Tetrabenazine Research Articles

Tetrabenazine is neuroprotective in Huntington's disease mice

BackgroundHuntington's disease (HD) is a neurodegenerative disorder caused by a polyglutamine (polyQ) expansion in Huntingtin protein (Htt). PolyQ expansion in Httexp causes selective degeneration of striatal medium spiny neurons (MSN) in HD patients. A number of previous studies suggested that dopamine signaling plays an important role in HD pathogenesis. A specific inhibitor of vesicular monoamine transporter (VMAT2) tetrabenazine (TBZ) has been recently approved by Food and Drug Administration for treatment of HD patients in the USA. TBZ acts by reducing dopaminergic input to the striatum.ResultsIn previous studies we demonstrated that long-term feeding with TBZ (combined with L-Dopa) alleviated the motor deficits and reduced the striatal neuronal loss in the yeast artificial chromosome transgenic mouse model of HD (YAC128 mice). To further investigate a potential beneficial effects of TBZ for HD treatment, we here repeated TBZ evaluation in YAC128 mice starting TBZ treatment at 2 months of age ("early" TBZ group) and at 6 months of age ("late" TBZ group). In agreement with our previous studies, we found that both "early" and "late" TBZ treatments alleviated motor deficits and reduced striatal cell loss in YAC128 mice. In addition, we have been able to recapitulate and quantify depression-like symptoms in TBZ-treated mice, reminiscent of common side effects observed in HD patients taking TBZ.ConclusionsOur results further support therapeutic value of TBZ for treatment of HD but also highlight the need to develop more specific dopamine antagonists which are less prone to side-effects.

Preparation and Characterization of Tetrabenazine Enantiomers against Vesicular Monoamine Transporter 2

As a clinical medication for the treatment of hyperkinetic movement disorders, in conditions such as Huntington's disease, tetrabenazine (TBZ) has been always used in its racemic form. To establish whether or not its beneficial therapeutic actions are enantiospecific, a practical total synthetic route was developed to yield each enantiomeric form to allow their chemical and pharmacological characterization. We briefly summarize the total synthesis of TBZ and report a detailed procedure for resolution of TBZ into its enantiomers, (+)-TBZ and (-)-TBZ. This allowed determination of the optical rotation and absolute configurations of each TBZ enantiomer, based on X-ray crystallographic analysis, together with characterization of their inhibitory action at the vesicular monoamine transporter 2, where (+)-TBZ proved three-fold more active than (-)-TBZ.

Tetrabenazine: the first approved drug for the treatment of chorea in US patients with Huntington disease

Huntington disease (HD) is a dominantly inherited progressive neurological disease characterized by chorea, an involuntary brief movement that tends to flow between body regions. HD is typically diagnosed based on clinical findings in the setting of a family history and may be confirmed with genetic testing. Predictive testing is available to those at risk, but only experienced clinicians should perform the counseling and testing. Multiple areas of the brain degenerate mainly involving the neurotransmitters dopamine, glutamate, and γ-aminobutyric acid. Although pharmacotherapies theoretically target these neurotransmitters, few well-conducted trials for symptomatic or neuroprotective interventions yielded positive results. Tetrabenazine (TBZ) is a dopamine-depleting agent that may be one of the more effective agents for reducing chorea, although it has a risk of potentially serious adverse effects. Some newer antipsychotic agents, such as olanzapine and aripiprazole, may have adequate efficacy with a more favorable adverse-effect profile than older antipsychotic agents for treating chorea and psychosis. This review will address the epidemiology and diagnosis of HD as background for understanding potential pharmacological treatment options. Because TBZ is the only US Food and Drug Administration-approved medication in the United States for HD, the focus of this review will be on its pharmacology, efficacy, safety, and practical uses. There are no current treatments to change the course of HD, but education and symptomatic therapies can be effective tools for clinicians to use with patients and families affected by HD.

Tetrabenazine as anti-chorea therapy in Huntington Disease: an open-label continuation study. Huntington Study Group/TETRA-HD Investigators

BackgroundTetrabenazine (TBZ) selectively depletes central monoamines by reversibly binding to the type-2 vesicular monoamine transporter. A previous double blind study in Huntington disease (HD) demonstrated that TBZ effectively suppressed chorea, with a favorable short-term safety profile (Neurology 2006;66:366-372). The objective of this study was to assess the long-term safety and effectiveness of TBZ for chorea in HD.MethodsSubjects who completed the 13-week, double blind protocol were invited to participate in this open label extension study for up to 80 weeks. Subjects were titrated to the best individual dose or a maximum of 200 mg/day. Chorea was assessed using the Total Maximal Chorea (TMC) score from the Unified Huntington Disease Rating Scale.ResultsOf the 75 participants, 45 subjects completed 80 weeks. Three participants terminated due to adverse events (AEs) including depression, delusions with associated previous suicidal behavior, and vocal tics. One subject died due to breast cancer. The other 26 subjects chose not to continue on with each ensuing extension for various reasons. When mild and unrelated AEs were excluded, the most commonly reported AEs (number of subjects) were sedation/somnolence (18), depressed mood (17), anxiety (13), insomnia (10), and akathisia (9). Parkinsonism and dysphagia scores were significantly increased at week 80 compared to baseline. At week 80, chorea had significantly improved from baseline with a mean reduction in the TMC score of 4.6 (SD 5.5) units. The mean dosage at week 80 was 63.4 mg (range 12.5-175 mg).ConclusionsTBZ effectively suppresses HD-related chorea for up to 80 weeks. Patients treated chronically with TBZ should be monitored for parkinsonism, dysphagia and other side effects including sleep disturbance, depression, anxiety, and akathisia.Trial RegistrationClinicaltrials.gov registration number (initial study): NCT00219804

Tetrabenazine

Background: Tetrabenazine (TBZ) depletes presynaptic dopamine in the CNS. It has been found to be beneficial in hyperkinetic movement disorders without carrying the extrapyramidal side effects that are characteristic of neuroleptics. Objective: To summarize current knowledge on the use of TBZ and draw conclusions about its efficacy and safety. Methods: PubMed literature searches using the term ‘tetrabenazine’ were carried out for the period prior to May 2009. Additional relevant studies referenced by these publications were included. Conclusions: Both short- and long-term studies have consistently yielded favorable results for the use of TBZ in the treatment of hyperkinetic movement in terms of efficacy and safety. TBZ is most effective in reducing chorea (including Huntington’s disease associated chorea), tic associated with Tourette’s syndrome and tardive dyskinesias. Furthermore, TBZ might also have potential for use in other hyperkinetic disorders (e.g., myoclonus and dystonia), for which future clinical trials are needed.

MPTP-induced neuroblast apoptosis in the subventricular zone is not regulated by dopamine or other monoamine transporters

For 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to exert neurotoxicity on dopaminergic neurons, 1-methyl-4-phenylpyridinium (MPP+), a metabolite of MPTP, must be taken up into the dopaminergic neuron via the dopamine transporter (DAT). Previous reports have shown that MPTP also causes neuroblast apoptosis in the subventricular zone (SVZ) of adult mice. The aim of this study is to elucidate the role of DAT and other monoamine transporters including vesicular monoamine transporter 2 (VMAT2), the serotonin transporter (SERT), and the norepinephrine transporter (NET) on the neuroblast apoptosis induced by MPTP administration. There were no DAT-positive neuroblasts in the SVZ, whereas some neuroblasts were immunopositive for VMAT2 and SERT. To examine whether these transporters are involved in MPTP-induced neuroblast apoptosis in the SVZ, terminal deoxynucleotidyl transferase-mediated dUTP endlabeling (TUNEL)-positive cells were semiquantitatively analyzed after the injection of GBR12909 (GBR), a DAT inhibitor; tetrabenazine (TBZ), a VMAT2 inhibitor; fluoxetine (FLU), a SERT inhibitor, or desipramine (DES), a NET inhibitor, prior to MPTP injection. However, the injection of these transporter inhibitors had no influence on the MPTP-induced neuroblast apoptosis in the SVZ. It is likely that neither DAT nor other monoamine transporters are involved in MPTP-induced neuroblast apoptosis. The present findings suggest that the neurotoxicity of MPTP to neuroblasts in the SVZ does not require DAT or other monoamine transporters, and the apoptosis it induces may be executed through other unknown pathways.

Treatment of Chorea Associated with Huntington's Disease: Focus on Tetrabenazine

Review Huntington's disease (HD) and the role of tetrabenazine (TBZ) in treating chorea associated with this disease. Discuss the pharmacology, side-effect profile, drug interactions, precautions, and contraindications of TBZ. Literature identified within MEDLINE and PubMED. Two manuscripts specifically regarding the management of chorea in patients with HD were identified. Additionally, studies involving the clinical use of TBZ were reviewed. The literature identified provided information regarding the efficacy, safety, and pharmacological actions of TBZ. HD is often accompanied by chorea, and the treatment with TBZ in this patient population often results in decreased chorea. Pharmacists managing patients on TBZ need to be well versed in TBZ's potential side effects, drug interactions, and unique dosing considerations.

Asymmetric Synthesis of Tetrabenazine and Dihydrotetrabenazine

The enantioselective synthesis of (+)-tetrabenazine (TBZ) and (+)-dihydrotetrabenazine (DTBZ), agents of significant interest for therapeutic and molecular imaging applications, has been completed in 21% (TBZ) and 16% (DTBZ) overall yield and in >97% ee from the starting dihydroisoquinoline. The synthesis utilizes Sodeoka's palladium-catalyzed asymmetric malonate addition to set the initial stereocenter followed by a number of diastereoselective transformations to incorporate the remaining asymmetric centers.

Treatment of the symptoms of Huntington's disease: Preliminary results comparing aripiprazole and tetrabenazine

Aripiprazole (AP), a dopamine (DA) D(2) receptor partial agonist, has recently been used to reduce schizophrenic symptoms, while tetrabenazine (TBZ), a DA depletor, has been used to treat hyperkinesias in Huntington's disease (HD). The aim of this study is to define the role of AP on chorea, motor performance, and functional disability, and to compare the effects of AP vs. TBZ in a small study of six patients with HD. Both AP and TBZ increased the Unified Huntington's Disease Rating Scale (UHDRS) chorea score in a similar way. However, AP caused less sedation and sleepiness than TBZ and was better tolerated by the patients on the trial. Moreover, AP showed a slight but not significant improvement of depression in the patients as compared to TBZ. A larger group of patients and a longer period of observation are an important prerequisite for further evaluations of AP's therapeutic use.

Tetrabenazine in Huntington's Disease Chorea

Huntington's disease (HD) is a heredodegenerative neurological disorder with chorea and other hyperkinetic movement disorders being part of the disease spectrum. These along with cognitive and neurobehavioral manifestations contribute significantly to patient's disability. Several classes of drugs have been used to treat the various symptoms of HD. These include typical and atypical neuroleptics along with dopamine depletors for treatment of chorea and antidepressants, GABA agonists, antiepileptic medications, cholinesterase inhibitors, antiglutamatergic drugs and botulinum toxin for treatment of other manifestations. Tetrabenazine (TBZ), a dopamine depleting medication was recently approved by the US FDA for treatment of chorea in HD. The purpose of this article is to briefly review information regarding HD and current treatments for chorea and specifically focus on TBZ and review the literature related to its use in HD chorea.

Tetrabenazine launched in US.

Tetrabenazine launched in US.

Tetrabenazine available in US for HD-associated chorea.

Tetrabenazine available in US for HD-associated chorea.

The Long-term Effect of Tetrabenazine in the Management of Huntington Disease

To enhance the knowledge on the long-term efficacy and safety of tetrabenazine (TBZ) in managing chorea. We analyzed 68 Huntington disease patients (mean disease duration, 55.8 +/- 34.7 months) who had been treated with TBZ for a mean period of 34.4 +/- 25.2 months (median, 34 months; mode, 48 months; range, 3-104 months). We measured the variation from pretreatment of the motor score of Unified Huntington's Disease Rating Scale at the first follow-up visit and at the latest. Mean Unified Huntington's Disease Rating Scale-chorea underscore at the time of the pretreatment visit was 10.4 +/- 4.1 (range, 0-28). At the first follow-up, 9.7 +/- 7.8 months after the prescription of TBZ (mean dose, 35.3 +/- 14.7 mg), mean score of chorea was 8.2 +/- 4.1 (-21% compared with baseline), whereas at the latest follow-up visit (mean dose, 57.5 +/- 14.7 mg), it was 9.5 +/- 5.0 (9%). During the follow-up, the clinical benefit persisted, but the magnitude was reduced despite a progressive increase of the doses (up to 60%). Motor improvement was not influenced by sex, or doses or duration of therapy; age at onset was the only predictor of a good outcome. Five patients (7%) did not gain any improvement, and TBZ was discontinued. There were 2 withdrawals because of side effects; 34 patients reported at least 1 side effect. Tetrabenazine was well tolerated and produced long-term improvement of motor symptoms in Huntington disease patients, although a slight reduction of benefit occurred during the course of treatment.

Role of vesicular monoamine transporter type 2 in rodent insulin secretion and glucose metabolism revealed by its specific antagonist tetrabenazine

Despite different embryological origins, islet beta-cells and neurons share the expression of many genes and display multiple functional similarities. One shared gene product, vesicular monoamine transporter type 2 (VMAT2, also known as SLC18A2), is highly expressed in human beta-cells relative to other cells in the endocrine and exocrine pancreas. Recent reports suggest that the monoamine dopamine is an important paracrine and/or autocrine regulator of insulin release by beta-cells. Given the important role of VMAT2 in the economy of monoamines such as dopamine, we investigated the possible role of VMAT2 in insulin secretion and glucose metabolism. Using a VMAT2-specific antagonist, tetrabenazine (TBZ), we studied glucose homeostasis, insulin secretion both in vivo and ex vivo in cultures of purified rodent islets. During intraperitoneal glucose tolerance tests, control rats showed increased serum insulin concentrations and smaller glucose excursions relative to controls after a single intravenous dose of TBZ. One hour following TBZ administration we observed a significant depletion of total pancreas dopamine. Correspondingly, exogenous L-3,4-dihydroxyphenylalanine reversed the effects of TBZ on glucose clearance in vivo. In in vitro studies of rat islets, a significantly enhanced glucose-dependent insulin secretion was observed in the presence of dihydrotetrabenazine, the active metabolite of TBZ. Together, these data suggest that VMAT2 regulates in vivo glucose homeostasis and insulin production, most likely via its role in vesicular transport and storage of monoamines in beta-cells.

A Study of Chorea After Tetrabenazine Withdrawal in Patients With Huntington Disease

To assess tetrabenazine (TBZ) efficacy by evaluating the change in Huntington disease-associated chorea resulting from TBZ treatment withdrawal. Thirty patients treated in the long term were randomized to 1 of 3 groups assigned to withdraw from TBZ in a double-blind, staggered fashion during a 5-day period. The chorea scores of subjects withdrawn from TBZ treatment increased by 5.3 units from days 1 to 3, whereas the scores of the group with partial or no withdrawal of TBZ treatment increased by 3.0 units (P = 0.0773). A post hoc analysis of the linear trend was positive for reemergent chorea (P = 0.0486). No serious adverse events were reported after abrupt withdrawal of TBZ treatment. The trend for reemergence of chorea in patients with Huntington disease who were withdrawn from TBZ treatment is consistent with the findings from previous studies, thus showing the effectiveness of TBZ in reducing chorea.

Neurotoxicity in murine striatal dopaminergic pathways following long-term application of low doses of permethrin and MPTP

The long-term effects of permethrin (PM) and its interaction with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on striatal dopaminergic pathways were investigated in C57BL/6 mice. In a 3-month exposure, technical PM (1.5 mg/kg) was administered once per week, with MPTP (20 mg/kg) given once on either the 7th week or 11th week. In a 6-month exposure, PM (0.8 mg/kg or 1.5 mg/kg) was administered once per week for 26 weeks, with MPTP (20 mg/kg) given once, on week 24. Alterations in the expression of tyrosine hydroxylase (TH), dopamine transporter (DAT), and α-synuclein proteins were analyzed 1 day after the last PM treatment using western blot assay. PM had no significant effect on striatal dopaminergic pathways by itself, whereas MPTP significantly reduced the expression of TH and DAT proteins. In both exposure paradigms, weekly 1.5 mg/kg PM treatments antagonized the toxic effect of MPTP on TH and DAT expression ( p < 0.05). There was no significant alteration of α-synuclein expression following any exposure to PM and/or MPTP. [ 3H]Tetrabenazine (TBZ) binding assay for expression of striatal vesicular monoamine transporter (VMAT) showed no effect of PM, but the reduction in this protein caused by MPTP was attenuated by PM, consistent with effects on other dopaminergic biomarkers. The overall findings demonstrate that long-term, low-dose exposure to PM alone did not cause signs of neurotoxicity to striatal dopaminergic neural terminals, or enhance the effects of MPTP. We conclude that under typical use conditions, PM poses little Parkinsonian hazard to humans, including when impregnated into clothing for control of biting flies.

Tetrabenazine as antichorea therapy in Huntington disease: A randomized controlled trial

The HSG described the important benefit of tetrabenazine (TBZ) in patients with Huntington disease.1 We would like to stress the mechanism of action of this valuable agent. The only action ascribed to TBZ in achieving the clinical benefit was inhibiting presynaptic vesicular monoamine transporters to block amine reuptake and secondarily decrease dopamine levels. Although this mechanism is clearly established, TBZ is also functionally effective as a dopamine receptor antagonist based on a large body of rigorous literature. This additional mechanism could well contribute to the clinical benefit observed and possibly explain some unexpected results. In support of an independent action as a dopaminergic antagonist, TBZ blocks dopamine-2 and apomorphine-mediated3 inhibition of pituitary prolactin release in vivo2,3 …

Short‐term effects of tetrabenazine on chorea associated with Huntington's disease

We sought to assess the short-term clinical effects of tetrabenazine (TBZ) on choreic movements in Huntington's disease patients. A total of 10 patients on stable doses of TBZ were enrolled in this observational study. Patients took their evening dose of TBZ and presented the next day to the Baylor College of Medicine Movement Disorders Clinic without taking the usual morning dose. They were assessed using the Unified Huntington's Disease Rating Scale (UHDRS) motor assessment and Beck Depression Inventory. The usual morning dose of TBZ was then administered and patients were followed with serial UHDRS motor examinations approximately every 2 hours until choreic movements subsided and then returned. TBZ decreased the UHDRS chorea score on average 42.4% +/- 17.8%. The duration of effect varied from a minimum of 3.2 hours to a maximum of 8.1 hours (mean = 5.4 +/- 1.3). No patient experienced an adverse event related to TBZ or its withdrawal. During short-term follow-up after a single dose, TBZ improves chorea for approximately 5 hours.

Long‐term tolerability of tetrabenazine in the treatment of hyperkinetic movement disorders

We sought to review the long-term tolerability of tetrabenazine (TBZ) and seek determinants of tolerability in the treatment of hyperkinetic movement disorders. A retrospective chart review was performed on patients treated with TBZ between 1997 and 2004. Efficacy of TBZ was assessed by a 1- to 5-point response scale (1 = marked reduction in abnormal movements, 5 = worsening). All adverse events (AEs) were captured according to their relationship with study drug. A total of 448 patients (42% male) were treated for a variety of hyperkinesias, including tardive dyskinesia (n = 149), dystonia (n = 132), chorea (n = 98), tics (n = 92), and myoclonus (n = 19). The mean age at onset of the movement disorder was 43.0 +/- 24.2 years, with TBZ starting at a mean age of 50.0 +/- 22.3 years. Patients remained on treatment for a mean of 2.3 +/- 3.4 years. An efficacy response rating of 1 or 2 was sustained in the majority of patients between the first and last visit. Common AEs included drowsiness (25.0%), Parkinsonism (15.4%), depression (7.6%), and akathisia (7.6%). Comparison of log-likelihood ratios revealed that age was a reliable predictor of Parkinsonism (P < 0.0001). TBZ is a safe and effective drug for the long-term treatment of hyperkinetic movement disorders.

Tetrabenazine therapy of pediatric hyperkinetic movement disorders

Tetrabenazine (TBZ), a presynaptic dopamine depletor and postsynaptic dopamine receptor blocker, is widely used for the treatment of hyperkinetic movement disorders in adults. However, reports of its use in children are limited. We review the efficacy and tolerability of TBZ therapy in 31 children with hyperkinetic movement disorders refractory to other medications. TBZ was effective in reducing the severity of movement disorders resistant to treatment with other medicines. When compared to adult patients, pediatric patients required higher doses. Side effects were similar to the adult population; however, children had a lower incidence of drug-induced Parkinsonism.