title: Chronobiotic effects of the melatonin agonist LY 156735 following a simulated 9h time shift: results of a placebo-controlled trial.
abstract: BACKGROUND
  The melatonin agonist LY 156735 (LY) is a new investigational drug under development to treat circadian rhythm disorders. The present study assessed the efficacy of LY to alleviate the symptoms of shift lag and to enhance readaptation of desynchronized circadian rhythms to a new time zone.
  
  
  METHODS
  Eight healthy male volunteers of age 25-35 yr participated in three identical trials of 13d duration in a temporal isolation unit separated by washout intervals. A high dose (HD) of 5 mg and a low dose (LD) of 0.5 mg of LY and placebo (PL) were administered double-blinded in a three-period cross-over design. Each trial consisted of an adaptation period, a pre-shift period for baseline measurements, a simulated 9h phase-advance shift, and a post-shift period for follow-up. The time shift was performed at 23:00h of day 6 by advancing the laboratory time to 08:00h of day 7. Double-blind study medication was administered at 14:30h on day 6, and at 22:30h on days 7-10. Subjective ratings of jet lag, alertness, tenseness, and daytime fatigue were assessed using visual analog scales (VAS) and standardized questionnaires. The objective markers of readaptation included core body temperature, wrist actigraphy, cortisol and electrolyte excretion, and a battery of computerized performance tests.
  
  
  RESULTS
  HD but not LD enhanced the readaptation speed of all physiological rhythms investigated, as demonstrated by a significantly faster movement of acrophases towards the post-shift target time. HD (p = 0.05) significantly blunted the post-shift deterioration of performance in those tests that were sensitive to shift lag. Parameters of subjective well-being were not significantly affected by either dose.
  
  
  CONCLUSIONS
  This pilot study demonstrates the chronobiotic efficacy of LY when taken at a dose of 5 mg/d.
authors.affiliation: Lilly Deutschland GmbH, Bad Homburg, Germany. nickelsen_thomas_n@lilly.com
authors.forename: Thomas
authors.initials: T
authors.lastname: Nickelsen
authors.forename: Alexander
authors.initials: A
authors.lastname: Samel
authors.forename: Martin
authors.initials: M
authors.lastname: Vejvoda
authors.forename: Juergen
authors.initials: J
authors.lastname: Wenzel
authors.forename: Brian
authors.initials: B
authors.lastname: Smith
authors.forename: Rupert
authors.initials: R
authors.lastname: Gerzer
mesh_terms: D000222:Adaptation, Physiological; D000328:Adult; D001831:Body Temperature / Q000187:drug effects; D002940:Circadian Rhythm / Q000187:drug effects*; D018592:Cross-Over Studies; D004311:Double-Blind Method; D006801:Humans; D006854:Hydrocortisone / Q000652:urine; D007211:Indoles / Q000494:pharmacology*; D020179:Jet Lag Syndrome / Q000188:drug therapy* / Q000503:physiopathology / Q000523:psychology; D008297:Male; D008550:Melatonin / Q000819:agonists* / Q000031:analogs & derivatives / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D011597:Psychomotor Performance / Q000187:drug effects
chemical_list: D007211:Indoles; C473427:LY 156735; D008550:Melatonin; D006854:Hydrocortisone