Tetrabenazine, a dopamine-depleting agent first synthesized half a century ago, was initially developed for the treatment of schizophrenia. Although psychotic disorders have since been treated more successfully with other neuroleptic medications, many studies have shown this drug to be effective in the treatment of hyperkinetic movement disorders (hyperkinesias). Hyperkinesias are neurologic disorders characterized by abnormal involuntary movements such as chorea associated with Huntington's disease, tics in Tourette's syndrome and stereotypies in tardive dyskinesia. Recently, clinical trials investigating tetrabenazine for the treatment of chorea associated with Huntington's disease found the drug to be safe and efficacious, making approval by the US Food and Drug Administration for this indication a distinct possibility.
"Lastly, our observations must be interpreted carefully. TBZ has been used to treat movement disorders for over 30 years (Kenney & Jankovic 2006) and effects on glucose homeostasis have not been reported. Nevertheless, our findings suggest that VMAT2 plays a role in glucose homeostasis and could be a therapeutic target in diabetes. "
[Show abstract][Hide abstract] ABSTRACT: 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.
Journal of Endocrinology 08/2008; 198(1):41-9. DOI:10.1677/JOE-07-0632 · 3.72 Impact Factor
"Diana small numbers of patients have demonstrated the benefi cial effects of TBZ for patients with chorea (Fog and Pakkenberg 1970; Gilligan et al 1972; Swash et al 1972; Huang 1976; Toglia et al 1978; Kingston 1979; Asher and Aminoff 1979; Jancovic 1982, 1983; Jancovic and Orman 1988; Gimenez-Roldan and Mateo 1989; Jancovic and Beach 1997; Ondo et al 2002; Paleacu et al 2004; Kenney and Jancovic 2006). TBZ was approved for the treatment of chorea in the United Kingdom in 1971. "
[Show abstract][Hide abstract] ABSTRACT: Tetrabenazine (TBZ), a catecholamine-depleting agent initially developed for the treatment of schizophrenia, when tested for other indications, has proven to be more useful for the treatment of a variety of hyperkinetic movement disorders. These disorders include neurological diseases characterized by abnormal involuntary movements such as chorea associated with Huntington's disease, tics in Tourette's syndrome, dyskinesias and dystonias in tardive dyskinesia, also primary dystonias and myoclonus. This review will include and discuss studies published during the period of 1960-2006 regarding the clinical efficacy and tolerability of TBZ in Huntington's disease (HD). It will also review the chemistry, pharmacokinetics and dynamics of the drug and its mechanism of action compared to that of reserpine, the only similar compound. This review emphasizes the advantage of TBZ over dopamine-depleting compounds used in the treatment of chorea and reveals its clinical efficacy and side effects.
Neuropsychiatric Disease and Treatment 11/2007; 3(5):545-51. · 1.74 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction
Tetrabenazine (TBZ) reduces chorea related to Huntington disease (HD); however, it is uncertain whether this effect improves functionally relevant motor skills such as hand coordination and balance. The objective of this study was to provide pilot data regarding three motor function tests, which might be useful in monitoring symptom progression and therapeutic response, pending formal validation.
The authors assessed 11 ambulatory patients with HD-related chorea on two occasions: (1) while off TBZ (either prior to starting therapy or following a >24 h washout) and (2) when on a stable dose of TBZ, titrated to optimal effect. Study evaluations included the Jebsen-Taylor Hand Function Test (JTHFT) and Berg Balance Scale, a timed 25-foot walk, the Montreal Cognitive Assessment (MoCA) and the complete United Huntington Disease Rating Scale (UHDRS).
Maximal chorea scores (UHDRS item 12) improved from 11.1 ± 2.9 to 8.5 ± 3.9 while on TBZ (P = 0.03), but we could not detect an improvement in functional measures while on TBZ in this small cohort. Scores of the JTHFT were globally slower than published normative data and correlated with MoCA summary scores, but not UHDRS chorea scores.
This pilot study did not detect significant functional gains with chorea suppression. The fact that performance on tests of hand function correlates with MoCA but not UHDRS chorea scores highlights the need for additional treatments targeted toward the cognitive aspects of HD.
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