Ramelteon for the treatment of insomnia.

BACKGROUND: Insomnia is a common sleep disorder with a significant potential for deleterious effects on activities of daily living, productivity, and overall quality of life. Ramelteon, a highly selective agonist for melatonin subtypes 1 and 2 receptors, is a hypnotic agent approved by the US Food and Drug Administration (FDA) for the treatment of insomnia characterized by difficulty falling asleep. OBJECTIVE: This article reviews the pharmacokinetic properties, efficacy, and tolerability of ramelteon in the treatment of insomnia characterized by difficulty falling asleep. METHODS: Relevant articles were identified through searches of MEDLINE (1966 to July 2006), International Pharmaceutical Abstracts (January 1970 to July 2006), EMBASE Drugs and Pharmacology (1980 to third quarter 2006), and Current Contents/Clinical Medicine (2005 week 32 to 2006 week 31). Search terms included ramelteon, TAK-375, melatonin agonist, melatonin receptor agonist, insomnia, and sleep disorders/drug therapy (MeSH). RESULTS: A literature search revealed 12 randomized, controlled clinical trials that examined the efficacy or tolerability of ramelteon. In addition, 17 studies were reviewed for pharmacology and pharmacokinetic data. The references of the clinical trials and recent review articles were examined to ensure the comprehensiveness of the literature search. In 2 trials of patients with primary insomnia, patients treated with ramelteon 4 to 32 mg had significant reductions in latency to persistent sleep (LPS) compared with placebo (P < 0.001). Additionally, improvements in total sleep time (TST) were observed (P < 0.001), although increases in TST were noted only on nights 1-2 of the second study. Similarly, improvement in sleep efficiency was reported only on nights 1-2 of the second trial (P < 0.001). In elderly patients with primary insomnia, significant reductions in subjective LPS were observed with ramelteon 4 and 8 mg (P = 0.008); however, average subjective LPS was >70 minutes. Mean reported TST was significantly increased in the 4-mg group (P = 0.004). A second study in elderly patients found decreases in LPS with ramelteon 4 mg (P < 0.001) and 8 mg (P < 0.01), as well as significant increases in TST (P < 0.05 and P < 0.01, respectively). Sleep efficiency improved for patients treated with 4 mg (P < 0.05) and 8 mg (P < 0.01). Overall, the mean decrease in LPS reported in trials of ramelteon ranged from 10 to 19 minutes, and the mean increase in TST was 8 to 22 minutes. The most common adverse events observed with ramelteon included headache (7%), dizziness (5%), somnolence (5%), fatigue (4%), and nausea (3%). No evidence of cognitive impairment, rebound insomnia, withdrawal effects, or abuse potential was noted. CONCLUSIONS: Based on this review, ramelteon, the first FDA-approved melatonin receptor agonist, represents a pharmacologic option for the treatment of insomnia characterized by difficulty falling asleep. In patients with insomnia, treatment with ramelteon was generally well tolerated and resulted in modest but statistically significant decreases in LPS. In the absence of published trials comparing ramelteon with other sedative-hypnotic agents, it is not yet possible to determine its efficacy relative to other therapeutic options for insomnia.

Topical alprostadil treatment of female sexual arousal disorder.

OBJECTIVE: To review the pharmacology, pharmacokinetics, efficacy, and safety of topical alprostadil in the treatment of female sexual arousal disorder (FSAD). DATA SOURCES: A literature search was conducted using MEDLINE (1966-May 2006), EMBASE, and International Pharmaceutical Abstracts with the search terms alprostadil, female, and sexual dysfunction/drug therapy. STUDY SELECTION AND DATA EXTRACTION: All published and unpublished clinical trials and abstracts involving the efficacy and safety of topical alprostadil use in women were reviewed. Data on file with the manufacturer were also included. DATA SYNTHESIS: Topical alprostadil is a vasodilatory agent under development for the treatment of FSAD. In-clinic application of alprostadil increases genital vasocongestion, vaginal erythema, transudates, and some patient-assessed indices of sexual arousal; however, these effects have not been consistently superior to placebo. Three of 4 trials investigating at-home use of topical alprostadil have demonstrated improvements in achievement of satisfactory levels of sexual arousal and successful sexual encounters in patients with FSAD. Adverse events appear to be mild and localized and consist of burning and itching at the application site. CONCLUSIONS: Two formulations of topical alprostadil are in Phase II clinical trials for the treatment of FSAD. Initial results of clinical trials have demonstrated some beneficial effects on arousal success rates and other subjective measures of sexual arousal; however, these results have been inconsistent and not reproducible in all trials. The results of ongoing clinical studies are needed to further define the role of topical alprostadil in the treatment of FSAD.