Treatments for restless legs syndrome

Details Treatments for restless legs syndrome Treatments for restless legs syndrome

2003-04-25

2004-04-06

Reamer, James H. (Department: 1614)

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Having -c-, wherein x is chalcogen, bonded directly to...

C514S331000, C514S426000, C514S428000, C514S429000

Reexamination Certificate

active

06716854

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to methods and use of heterocyclic amines and substituted phenylazacycloalknes, and the pharmaceutically acceptable salts thereof, in the treatment of Restless Legs Syndrome.
BACKGROUND OF THE INVENTION
Restless legs syndrome (RLS) is a neurosensorimotor disorder with parestethesias, sleep disturbances and, in most cases, periodic limb movements of sleep (PLMS).
Two forms of RLS appear to exist: the idiopathic and the uremic form. In this document both forms will be referred to as RLS. RLS is characterized by (1) a desire to move the legs, usually associated with paresthesias/dysesthesias, (2) motor restlessness, (3) worsening or exclusive presence of symptoms at rest (i.e. lying, sitting) with at least partial or temporary relief by activity, and (4) worsening of symptoms during the evening or night. RLS is fully described in references cited in U.S. Pat. Nos. 6,001,861 and 6,114,326, incorporated herein by reference. According to the International RLS Study Group, these four minimal criteria already allow clinical diagnosis. RLS is considered by some to be a sleep disorder in which a person experiences unpleasant sensation in the legs described as creeping, tingling, pulling, or painful. One or both legs may be affected. The sensations occur when the person with RLS lies down or sits for prolonged periods of time, such as at a desk, riding in a car, or watching a movie. RLS symptoms worsen during periods of relaxation and decreased activity. The evening and night hours tend to be more troublesome for RLS sufferers.
Sensory and motor symptoms in RLS often result in severe sleep disturbances with prolonged sleep latency, decreased total sleep time with reduced or absent slow wave sleep and decreased sleep efficiency. RLS patients often sleep best toward the end of the night or during the morning hours. Because of less sleep at night, people with RLS may feel sleepy during the day on an occasional or regular basis. Almost all RLS patients present periodic leg movements (PLM) during sleep (PLMS) and also while being awake. The number of PLM and related parameters are considered to be a marker for the severity of RLS since PLM are frequently associated with nocturnal arousals or awakenings and if present during wakefulness may prevent patients from falling asleep. Therefore performing polysomnography is usually needed to evaluate the efficacy of drug therapies.
As a result of problems both in sleeping and while awake, people with RLS may have difficulties with their job, social life, and recreational activities. RLS is reasonably common and always distressing. In the past some have called it “Crazy Legs.” RLS sensations have been described as pulling, drawing, crawling, wormy, boring, tingling, pins and needles, prickly and sometimes painful sensations that are usually accompanied by an overwhelming urge to move the legs. Sudden muscle jerks may occur.
Various agents have been used to treat RLS. While there have been reports of the use of a levodopa-based product called Restex® made by Roche Pharmaceuticals in Germany, no substance is currently approved in the U.S. for this indication.
Over the years, several treatments have been proposed for RLS. Typically treatments are grouped into four categories: anticonvulsant drugs, benzodiazepines, opioids and dopaminergic agents.
Anticonvulsants. Several anticonvulsant drugs have been tested for use in treating RLS. Anticonvulsants appear to work by decreasing sensory disturbances (the unpleasant sensations) and the urge to move. These drugs are particularly effective for some, but not all, patients with marked daytime symptoms, particularly people who have pain syndromes associated with their RLS. Gabapentin (Neurontin) is the anticonvulsant that has shown the promise in treating the symptoms of RLS. Possible side effects of gabapentin include dizziness, sleepiness, fatigue, increased appetite, and unsteadiness. The sedative properties of gabapentin may impair the ability to operate heavy machinery, including a motor vehicle.
Benzodiazepines. Several benzodiazepines, including clonazepam (Klonopin), nitrazepam, lorazepam and temazepam, have been used to treat RLS and sometimes improve the quality of nocturnal sleep. Benzodiazepines are central nervous system depressants that do not fully suppress RLS sensations or leg movements, but allow patients to obtain more sleep despite the problems. Some drugs in this group result in daytime drowsiness.
Opioids are narcotic analgesic (pain-killing) drugs and relaxing drugs that can suppress RLS and PLMS in some people especially those with severe and relentless symptoms of RLS. Some examples of medications in this category include codeine, propoxyphene (Darvon or Darvocet), oxycodone (Percocet, Tylox, Roxiprin), pentazocine (Talwin), hydrocodone (Vicodin), and methadone.
The therapeutic action of opioids was mentioned in the original description of RLS by Ekbom. Recently, this effect has been further documented in open clinical trials, see Trzepacz P T, Violette E J, Sateia M J (1984). Response to opioids in three patients with restless legs syndrome.
Am J. Psychiatry
; 141:993-99, and Hening W A, and periodic movements in sleep in restless legs syndrome; treatment with opioids.
Neurology
; 36:1363-1366 (1986). In these studies RLS was found to be reversible by naloxone, an opioid receptor antagonist. Opioids are potent suppressors of RLS and PLMS, but they carry the risk for abuse and the danger of addiction limit. Side effects and adverse reactions include dizziness, sedation, nausea, vomiting, constipation, hallucination, and headache. In severe cases, however, and especially in those undergoing hemodialysis, opiates may be an alternative treatment.
Dopaminergic drugs have produced some interesting results. Dopaminergic agents are drugs that are usually used to treat Parkinson's disease and in some cases may appear to provide some short term relief for some people with RLS. RLS is not a form of Parkinson's disease but is a distinct neurologic condition. Several studies have shown that L-dopa given with a peripheral carboxylase inhibitor at a 10:1 ratio is effective in treating RLS. See for example the following articles: Brodeur C, Montplaisir J, Marinier R, Godbout R., “Treatment of RLS and PMS with L-dopa: a double-blind controlled study,”
Neurology
; 35:1845-1848 (1988). Montplaisir J, Godbout R, Poirier G, Bédard M. A., “Restless legs syndrome and periodic movements in sleep: physiopathology and treatment with L-dopa,”
Clinical Neuropharmacology
; 9:456-463 (1986). Von Scheele C, “Levodopa in restless legs,”
Lancet
; 2:426-427 (1986). Akpinar S., “Restless legs syndrome treatment with dopaminergic drugs,”
Clinical Neuropharmacology
; 10:69-79 (1987).
A controlled study using polysomnography (PSG) recordings in a double-blind design also showed that L-dopa administered twice at night produces a significant reduction of RLS occurring at bedtime and of PLMS throughout the night. Brodeur C, Montplaisir J, Marinier R, Godbout R., “Treatment of RLS and PMS with L-dopa: a double-blind controlled study,”
Neurology
; 35:1845-1848 (1988). In most cases, L-dopa 100 mg, in conjunction with the decarboxylase inhibitor carbidopa 10 mg, completely suppresses RLS although a rebound (augmentation) of PLMS is often observed in the last part of the night. Montplaisir J, Godbout R, Poirier G, Bédard M. A.,
Clinical Neuropharmacology
; 9:456-463 (1986). The two major side effects frequently seen in patients treated with L-dopa are: 1) a rebound of symptoms during daytime when patients are only treated at night; and 2) a single dose of L-dopa at bedtime decreases PLMS in the first third of the night but induces a rebound of these movements in the last third of the night when L-dopa is no longer effective. Id. Similarly, the same study showed that when L-dopa treatment is repeated in the middle of the night, patients with severe cases may experience de novo paraesthesia and restlessness during the daytime.
Bromocriptine, a D2 receptor agonis

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