Assessment of the Abuse Liability of a Dual Orexin Receptor Antagonist: A Crossover Study of Almorexant and Zolpidem in Recreational Drug Users

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• 作者：Hans G. Cruz (1)
  Petra Hoever (1)
  Bijan Chakraborty (2)
  Kerri Schoedel (3)
  Edward M. Sellers (4)
  Jasper Dingemanse (1)
  
• 刊名：CNS Drugs
• 出版年：2014
• 出版时间：April 2014
• 年：2014
• 卷：28
• 期：4
• 页码：361-372
• 全文大小：360 KB
• 参考文献：1. Wilson SJ, Nutt DJ, Alford C, et al. British Association for Psychopharmacology consensus statement on evidence-based treatment of insomnia, parasomnias and circadian rhythm disorders. J Psychopharmacol. 2010;24(11):1577-01. CrossRef
  2. Licata SC, Rowlett JK. Abuse and dependence liability of benzodiazepine-type drugs: GABA(A) receptor modulation and beyond. Pharmacol Biochem Behav. 2008;90(1):74-9. CrossRef
  3. Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry. 2005;66(Suppl 9):31-1.
  4. Brisbare-Roch C, Dingemanse J, Koberstein R, et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med. 2007;13(2):150-. CrossRef
  5. Hoever P, Dorffner G, Benes H, et al. Orexin receptor antagonism, a new sleep-enabling paradigm: a proof-of-concept clinical trial. Clin Pharmacol Ther. 2012;91(6):975-5. CrossRef
  6. Hoever P, de Haas SL, Dorffner G, et al. Orexin receptor antagonism: an ascending multiple-dose study with almorexant. J Psychopharmacol. 2012;26(8):1071-0. CrossRef
  7. Steiner MA, Lecourt H, Strasser DS, et al. Differential effects of the dual orexin receptor antagonist almorexant and the GABA(A)-alpha1 receptor modulator zolpidem, alone or combined with ethanol, on motor performance in the rat. Neuropsychopharmacology. 2011;36(4):848-6. CrossRef
  8. Hoch M, Hay JL, Hoever P, et al. Dual orexin receptor antagonism by almorexant does not potentiate impairing effects of alcohol in humans. Eur Neuropsychopharmacol. 2013;23(2):107-7. CrossRef
  9. Steiner MA, Lecourt H, Jenck F. The dual orexin receptor antagonist almorexant, alone and in combination with morphine, cocaine and amphetamine, on conditioned place preference and locomotor sensitization in the rat. Int J Neuropsychopharmacol. 2013;16(2):417-2. CrossRef
  10. Brisbare-Roch C, Fischer W, Jenck F. Effect of once-daily almorexant treatment for 6?weeks on the sleep–wake cycle of normal Wistar rats. Eur Neuropsychopharmacol. 2010;20(Suppl 3):S253-. CrossRef
  11. Actelion Pharmaceuticals Ltd. Almorexant (ACT-078573) in adult subjects with chronic primary insomnia (RESTORA1) [ClinicalTrials.gov identifier NCT00608985]. US National Institutes of Health, ClinicalTrials.gov. http://clinicaltrials.gov/ct2/show/NCT00608985?term=restora&rank=1.
  12. Mahler SV, Smith RJ, Moorman DE, et al. Multiple roles for orexin/hypocretin in addiction. Prog Brain Res. 2012;198:79-21. CrossRef
  13. Kim AK, Brown RM, Lawrence AJ. The role of orexins/hypocretins in alcohol use and abuse: an appetitive-reward relationship. Front Behav Neurosci. 2012;6:78.
  14. Srinivasan S, Simms JA, Nielsen CK, et al. The dual orexin/hypocretin receptor antagonist, almorexant, in the ventral tegmental area attenuates ethanol self-administration. PLoS One. 2012;7(9):e44726. CrossRef
  15. LeSage MG, Perry JL, Kotz CM, et al. Nicotine self-administration in the rat: effects of hypocretin antagonists and changes in hypocretin mRNA. Psychopharmacology (Berl). 2010;209(2):203-2. CrossRef
  16. O’Connor EC, Chapman K, Butler P, et al. The predictive validity of the rat self-administration model for abuse liability. Neurosci Biobehav Rev. 2011;35(3):912-8. CrossRef
  17. Bardo MT, Bevins RA. Conditioned place preference: what does it add to our preclinical understanding of drug reward? Psychopharmacology (Berl). 2000;153(1):31-3. CrossRef
  18. Riegel AC, Kalivas PW. Neuroscience: lack of inhibition leads to abuse. Nature. 2010;463(7282):743-. CrossRef
  19. Tan KR, Brown M, Labouebe G, et al. Neural bases for addictive properties of benzodiazepines. Nature. 2010;463(7282):769-4. CrossRef
  20. Schoedel KA, Sellers EM. Assessing abuse liability during drug development: changing standards and expectations. Clin Pharmacol Ther. 2008;83(4):622-. CrossRef
  21. Griffiths RR, Bigelow GE, Ator NA. Principles of initial experimental drug abuse liability assessment in humans. Drug Alcohol Depend. 2003;70(3 Suppl):S41-4. CrossRef
  22. Chen L, Tsong Y. Design and analysis for drug abuse potential studies: issues and strategies for implementing a crossover design. Drug Inf J. 2007;41(4):481-.
  23. Center for Drug Evaluation and Research, Food and Drug Administration. Assessment of abuse potential of drugs (draft guidance). Guidance for industry. Jan 2010.
  24. Parasrampuria DA, Schoedel KA, Schuller R, et al. Do formulation differences alter abuse liability of methylphenidate? A placebo-controlled, randomized, double-blind, crossover study in recreational drug users. J Clin Psychopharmacol. 2007;27(5):459-7. CrossRef
  25. Bowdle TA, Radant AD, Cowley DS, et al. Psychedelic effects of ketamine in healthy volunteers: relationship to steady-state plasma concentrations. Anesthesiology. 1998;88(1):82-. CrossRef
  26. Martin WR, Sloan JW, Sapira JD, et al. Physiologic, subjective, and behavioral effects of amphetamine, methamphetamine, ephedrine, phenmetrazine, and methylphenidate in man. Clin Pharmacol Ther. 1971;12(2):245-8.
  27. Milovan D, Almeida L, Romach MK, et al. Effect of eslicarbazepine acetate and oxcarbazepine on cognition and psychomotor function in healthy volunteers. Epilepsy Behav. 2010;18(4):366-3. CrossRef
  28. Romach MK, Schoedel KA, Rosen LB, et al. Adverse effects of gaboxadol and zolpidem at high doses in recreational drug users [poster]. 47th Annual Meeting American College of Neuropsychopharmacology, 7-1 Dec 2008, Scottsdale (AZ).
  29. Schoedel KA. Measures of abuse potential in human abuse liability trials: application to anti-epileptics [workshop]. College on Problems of Drug Dependence, 22 June 2009, Reno-Sparks (NV).
  30. Schoedel KA, Rosen LB, Alexander R, et al. A Single-dose, randomized, double-blind, crossover abuse liability study to evaluate the subjective and objective effects of gaboxadol and zolpidem in recreational drug users [poster]. American Society for Clinical Pharmacology and Therapeutics, 18-1 March 2009, National Harbor (MD).
  31. Rush CR, Baker RW, Wright K. Acute behavioral effects and abuse potential of trazodone, zolpidem and triazolam in humans. Psychopharmacology (Berl). 1999;144(3):220-3. CrossRef
  32. Shram MJ, Schoedel KA, Bartlett C, et al. Evaluation of the abuse potential of lorcaserin, a serotonin 2C (5-HT2C) receptor agonist, in recreational polydrug users. Clin Pharmacol Ther. 2011;89(5):683-2. CrossRef
  33. de Haas S, Dingemanse J, Hoever P, et al. Pseudohallucinations after zolpidem intake: a case report. J Clin Psychopharmacol. 2007;27(6):728-0. CrossRef
  34. Johanson CE, Balster RL, Henningfield JE, et al. Risk management and post-marketing surveillance for the abuse of medications acting on the central nervous system: expert panel report. Drug Alcohol Depend. 2009;105(Suppl 1):S65-1. CrossRef
  35. Carter LP, Griffiths RR. Principles of laboratory assessment of drug abuse liability and implications for clinical development. Drug Alcohol Depend. 2009;105(Suppl 1):S14-5. CrossRef
  36. Johnson MW, Suess PE, Griffiths RR. Ramelteon: a novel hypnotic lacking abuse liability and sedative adverse effects. Arch Gen Psychiatry. 2006;63(10):1149-7. CrossRef
  37. Martinotti G, Lupi M, Sarchione F, et al. The potential of pregabalin in neurology, psychiatry and addiction: a qualitative overview. Curr Pharm Des. 2013;19(35):6367-4.
  38. Harris GC, Aston-Jones G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 2006;29(10):571-. CrossRef
  39. Aston-Jones G, Smith RJ, Sartor GC, et al. Lateral hypothalamic orexin/hypocretin neurons: a role in reward-seeking and addiction. Brain Res. 2010;1314:74-0. CrossRef
  40. Tsujino N, Sakurai T. Orexin/hypocretin: a neuropeptide at the interface of sleep, energy homeostasis, and reward system. Pharmacol Rev. 2009;61(2):162-6. CrossRef
  41. Scammell TE, Winrow CJ. Orexin receptors: pharmacology and therapeutic opportunities. Annu Rev Pharmacol Toxicol. 2011;51:243-6. CrossRef
  42. Smith RJ, See RE, Aston-Jones G. Orexin/hypocretin signaling at the orexin 1 receptor regulates cue-elicited cocaine-seeking. Eur J Neurosci. 2009;30(3):493-03. CrossRef
  43. Smith RJ, Aston-Jones G. Orexin/hypocretin 1 receptor antagonist reduces heroin self-administration and cue-induced heroin seeking. Eur J Neurosci. 2012;35(5):798-04. CrossRef
  44. Jupp B, Krstew E, Dezsi G, et al. Discrete cue-conditioned alcohol-seeking after protracted abstinence: pattern of neural activation and involvement of orexin(1) receptors. Br J Pharmacol. 2011;162(4):880-. CrossRef
  45. Hollander JA, Pham D, Fowler CD, et al. Hypocretin-1 receptors regulate the reinforcing and reward-enhancing effects of cocaine: pharmacological and behavioral genetics evidence. Front Behav Neurosci. 2012;6:47. CrossRef
  46. Espana RA, Oleson EB, Locke JL, et al. The hypocretin-orexin system regulates cocaine self-administration via actions on the mesolimbic dopamine system. Eur J Neurosci. 2010;31(2):336-8. CrossRef
  47. Borgland SL, Chang SJ, Bowers MS, et al. Orexin A/hypocretin-1 selectively promotes motivation for positive reinforcers. J Neurosci. 2009;29(36):11215-5. CrossRef
  48. Willie JT, Chemelli RM, Sinton CM, et al. Distinct narcolepsy syndromes in Orexin receptor-2 and Orexin null mice: molecular genetic dissection of non-REM and REM sleep regulatory processes. Neuron. 2003;38(5):715-0. CrossRef
  49. Dugovic C, Shelton JE, Aluisio LE, et al. Blockade of orexin-1 receptors attenuates orexin-2 receptor antagonism-induced sleep promotion in the rat. J Pharmacol Exp Ther. 2009;330(1):142-1. CrossRef
  50. Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012;76(3):470-5. CrossRef
  51. Koob GF, Volkow ND. Neurocircuitry of addiction. Neuropsychopharmacology. 2010;35(1):217-8. doi:10.1038/npp.2009.110 . CrossRef
  52. Lena I, Parrot S, Deschaux O, et al. Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep–wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. J Neurosci Res. 2005;81(6):891-. CrossRef
  53. Hoever P, de Haas S, Winkler J, et al. Orexin receptor antagonism, a new sleep-promoting paradigm: an ascending single-dose study with almorexant. Clin Pharmacol Ther. 2010;87(5):593-00. CrossRef
  
• 作者单位：Hans G. Cruz (1)
  Petra Hoever (1)
  Bijan Chakraborty (2)
  Kerri Schoedel (3)
  Edward M. Sellers (4)
  Jasper Dingemanse (1)
  
  1. Actelion Pharmaceuticals Ltd, Clinical Pharmacology, Gewerbestrasse 16, 4123, Allschwil, Switzerland
  2. INC Research Toronto, Inc., Toronto, ON, Canada
  3. Altreos Research Partners, Inc., Toronto, ON, Canada
  4. DL Global Partners, Inc., Toronto, ON, Canada
  
• ISSN：1179-1934

文摘

Background Dual orexin receptor antagonists (DORAs) enable initiation and maintenance of sleep in patients with primary insomnia. Blockade of the orexin system has shown reduction of drug-seeking behavior in animal studies, supporting the role of orexin antagonism as a novel approach for treating substance abuse. Since hypnotics are traditionally associated with misuse, a lack of abuse liability of DORAs would offer significant benefits over current therapies for sleep disorders. Methods In this randomized, crossover, proof-of-concept study, single oral doses of the DORA almorexant (200, 400, and 1,000?mg) were administered to healthy subjects with previous non-therapeutic experience with central nervous system depressants and were compared with placebo and single oral doses of zolpidem (20 and 40?mg), a benzodiazepine-like drug. Subjective measures of abuse potential (visual analog scales [VAS], Addiction Research Center Inventory, and Subjective Drug Value) and objective measures (divided attention [DA]) were evaluated over 24?h post-dose in 33 evaluable subjects. Results Drug Liking VAS peak effect (E max; primary endpoint) was significantly higher for all doses of almorexant and zolpidem compared with placebo (p?<?0.001). Almorexant 200?mg showed significantly less ‘Drug Liking-than both zolpidem doses (p?<?0.01), and almorexant 400?mg had smaller effects than zolpidem 20?mg (p?<?0.05), while almorexant 1,000?mg was not different from either zolpidem dose. Results were similar for other subjective measures, although almorexant generally showed smaller negative and perceptual effects compared with zolpidem. Almorexant also showed less cognitive impairment compared with zolpidem on most DA endpoints. Conclusion This study in humans investigating single doses of almorexant is the first to explore and show abuse liability of a DORA, a class of compounds that is not only promising for the treatment of sleep disorders, but also of addiction.