Tetrabenazine in the treatment of hyperkinetic movement disorders

Kenney, C; Jankovic, J

doi:10.1586/14737175.6.1.7

Cited by 150 publications

(101 citation statements)

References 72 publications

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“…56 First introduced in 1956 as an antipsychotic drug, 57 TBZ is currently used to treat hyperkinetic movement disorders, such as chorea associated with Huntington ' s disease, tics in Tourette ' s syndrome, and movement stereotypes in tardive dyskinesia. [58][59][60] The side effects associated with TBZ include sedation, depression, akathisia, and parkinsonism. 58 TBZ inhibits catecholamine uptake by VMAT2 with a K i of 3 nM 14 and acts as an inhibitor of both presynaptic and postsynaptic DA receptors in rat brain.…”

Section: Tbz and Its Analogsmentioning

confidence: 99%

Vesicular monoamine transporter 2: Role as a novel target for drug development

Zheng

Dwoskin

Crooks

2006

AAPS J

107

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Section: Tbz and Its Analogsmentioning

confidence: 99%

Vesicular monoamine transporter 2: Role as a novel target for drug development

Zheng

Dwoskin

Crooks

2006

AAPS J

107

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“…Reserpine is an indole alkaloid, an antipsychotic and antihypertensive drug rarely used today (16,17). TBZ is a clinically relevant drug that is used for treatment of hyperkinetic disorders associated with Huntington's disease and Tourette's syndrome (18).…”

mentioning

confidence: 99%

Emulating proton-induced conformational changes in the vesicular monoamine transporter VMAT2 by mutagenesis

Yaffe

Vergara-Jaque

Forrest

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Neurotransporters located in synaptic vesicles are essential for communication between nerve cells in a process mediated by neurotransmitters. Vesicular monoamine transporter (VMAT), a member of the largest superfamily of transporters, mediates transport of monoamines to synaptic vesicles and storage organelles in a process that involves exchange of two H + per substrate. VMAT transport is inhibited by the competitive inhibitor reserpine, a second-line agent to treat hypertension, and by the noncompetitive inhibitor tetrabenazine, presently in use for symptomatic treatment of hyperkinetic disorders. During the transport cycle, VMAT is expected to occupy at least three different conformations: cytoplasm-facing, occluded, and lumen-facing. The lumen-to cytoplasm-facing transition, facilitated by protonation of at least one of the essential membrane-embedded carboxyls, generates a binding site for reserpine. Here we have identified residues in the cytoplasmic gate and show that mutations that disrupt the interactions in this gate also shift the equilibrium toward the cytoplasm-facing conformation, emulating the effect of protonation. These experiments provide significant insight into the role of proton translocation in the conformational dynamics of a mammalian H + -coupled antiporter, and also identify key aspects of the mode of action and binding of two potent inhibitors of VMAT2: reserpine binds the cytoplasm-facing conformation, and tetrabenazine binds the lumen-facing conformation.neurotransmitter transporter | ion coupling | reserpine | tetrabenazine

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“…Another dopamine depleter, tetrabenazine (TBZ), has largely replaced reserpine. 11 The first case reports of HD patients improving after treatment with TBZ date to the 1960s. 12,13 Since then, numerous case reports and clinical trials, most of them open-label, retrospective or using a small number of subjects, have provided evidence for the benefits of TBZ in the treatment of chorea associated with HD or other causes.…”

Section: Dopamine Depletersmentioning

confidence: 99%

“…19 TBZ inhibits VMAT2 reversibly, accounting for its short duration of action, as opposed to reserpine, which inhibits irreversibly not only the central VMAT2, but also the peripheral VMAT1 (the latter being responsible for some of the peripheral side effects, including orthostatic hypotension and diarrhea). 11,20 The most compelling evidence for the efficacy of TBZ in HD comes from a multicenter, randomized, doubleblind, placebo-controlled study of 84 HD patients (TET-RA-HD), conducted by the HSG. 21 The patients were randomized 2:1 to receive TBZ or placebo for 12 weeks.…”

Section: Dopamine Depletersmentioning

confidence: 99%

“…The data regarding the pharmacokinetics of TBZ are sparse. The half-life is relatively short, TBZ being metabolized by first-passage to an active compound, ␤-dihydrotetrabenazine (DTBZ), which has a higher bioavailability and longer half-life (10 h, compared with 6 h for TBZ) 11 , but it is not clear if DTBZ is responsible for the central action of TBZ.…”

Section: Dopamine Depletersmentioning

confidence: 99%

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Symptomatic Treatment of Huntington Disease

2008

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Summary: Huntington disease (HD) is a progressive heredoneurodegenerative disease manifested by chorea and other hyperkinetic (dystonia, myoclonus, tics) and hypokinetic (parkinsonism) movement disorders. In addition, a variety of psychiatric and behavioral symptoms, along with cognitive decline, contribute significantly to the patient's disability. Because there are no effective neuroprotective therapies that delay the progression of the disease, symptomatic treatment remains the cornerstone of medical management. Several classes of medications have been used to ameliorate the various symptoms of HD, including typical and atypical neuroleptics, dopamine depleters, antidepressants, antiglutamatergic drugs, GABA agonists, antiepileptic medications, acetylcholinesterase inhibitors, and botulinum toxin. Recently, surgical approaches including pallidotomy, deep brain stimulation, and fetal cell transplants have been used for the symptomatic treatment of HD. The selected therapy must be customized to the needs of each patient, minimizing the potential adverse effects. The primary aim of this article is to review the role of the different therapies, both available and investigational, for the treatment of the motor, psychiatric, behavioral, and cognitive symptoms of HD, and to examine their impact on the patient's functionality and quality of life.

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Tetrabenazine in the treatment of hyperkinetic movement disorders

Cited by 150 publications

References 72 publications

Vesicular monoamine transporter 2: Role as a novel target for drug development

Vesicular monoamine transporter 2: Role as a novel target for drug development

Emulating proton-induced conformational changes in the vesicular monoamine transporter VMAT2 by mutagenesis

Symptomatic Treatment of Huntington Disease

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