Skip to main content Accessibility help
×
×
Home

Tolerability and efficacy of the monoaminergic stabilizer (−)-OSU6162 (PNU-96391A) in Huntington’s disease: a double-blind cross-over study

  • Angelica Kloberg (a1), Radu Constantinescu (a2), Marie Karin Lena Nilsson (a3), Maria Lizzie Carlsson (a3), Arvid Carlsson (a3), Jan Wahlström (a4) and Sara Haghighi (a5)...

Abstract

Objective

To evaluate the safety (primary objective) and efficacy (secondary objective) of (−)-OSU6162 in Huntington’s disease (HD).

Methods

In a double-blind, cross-over trial, patients with HD were randomly assigned to start treatment on either (−)-OSU6162 or placebo. After 4 weeks, those patients who initially received active drug were switched to placebo for another 4 weeks, and vice versa. During the first week the (−)-OSU6162 dose was 15 mg twice daily, during the second week 30 mg twice daily, and during the last 2 weeks 45 mg twice daily. Motor, cognitive, mental and social functions were rated by the clinical investigator or by self-assessment, using established rating scales.

Results

Fifteen patients fulfilling inclusion and exclusion criteria completed the study. (−)-OSU6162 was well tolerated by all patients and no adverse effects were observed. (−)-OSU6162 treatment significantly improved the Short Form 36 Vitality score, mainly due to an improvement of the individual item ‘worn-out’ (VT3). In addition, an improvement of depressive symptoms was found using Beck Depression Inventory. In contrast to a general trend of improvement in several non-motor variables only small and non-significant differences between (−)-OSU6162 and placebo were found regarding motor functions.

Conclusions

(−)-OSU6162 offers promise for the treatment of HD, as a drug with good tolerability, capable of improving the patients’ experienced non-motor functions such as energy and mood and thus alleviating symptoms of great importance for their quality of life.

Copyright

Corresponding author

Dr. Angélica Kloberg, PhD, A Carlsson Research AB, Sahlgrenska Science Park, Medicinaregatan 8A, vån 2, lab SE 413 46 Gothenburg, Sweden. Tel: +46-31-7411892; E-mail: angelica.kloberg@carlssonresearch.eu

Footnotes

Hide All

Deceased

Footnotes

References

Hide All
1.Petersén, Å, Björkqvist, M. Hypothalamic-edocrine aspects in Huntington’s disease. Euro J Neurosci 2006;24:961967.
2.Walker, FO. Huntington’s disease. Lancet 2007;369:218228.
3.Paleacu, D. Tetrabenazine in the treatment of Huntington’s disease. Neuropsychiatr Dis Treat 2007;3:545551.
4.Rung, JP, Rung, E, Helgeson, Let al. Effects of (–)-OSU6162 and ACR16 on motor activity in rats, indicating a unique mechanism of dopaminergic stabilization. J Neural Trasm 2008;115:899908.
5.Carlsson, ML, Burstein, ES, Kloberg, Aet al. I. In vivo evidence for partial agonist effects of (–)-OSU6162 and (+)-OSU6162 on 5-HT2A serotonin receptors. J Neural Trasm 2011;118:15111522.
6.Burstein, ES, Carlsson, ML, Owens, Met al. II. In vitro evidence that (–)-OSU6162 and (+)-OSU6162 produce their behavioral effects through 5-HT2A serotonin and D2 dopamine receptors. J Neural Transm 2011;118:15231533.
7.Tedroff, J, Ekesbo, A, Sonesson, C, Waters, N, Carlsson, A. Long-lasting improvement following (–)-OSU6162 in a patient with Huntington’s disease. Neurology 1999;53:16051606.
8.de Yebenes, JG, Landwehrmeyer, B, Squitieri, Fet al. Pridopidine for the treatment of motor function in patients with Huntington’s disease (MermaiHD): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet Neurol 2011;10:10491057.
9.The Huntington Study Group HART Investigators. A randomized, double-blind, placebo-controlled trial of pridopidine in Huntington’s disease. Mov Disord 2013;28:14071415.
10.Landwehrmeyer, GB, Marder, K, Biilmann-Ronn, Bet al. Effects of the dopaminergic stabilizer pridopidine on motor symptoms in Huntington’s disease: a meta-analysis. Clin Genet 2011;80(Suppl. 1):48. (Abstract).
11. European Huntington’s Disease Network: www.euro-hd.net
12.Shoulson, I, Kurlan, R, Rubin, A. Assessment of functional capacity in neurodegenerative movement disorders: Huntington’s disease as a prototype. In: Munsat T, editor. Quantification of Neurologic Deficit. Stoneham, MA: Butterworths, 1989. p. 271283.
13.Sonesson, C, Lin, CH, Hansson, Let al. Substituted (S)-phenylpiperidines and rigid congeners as preferential dopamine autoreceptor antagonists: synthesis and structure-activity relationships. J Med Chem 1994;37:27352753.
14.Huntington Study Group. Unified Huntington’s Disease Rating Scale: reliability and consistency. Mov Disord 1996;11:136142.
15.Ware, JE, Snow, KK, Kosinski, Met al. SF-36 Health Survey: manual and interpretation guide. Boston: The Health Institute, New England Medical Centre, 1993.
16. Website: www.alswh.org.au, ALSWH (Australian Longitudinal Study on Women’s Health). Additional site information: For Researchers/Data/Data Dictionary Supplement/ Section 2, Core Survey Dataset/ 2.3 Health-related Quality of Life Variables, SF-36 (http://www.alswh.org.au/for-researchers/data/data-dictionary-supplement).
17.Altman, DG. Practical Statistics for Medical Research, 1st edn. London: Chapman and Hall, 1991.
18.Hodges, JL Jr, Lehmann, EL. Hodges-Lehmann estimators. In: Kotz S, Johnson NL, READ CB, editors. Encyclopedia of Statistical Sciences, Volume 3. New York: John Wiley & Sons, 1983. p. 463465.
19.Hollander, M, Wolfe, DA. Nonparametric Statistical Methods, 2nd edn. New York: John Wiley & Sons, 1999.
20.Suchman, AL, Ader, R. Pharmacodynamics and drug action. Classic conditioning and placebo effects in crossover studies. Clin Pharmacol Ther 1992;52:372377.
21.Faria, V, Fredrikson, M, Furumark, T. Imaging the placebo response: a neurofunctional review. Eur Neuropsychopharmacol 2008;18:473485.
22.Elbourne, DR, Altman, DG, Higgins, JPTet al. Meta-analyses involving cross-over trials: methodological issues. Int J Epidemiol 2002;31:140149.
23.Johansson, B, Carlsson, A, Carlsson, MLet al. Placebo-controlled cross-over study of the monoaminergic stabiliser (–)-OSU6162 in mental fatigue following stroke or traumatic brain injury. Acta Neuropsychiatrica 2012;24:266274.
24.Svensson, KA, Falcone, JF, Johansson, AMet al. The actions of the dopamine stabilizer ACR16, but not (–)-OSU6162, in behavioral and neurochemical assays are not dependent on the presence of functional D2 receptors. Society for Neuroscience Annual Meeting, 9–13 November 2009, San Diego.
25.Natesan, S, Svensson, KA, Reckless, GEet al. The dopamine stabilizers (S)-(–)-(3-methanesulfonyl-phenyl)-1-propyl-piperidine [(–)-OSU6162] and 4-(3-methanesulfonylphenyl)-1-propyl-piperidine (ACR16) show high in vivo D2 receptor occupancy, antipsychotic-like efficacy, and low potential for motor side effects in the rat. J Pharmacol Exp Ther 2006;318:810818.
26.Tolboom, N, Berendse, HW, Leysen, JEet al. The dopamine stabilizer (–)-OSU6162 occupies a subpopulation of striatal dopamine D2/D3 receptors: an [11C]-raclopride PET study in healthy human subjects. 2014. Submitted to Neuropsychopharmacology, minor revision.
27.Rodriguez, CA, Azie, NE, Adams, Get al. Single oral dose safety, tolerability, and pharmacokinetics of PNU-96391 in healthy volunteers. J Clin Pharmacol 2004;44:276283.
28.Ruiz, C, Casarejos, MJ, Rubio, Iet al. The dopaminergic stabilizer, (–)-OSU6162, rescues striatal neurons with normal and expanded polyglutamine chains in huntingtin protein from exposure to free radicals and mitochondrial toxins. Brain Res 2012;1459:100112.
Recommend this journal

Email your librarian or administrator to recommend adding this journal to your organisation's collection.

Acta Neuropsychiatrica
  • ISSN: 0924-2708
  • EISSN: 1601-5215
  • URL: /core/journals/acta-neuropsychiatrica
Please enter your name
Please enter a valid email address
Who would you like to send this to? *
×

Keywords

Metrics

Altmetric attention score

Full text views

Total number of HTML views: 0
Total number of PDF views: 0 *
Loading metrics...

Abstract views

Total abstract views: 0 *
Loading metrics...

* Views captured on Cambridge Core between <date>. This data will be updated every 24 hours.

Usage data cannot currently be displayed