Armodafinil, the R-Enantiomer of Modafinil: Wake-Promoting Effects and Pharmacokinetic Profile in the Rat

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Armodafninil

ABSTRACT

Modafinil reduces the excessive sleepiness associated with narcolepsy, obstructive sleep apnea/hypopnea syndrome, and shift work sleep disorder. In rats, modafinil promotes dose-dependent increases in wake duration. The wake-promoting activity of the R-enantiomer of modafinil (armodafinil) was evaluated in WKY rats and compared to the classical stimulant, d-methamphetamine. Electroencephalographic and electromyographic signals were assessed via a tethered cranial implant. Body temperature and locomotor activity were assessed by telemetry via intraperitoneal implant. Rats (n=60, 12 per group) were subjected to one of five parallel treatments: armodafinil at 30, 100 and 300 mg/kg i.p.; d-methamphetamine, 1 mg/kg i.p. and vehicle. Armodafinil and d-methamphetamine increased time spent awake relative to vehicle. Armodafinil-evoked increases in wake duration were dose-dependent and proportional to plasma compound exposure. Induction of wakefulness by d-methamphetamine was associated with an approximately two-fold increase in locomotor activity during the 2-h period immediately following administration relative to vehicle. d-methamphetamine also increased body temperature over the same time interval. The dose of armodafinil (100 mg/kg, i.p.) that was closest to d-methamphetamine in its wake-promoting efficacy did not produce changes in either body temperature or the intensity of locomotor activity relative to vehicle. Acute rebound hypersomnolence, characterized by increases in non-rapid eye movement sleep (NREMS) as a percentage of time and NREMS bout duration and by a decreased frequency of brief awakenings following sleep deprivation, occurred following d-methamphetamine-but not armodafinil-induced wake in this rat model which has been shown to be predictive of human drug responses.

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