The Effects of Aplindore on the Treatment of Signs and Symptoms of Restless Legs Syndrome

Restless legs syndrome (RLS) is a neurosensorimotor disorder of uncertain etiology that commonly disturbs sleep. The main feature of the disorder is paresthesia felt deep in the limbs that troubles the individual when he or she is at rest. The paresthesias of RLS commonly increase during the evening or the early part of the night. Patients are commonly less bothered by symptoms in the morning, unless they are severely affected. The repetitive movements that lead to arousal may also cause a subset of patients to become quite sleepy during the daytime. This sleepiness is usually not as severe as that found in patients with sleep apnea or narcolepsy but can be quite disruptive to quality of life and daytime functioning. Recent surveys indicate that RLS occurs in 10% to 15% of the North American population. A common associated feature of RLS is Periodic Limb Movements during Sleep (PLMS). These are repetitive movements that typically occur as flexions of the foot, knee, and hip at intervals of 5 to 90 seconds. Most commonly, the interval is 20 to 40 seconds. The movements are present during non-rapid-eye-movement (REM) sleep and are less common during REM sleep. Population-based studies have found that RLS is associated with an increased risk for hypertension and coronary artery disease. Periodic leg movements -related repetitive nocturnal blood pressure fluctuations may contribute to this increased risk of cardiovascular disease especially in the elderly19. There is a possibility that dopamine agonist (DA) reduction of PLMS may mitigate the risk of the cardiovascular complications of RLS. The potential role of aplindore in reducing PLMS and nocturnal blood pressure fluctuations will be evaluated in this study. Dopaminergic agents have become the most common medications used in the treatment of RLS and PLMS. Aplindore is an orally available, small molecule partial agonist of the D2 dopamine receptor. Preclinical in vitro and in vivo results have demonstrated the functional agonist selectivity of aplindore for supersensitive D2 receptors in the striatum, but not extra-striatal D2 receptors. Stimulation of D2 receptors in areas deficient in dopamine is attributed to aplindore's low intrinsic activity and high affinity for these receptors. Aplindore has been studied in preclinical toxicology studies in rats for up to 6 months and in monkeys for up to 1 year with safety margins in excess of 100-fold relative to projected human efficacious doses. The primary objective of this study is to assess the efficacy and tolerability of single doses of aplindore compared to placebo in RLS. The secondary objectives are to generate safety data with aplindore to support outpatient trials in RLS. b) To generate pilot data on the effects of aplindore on changes in blood pressure and heart rate associated with PLMS in patients with RLS. c) To understand the concentration-effect relationships of aplindore on RLS symptoms.