Entrainment was assessed using urinary Cortisol rhythms.64 As their endogenous rhythms were longer than 24 hours, subjects required a daily phase advance (ie, a shift to an earlier time) to become entrained to 24 hours. Three of the subjects exhibited entrained Cortisol rhythms and one had a shortened period during treatment. The remaining three subjects were not affected by melatonin. Post-hoc analysis of melatonin treatment timing indicated that those Inhibitors,research,lifescience,medical subjects

who failed to entrain had treatment initiated at a time that corresponded to the delay phase of the melatonin phase response curve (PRC)110 (equivalent to -1:00-13:00 h in a normally-entrained subject) where melatonin causes a phase delay shift (ie, to a later time), the check details opposite of that required to entrain. Surprisingly, the subjects did not entrain Inhibitors,research,lifescience,medical once they free-ran into the correct window to cause a phase advance, unlike previous animal models.93 Those subjects who became entrained or had a shortened period had their treatment Inhibitors,research,lifescience,medical initiated during the phase-advance portion of the PRC (-13:00-1:00 h in normal subjects), a time consistent with the observed daily advance achieved. We hypothesized at the time that the

inappropriate initial timing in the nonentrained subjects may have affected the sensitivity to melatonin (for example, by receptor downregulation) when the appropriate treatment time was reached. Shortly following publication of these data, similar results were published by Sack and colleagues using a 10-mg dose of melatonin initiated during the phase-advance window, who also showed entrainment of plasma melatonin rhythms when assessed during temporary Inhibitors,research,lifescience,medical suspensions of melatonin treatment.111 In addition, they demonstrated that the 10-mg dose could be gradually stepped down to 0.5 mg and entrainment could be maintained.111 These data raised the question as to whether a 0.5-mg de novo dose could also reset the clock, and both we and others confirmed

that it could.112-114 This low dose Inhibitors,research,lifescience,medical was also more likely to entrain than treatment SSR128129E solubility dmso with higher doses (5 to 20 mg) maybe through providing a more discreet time signal than a higher dose with a more prolonged duration In the circulation. The Individual clrcadlan period may also affect the likelihood of entrainment with melatonin,115 as those subjects with periods furthest from 24 hours may be outside the range of entrainment for this relatively weak time cue. Inconsistencies still exist, however, as to whether the circadian time of initial treatment affects subsequent entrainment. In our studies, using both 5 and 0.5 mg melatonin, entrainment was more likely if treatment was initiated in the advance, compared with the delay, phase of the PRC in both between and within-subjects designs (109,113, Lockley et al, unpublished results). At low doses, however, (0.