valbenazine for up to 48 weeks.


Assuntos
Antipsicóticos/efeitos adversos , Transtornos do Humor/tratamento farmacológico , Avaliação de Resultados em Cuidados de Saúde , Transtornos Psicóticos/tratamento farmacológico , Esquizofrenia/tratamento farmacológico , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Pessoa de Meia-Idade , Discinesia Tardia/etiologia , Tetrabenazina/administração & dosagem , Tetrabenazina/efeitos adversos , Tetrabenazina/sangue , Tetrabenazina/farmacologia , Valina/administração & dosagem , Valina/efeitos adversos , Valina/sangue , Valina/farmacologia , Adulto Jovem
18.
J Pharmacol Exp Ther ; 371(1): 219-230, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31209099

RESUMO

Vesicular monoamine transporter-2 is expressed in the presynaptic secretory vesicles membrane in the brain. Its blockade by tetrabenazine (TBZ) causes depletion of dopamine at striatal basal ganglia; this is the mechanism underlying its long-standing use in the treatment of Huntington's disease. In the frame of a project aimed at investigating the kinetics of exocytosis from vesicles with partial emptying of their neurotransmitter, we unexpectedly found that TBZ facilitates exocytosis; thus, we decided to characterize such effect. We used bovine chromaffin cells (BCCs) challenged with repeated pulses of high K+ Upon repeated K+ pulsing, the exocytotic catecholamine release responses were gradually decaying. However, when cells were exposed to TBZ, responses were mildly augmented and decay rate delayed. Facilitation of exocytosis was not due to Ca2+ entry blockade through voltage-activated calcium channels (VACCs) because, in fact, TBZ mildly blocked the whole-cell Ca2+ current. However, TBZ mimicked the facilitatory effects of exocytosis elicited by BayK8644 (L-subtype VACC agonist), an effect blocked by nifedipine (VACC antagonist). On the basis that TBZ augmented the secretory responses to caffeine (but not those of histamine), we monitored its effects on cytosolic Ca2+ elevations ([Ca2+]c) triggered by caffeine or histamine. While the responses to caffeine were augmented twice by TBZ, those of histamine were unaffected; the same happened in rat cortical neurons. Hence, we hypothesize that TBZ facilitates exocytosis by increasing Ca2+ release through the endoplasmic reticulum ryanodine receptor channel (RyR). Confirming this hypothesis are docking results, showing an interaction of TBZ with RyRs. This is consonant with the existence of a healthy Ca2+-induced-Ca2+-release mechanism in BCCs. SIGNIFICANCE STATEMENT: A novel mechanism of action for tetrabenazine (TBZ), a drug used in the therapy of Huntington's disease (HD), is described here. Such mechanism consists of facilitation by combining TBZ with the ryanodine receptor of the endoplasmic reticulum, thereby increasing Ca2+-induced Ca2+ release. This novel mechanism should be taken into account when considering the efficacy and/or safety of TBZ in the treatment of chorea associated with HD and other disorders. Additionally, it could be of interest in the development of novel medicines to treat these pathological conditions.


Assuntos
Inibidores da Captação Adrenérgica/farmacologia , Sinalização do Cálcio , Células Cromafins/efeitos dos fármacos , Exocitose , Canal de Liberação de Cálcio do Receptor de Rianodina/metabolismo , Tetrabenazina/farmacologia , Animais , Sítios de Ligação , Canais de Cálcio Tipo N/metabolismo , Bovinos , Células Cultivadas , Células Cromafins/metabolismo , Ligação Proteica , Canal de Liberação de Cálcio do Receptor de Rianodina/química
19.
J Psychosoc Nurs Ment Health Serv ; 57(5): 11-14, 2019 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-31042295

RESUMO

Tardive dyskinesia (TD), the choreoathetoid movements of fingers, arms, legs, and trunk and irregular stereotypical movements of the mouth, face, and tongue, has been the scourge of antipsychotic medications since the approval of chlorpromazine. TD tends to occur late in treatment and sometimes remains after discontinuation of the antipsychotic medication. With the recent approval of two medications, valbenazine (Ingrezza®) and deutetrabenazine (Austedo®), there are now treatments for this disfiguring consequence of dopamine-blocking medications. The current article distinguishes the movement disorder adverse effects of dopamine antagonists, explains the putative mechanism of action, and describes how best to treat TD with the new vesicular monamine transporter 2 (VMAT2) medications now approved by the U.S. Food and Drug Administration. [Journal of Psychosocial Nursing and Mental Health Services, 57(5), 11-14.].


Assuntos
Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Discinesia Tardia/tratamento farmacológico , Tetrabenazina/análogos & derivados , Valina/análogos & derivados , Antipsicóticos/uso terapêutico , Clorpromazina/uso terapêutico , Humanos , Enfermagem Psiquiátrica , Tetrabenazina/farmacologia , Tetrabenazina/uso terapêutico , Valina/farmacologia , Valina/uso terapêutico
20.
Clin Neuropharmacol ; 42(2): 37-41, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30870235

RESUMO

OBJECTIVES: The aim of this study was to review our "real-world" experience with the vesicular monoamine transporter 2 (VMAT2) inhibitors tetrabenazine (TBZ), deutetrabenazine (DTBZ), and valbenazine (VBZ) for treatment of hyperkinetic movement disorders. Access and adherence to VMAT2 inhibitors may be limited by insurance and regulatory issues, inexperience with their use by the prescribing physician, lack of efficacy, or side effects. METHODS: We performed a retrospective chart review, supplemented with a questionnaire, of all our patients treated with a VMAT2 inhibitor between January 1, 2017, and August 30, 2018. RESULTS: We identified 135 patients (57.8% male) and 178 prescriptions for VMAT2 inhibitors (TBZ, n = 45 [25.3%]; DTBZ, n = 104 [58.4%]; VBZ, n = 29 [16.3%]). Tourette syndrome/tics was the most common diagnosis (n = 67 [49.6%]) for which VMAT2 inhibitors were prescribed. The VMAT2 inhibitor mean treatment durations (range; SD) and daily dosages (range; SD) were as follows: TBZ (n = 31), 5.1 months (1-19; 3.9) at 48.8 mg (12.5-112.5; 29.6); DTBZ (n = 51), 8.0 months (0.25-16.5; 4.4) at 34.4 mg (6-96; 20.7); and VBZ (n = 20), 6.0 months (0.1-16; 5.6) at 64 mg (40-160; 35.3). The VMAT2 inhibitors effectively controlled hyperkinetic movement disorders as measured by a 1- to 4-point Likert scale (1 = normal or mildly ill, 4 = severely ill) comparing illness severity before starting and while on treatment (score of 1 in 13.0%-26.7% vs 60.9%-71.9% of patients). Side effects were mild and improved or resolved following dose reduction, drug cessation, or addition of adjunctive medications. CONCLUSIONS: The VMAT2 inhibitors are effective and safe in a range of hyperkinetic movement disorders but are not readily accessible by patients in the United States for indications not approved by the Food and Drug Administration.


Assuntos
Tetrabenazina/análogos & derivados , Tetrabenazina/uso terapêutico , Tiques/tratamento farmacológico , Síndrome de Tourette/tratamento farmacológico , Valina/análogos & derivados , Proteínas Vesiculares de Transporte de Monoamina/antagonistas & inibidores , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Tetrabenazina/farmacologia , Tiques/diagnóstico , Síndrome de Tourette/diagnóstico , Valina/farmacologia , Valina/uso terapêutico , Adulto Jovem
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