MXPA00009395A - Use of cabergoline in the treatment of restless legs syndrome - Google Patents

Abstract

The present invention provides for the use of cabergoline and other agents for the treatment of restless legs syndrome (RLS).

Description

USE OF CABERGOLINE IN THE TREATMENT OF INQUIRED LEG SYNDROME FIELD OF THE INVENTION The present invention relates to the use of cabergoline and pharmacologically acceptable salts thereof, in the treatment of restless legs syndrome.

BACKGROUND OF THE INVENTION Restless Legs Syndrome (RLS) is a neurosensory motor disorder with paresthesias, sleep disturbances and in most cases periodic limbic movements during sleep.

(PLMS for its acronym in English). It seems that there are two forms of RLS: the idiopathic and uraemic form. In this document we will refer to the two forms as RLS. RLS or restless legs syndrome is characterized by (1) a desire to move the legs, generally associated with paresthesias and / or dysesthesias, (2) motor restlessness, (3) aggravation or exclusive presence of symptoms during rest (it is say, at bedtime, when sitting) with at least partial or temporary relief through activity and (4) aggravation of symptoms during the evening or night. According to the International Group for the Study of EPIRB, these four minimum criteria already allow the clinical diagnosis. Some people believe that RLS is a sleep disorder in which the person experiences unpleasant sensation in the legs, described as tingling or itching, stretching or pain. It is possible that both legs are affected. The sensations occur when the person with RLS goes to bed or sits for prolonged periods of time, such as when sitting at the desk, reading in a car or watching a movie. The symptoms of RLS are aggravated during periods of relaxation and decreased activity. The hours of the afternoon and night tend to be more problematic for people suffering from RLS. Sensory and motor symptoms in the RLS often result in severe sleep disturbances with prolonged sleep latency, total sleep time reduction, slow, absent or reduced sleep cycles and decreased sleep efficiency. Patients with RLS often sleep better at the end of the night or during the morning hours. Because they sleep less at night, people with RLS may feel sleepy during the day on a regular or occasional basis. Almost all patients with RLS present periodic leg movements (PLM) during sleep (PLMS) and also while they are awake. It is considered that the number of PLM and related parameters are a marker of the RLS severity, since the PLM are frequently associated with nocturnal excitations or awakening and if they are present during insomnia they can prevent patients from sleeping. Therefore, it is usual to perform polysomnography to evaluate the effectiveness of drug therapies. As a consequence of the problems of both sleeping and being awake, people with RLS may have difficulties in their work, social life and recreational activities. RLS is quite common and always distressing. In the past some called him "Crazy Legs". RLS sensations have been described as sensations of tightness, stretching, slowness, worms, heaviness, tingling, feeling pins, needles, spines and sometimes painful sensations that are usually accompanied by an irresistible urge to move the legs. Abrupt muscle spasms may occur. Several agents have been used to treat RLS.

However, at present no substance is approved for this indication. Over the years, several disorders have been proposed for RLS. In general, the disorders are grouped into four categories: anticonvulsant drugs, benzodiazepines, opioids and dopaminergic agents. Anticonvulsants Several anticonvulsant drugs have been tested for use in the treatment of RLS. It seems that anticonvulsants work by decreasing sensory disturbances (unpleasant sensations) and the impulse to move. These drugs, are particularly effective not for everyone, but for some patients with symptoms during the day, particularly people who have had pain syndromes associated with their RLS. Gabapentin (Neurontin) is the anticonvulsant that has been promising for the treatment of RLS symptoms. Possible side effects of gabapentin include dizziness, drowsiness, fatigue, increased appetite and instability. The sedative properties of gabapentin can decrease the ability to operate heavy machinery, and even motor vehicles. Benzodiazepines Several benzodiazepines have been used, including clonazepam (Klonopin), nitrazepam, lorazepam and temazepam, to treat RLS and sometimes improve the quality of nighttime sleep. Benzodiazepines are central nervous system depressants that do not completely suppress RLS sensations or leg movements, but allow patients to sleep more, despite the problems. Some drugs in this group result in drowsiness during the day. Opioids They are narcotic analgesic drugs (which eliminate pain) and relaxing drugs that can suppress RLS and PLMS is some people, especially those with symptoms of severe and incessant 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 EPIRB by Ekbom. In recent years, this effect has been subsequently documented in open clinical trials, see, Trzepacz PT., Violette EJ. , Sateia MJ. (1984). Response to opioids in three patients with restless legs syndrome. Am. ". Psychiatry; 141: 993-995 and Hening WA, Walters A., Kavey N., Gidro-Frank S., Cote L., Fahn S. (1986) Dyskinesias during wakefulness and periodic movements during sleep in restless legs syndrome: treatment with opioids Neurology, 36: 1363-1366 (1986) In these studies it was found that RLS is reversible by means of naxolone and an opioid receptor antagonist.Opioids are potent suppressors of opioids. RLS and PLMS, but have the risk of abuse in consumption and danger of causing addiction.Side effects and adverse reactions include dizziness, sedation, nausea, vomiting, constipation, hallucinations and headache.However, in severe cases and especially in those with hemodialysis, opiates may be an alternative treatment Dopaemergic drugs Dopaminergic agents have produced some interesting results Dopaminergic agents are drugs that are normally used to treat Parkinson's disease n and in some cases it seems that they provide some short-term relief for some people with RLS. RLS is not a form of Parkinson's disease but a distinct neurological state. Several studies have shown that L-dopa administered with a peripheral carboxylase inhibitor in a ratio of 10: 1 is effective in the treatment of 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 P1114 (1987). A controlled study using polysomnography (PSG) records in a double-blind design also showed that L-dopa administered twice during the night produced a significant decrease in the RLS that occurs at bedtime and PLMS throughout the night. 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, 100 mg of L-dopa, together with 10 mg of carbidopa, the carboxylase inhibitor, completely suppress the RLS, although a rebound is often observed (increase) of PLMS in the last part of the night.

Montplaisir J., Godbout R., Poirier G., Bédard M.A. , Clinical Neuropharmacology; 9: 456-463 (1986). The two main side effects that are frequently observed in patients treated with L-dopa are: 1) a rebound of symptoms during the day when patients are treated only at night; and 2) a simple 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 it, when L-dopa is no longer effective. Td. Similarly, the same study showed that when treatment with L-dopa is repeated in the middle of the night, patients with severe cases can P1114 experience de novo paresthesia and restlessness during the day. Bromocriptine, a D2 receptor agonist, was also used in the RLS treatment. Walters AS. , Hening WA. , Chokroverty S., Gidro-Franck S. A double blind randomized crossover trial of bromocriptine and placebo in resless leg syndrome. Ann. Neurol; 1988, 24: 455-458 (1988). After a 7.5 mg dose of 1 to 3 hours before sleep was administered, 5 to 6 patients reported a greater subjective improvement in restlessness and paresthesia, compared to placebo. The side effects that were reported were transient nasal congestion and dizziness, in one patient. Pergolide, the dopamine D1 / D2 agonist, (half-life from 7 to 16 hours) in combination with a low dose of L-dopa, can lead to clinical improvement in patients who do not respond to L-dopa alone, but can cause serious side effects, such as orthostatic hypotension and gastrointestinal problems. The RLS website, http://www.rls.org., Said the following about treatments with dopaminergic drugs. To note that the website can be updated at any time, the following citations were copied in March 1999. "The primary and first-line treatment for RLS is with dopaminergic agents, which act on the central nervous system increasing the levels of dopamine, a chemical that the body produces naturally and that regulates the delivery of messages between cells in the central nervous system. " But then the site provides this warning: "The dopaminergic agent that has been used most frequently is carbidopa-levodopa (Sinemet® DuPont -Merck). The advantages of using Sinemet® is that this drug is the dopaminergic agent that has been available for the longest time and is the least expensive. However, the Sinemet® has a very important disadvantage: up to 85% of people who take this drug for the treatment of RLS, develop a phenomenon known as augmentation. "The site provides another description of increase.

"This is what happens with the increase: the usual dose of Sinemet® will allow you to get relief from your symptoms, so you can sleep at night, but the sensations, the need to move and restlessness (often of increased intensity ) will appear earlier in the day (during the afternoon or even during the morning). If this happens, you may want to increase your dose of Sinemet® to treat these symptoms during the day, but this would be the wrong approach. If the increase is developed, increasing your dose of Sinemet®, rather than improving your symptoms will only make them worse. Most people with RLS who develop an increase should switch to another medication. " P1114"Although Sinemet® works well for many people and has minimal side effects (mainly gastrointestinal discomfort, nausea, vomiting and headache), anyone who takes this drug for RLS treatment needs to understand very well the possibility of developing it. Another consideration that you should understand is that because the protein interferes with the absorption of Sinemet®, you should avoid consuming high-protein foods, just before taking this medication. " The website continues and analyzes other possible treatments. "A newer drug, pergolide mesylate (Permax®), is proving very promising in the treatment of RLS, and recent studies have shown that this drug is as effective as Sinemet® and much less likely to cause an increase ( 10% for Permax® versus 80% for Sinemet®) The disadvantages of Permax® are that it is more expensive than Sinemet® and has not been used for so long, so doctors are less familiar with this drug when prescribing it. Main side effects are dizziness, nausea and nasal congestion. " Bromocriptine mesylate (Parlodel®) is another dopaminergic agent that is used to treat RLS. The I caught ll The results of the studies, related to the efficacy of bromocriptine, are confusing, although individual patients have reported good results. "Both Permax® and Parlodel® are dopamine receptor agonists, which means that they act on the site of Dopamine binding, while Sinemet® increases the normal production of dopamine in the body. "Other studies suggest that patients treated with Permax® (pergolide) will develop tolerance to the drug. Considering the problems related to all the possible treatments mentioned before, it is fair to say that there is no optimally effective treatment for RLS. An RLS patient who visits the Internet and sees the previous comments, will be overwhelmed with all possible treatments, such as iron supplements, melatonin, Prozac®, Sinemet®, Klonopin, clonazepam, all drugs and drug categories mentioned above and still electrical stimulation to the legs or feet before going to bed. See http://www.rls.org. The information found on the Internet may suggest that there is no good treatment regimen for RLS, that the medical books enunciate more than 15 treatments or different protocols but none of them is very effective. The following quote from a patient suffering from RLS is on the RLS website: "I feel as if the worms are sliding and crawling around the legs, I feel the need to move my legs to remove the sensations. In the afternoon, when I'm driving or just sitting in the cinema or watching television, I have the desire to keep moving my legs, I want to hit them with a hammer, "http://www.rls.org. Currently, a doctor is leaning toward the use of levodopa along with a dopa decarboxylase inhibitor (DDCI) such as carbidopa. Studies controlled with levodopa have shown advantageous effects in the subjective symptoms of RLS and in the quality of sleep, confirmed by polysomnographic studies. Since regular release formulas often do not maintain therapeutic coverage throughout the night, sustained release formulas are tried. Although many RLS patients show an excellent response to levodopa, there is increasing evidence that the relatively short duration of action and the increase in symptoms could be a limiting factor for levodopa therapy. The increase is described earlier, includes an earlier appearance in the evening of RLS symptoms than before treatment, onset of symptoms during the day, involvement of other parts of the body (for example, arms) or an increase in the severity of the symptoms. Therefore, alternative treatment options are of great interest, especially in patients with severe RLS. The choice about where to go for a possible treatment of RLS, is a problem for any doctor, with the possible treatments that are known and that present serious disadvantages. We present here a novel approach to treating RLS and a preferred approach to this problem that seems to be the first good treatment for this serious, distressing and common medical syndrome.

EXPOSURE OF INFORMATION The following references are related to RLS and its possible treatments. In order that this information may be useful to someone skilled in the art or to more fully describe this invention, it is considered part of the present, as a reference. None of these documents or citations, nor others referred to herein, nor citations to any of the references, are admitted as documents or citations of the prior art.

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SUMMARY OF THE INVENTION Surprisingly and unexpectedly, it has been found that cabergoline and pharmacologically acceptable salts thereof can be administered to patients P1114 who need it for the treatment of the symptoms of restless legs syndrome (RLS). This is especially effective for the treatment of RLS patients who experience or are susceptible to increased RLS and / or tolerance. See the description and definitions of increase and tolerance, in this. A preferred treatment, which is set forth herein for the treatment of Restless Legs Syndrome (RLS) in a patient suffering or being susceptible to that condition, comprises the administration of an effective amount of the compound called cabergoline. The chemical name of the compound is 1 (((6-alylergolin-8β-yl)) -carbonyl) -1- (3- (dimethylamino) propyl) -3-ethylurea. Cabergoline is the active ingredient in DOSTINEX® or CABASER® Tablets, marketed in the United States, Europe and Latin America as a treatment for hyperprolactinemic disorders and / or as a treatment for Parkinson's disease. The synthesis and use of cabergoline is disclosed and claimed in U.S. Patent 4,526,892, which is considered part of the present, as a reference. Conventional pharmaceutical preparations can be used, for example, those basically consisting of an inert pharmaceutical carrier and an effective dose of the active substance; for example, simple tablets or P1114 coated, capsules, pills, powders, solutions, suspensions, emulsions, syrups, suppositories, transdermal patches, etc. The tablets are preferred. The effective dose range is between 0.01 and 10.0 mg / day and patient, frequently more than 0.1 mg per administration and per day will be administered to a patient and preferably between 0.25 and 10.0 mg / day, more preferably between 1 and 6 mg / day, more preferably between 1 and 4 mg / day and even more preferably between 1 and 2 mg / day and patient, orally. While these previous levels are indicated in mg / day and will normally be administered once or twice a day, surprisingly, they can be administered in these dosages on a less than daily basis. While the drug can be administered once or twice a day, it may be administered only three times a week, twice a week or even once a week, in some patients. For a dosage less than daily, the size of the tablet or the amount of administration of the drug and the mg of drug administered per patient may vary, may in fact be the dose in mg / day suggested above. When administered in a daily or less frequent scheme, the daily doses mentioned here would be given only on the day of administration. It would be expected that patients with forms of RLS P1114 more benign, need less drug, in some cases, 0.05, 0.1 or more preferably 0.25 mg / day may be adequate. It could be expected that patients with more severe forms of RLS and those who have been treated with other dopaminergic agents need more drug. The combination of cabergoline and levodopa is also discussed. The dosages should be increased gradually. As long as patients do not experience intolerable side effects, dosing should be titrated to achieve maximum therapeutic effect.

DESCRIPTION OF THE PREFERRED MODALITIES Cabergoline is a synthetic derivative of ergoline and a dopamine agonist. Cabergoline is a unique dopamine agonist with unusual properties.

Most of the words used in this document can be described with definitions that are commonly used or that are used by someone skilled in the art. In the present, one skilled in the art would be a doctor treating a patient with RLS or a researcher in RLS, as a doctor of science, that considers or evaluates the possible RLS treatments with RLS drugs. The authors will also provide some special definitions to better describe this invention.

P1114 Definitions Dopamine receptors. Traditionally, dopamine receptors were grouped into two "families" of receptors, DI or D2, where the groupings were based on the pharmacological response. With the use of this type of nomenclature, cabergoline could be characterized as a D2 (DI) receptor agonist; which means that the drug acts in the "family" D2 of receptor sites and affects the DI family a little. In a strange way, cabergoline is unique, since it is a total agonist of the D2 family with partial activity in the DI family. In more recent years, with the advent of better techniques in molecular biology, dopamine receptors have been classified into subfamilies, according to their molecular binding attributes. With the use of this molecular receptor classification scheme, it can be said that the "family" of DI physiology has molecular receptors DI and D5 and it can be said that the "family" of physiology D2 has molecular receptors D2, D3 and D4 that belong to that family. It can be said that cabergoline binds to molecular receptors D2 and D3 with a higher degree of binding to D2 with respect to D3. Scientists will be able to discover or recognize even more families in the future. They also know that different areas of the brain have different P1114 quantities of receptors DI, D5, D2, D3 and D4 although they do not fully understand how they are distributed among cell types or the total physiological significance of their existence. A dopaminergic agent is any chemical compound that acts like dopamine in the human body. See below the dopamine agonist. L-dopa or levodopa is a dopaminergic agent because in the human organism it is converted to dopamine. The dopamine agonist or dopaminergic agonist is any drug or chemical compound that can stimulate a dopamine receptor, either through binding to the receptor or by binding or association with proteins or receptors that then bind or affect a receptor. of dopamine. A dopaminergic agonist can "act like dopamine, in the human body" and therefore be a dopaminergic agent, but does not need to be converted to dopamine, it can mimic only some of the effects of dopamine due to its stimulation of dopamine receptors. Cabergoline is described in U.S. Patent 4,526,892, which is considered part of the present, as a reference. Unlike other agonists in the D2 receptor family, cabergoline is also unique from the pharmacological point of view, since P1114 which is a total agonist of D2 with partial activity in DI. The cabergoline has a unique long duration in its action, at least 24 hours or more, Ahlskog JE., Wright KF., Muenter MD., Adler CH. (nineteen ninety six). Adjunctive carbegoline therapy of Parkinson 's disease: comparison with placebo and assessment of dose response a duration of effect. Clin. Neuropharmacol; 19: 202-212 (1996). Here we report that cabergoline can last up to 65 hours and can be an effective treatment for RLS for 65 hours or more, perhaps up to a week.

New Treatments for RLS Here we report several novel and surprising treatments useful for treating patients with RLS. The most important thing is that cabergoline can be used to treat RLS. Other new treatments for RLS include Lisuride a.k.a. DOPERGIN® as one of the other compounds and selegiline and the category of compounds known as COMT (catechol-0-methyltransferase) inhibitors, which include the drug entacapon, which still represents another of the compounds that can be used, either by itself alone or with greater preference, in combination with cabergoline or in another modality in combination with both L-dopa and cabergoline; for the treatment of RLS. All these compounds and combinations P1114 should be administered in pharmaceutically effective amounts as determined by titration or by methods generally used by those skilled in the art. The use of cabergoline or its pharmaceutically acceptable salts is also discussed, in the manufacture of a medicament for treating RLS and any of the RLS symptoms described herein, as well as a pharmaceutical composition that is used as a treatment for RLS and any of the symptoms described herein. Cabergoline is surprisingly effective in treating patients with RLS, because of its long half-life and because it provides those with RLS, benefits that no other drug therapy provides. I) The unique activity of the drug can maintain a dosage that is infrequent. Unlike any other known compound and especially other dopamine agonists, cabergoline can provide long-lasting relief to patients suffering from RLS. Dosing twice a day can be effective, but once-a-day dosing is preferred and in some cases less than once a day dosing is possible. Some patients can achieve effective relief with dosages every third day or even only once a week. The administration of cabergoline can be P1114 afternoon, although it is not necessary. With surprise, it has been discovered that cabergoline has a half-life of 65 hours. This long half-life will provide an unexpected benefit to patients with RLS. Cabergoline can be effective when administered daily, every third day, three times a week or even once a week. In some patients, cabergoline can be administered only 1, 2 or 3 times a week, depending on the patient in particular and their individual response to the drug. Perhaps most surprising is that in some patients cabergoline will not need to be administered on a regular basis. Because of its unique properties discovered and described here, cabergoline could be administered at different times of the day and perhaps not every day, more than the current treatments for RLS, which require a particular adherence to a strict dosage scheme to maintain the relief. For example, compare cabergoline with ropinirole, which some studies suggest should be given in doses of 1, 2 or 3 times a day to be effective. See, Ondo, William, "Ropinirole for Restless Legs Syndrome", Movement Disorders; 14: 138-140 (1999). The effective dose range is between 0.01 and 10.0 mg / day and patient, in general a patient will be administered more than 0.1 mg per day and preferably, between 0.25 P1114 and 10.0 mg / day, more preferably between 1 and 6 mg / day, more preferably between 1 and 4 mg / day and even more preferably between 1 and 2 mg / day and patient, orally. While these previous levels are indicated in mg / day and will normally be administered once or twice a day, surprisingly, they can be administered at these dosages on a less than daily basis. While the drug can be administered once or twice a day, it may be administered only three times a week, twice a week or even once a week, in some patients. For a dosage less than daily, the size of the tablet or the amount of administration of the drug and the mg of drug administered per patient may vary, may in fact be the dose in mg / day suggested above. When administered in a daily or less frequent scheme, the daily doses mentioned here would be given only on the day of administration. It is expected that the attending physician will provide the patient with an adequate amount of drug depending on several factors, including patient weight, age, medical history, physiological status, special needs, etc. and an appropriate titration of the drug. It would be expected that patients with less severe forms of RLS, need less drug, in some cases P1114 may be adequate 0.05, 0.1, 0.5 or more preferably, 0.25 mg / day. It may be expected that patients with more severe forms of RLS and those who have been treated with other dopaminergic agents need more drug. In addition to having a long half-life, cabergoline seems to be effective as a monotherapy, without having to administer it with other drugs. In some cases, instead of patients being treated with multiple drug formulations, such as levodopa administered twice at night or levodopa combined with a decarboxylase inhibitor such as carbidopa, they can be treated only with a medication, cabergoline. Although in some embodiments of this invention, cabergoline plus levodopa is also described as a novel treatment. Cabergoline can be titrated for each patient, but will often need to be taken only once a day or less and may even not matter what time of day it is taken. II) Here we report that cabergoline has a lower frequency of harmful side effects common to other RLS treatments, the side effects known as augmentation or rebound. In addition to the above description, the increase or rebound is described below. The increase includes: a) one more appearance P1114 early in the afternoon, of the RLS symptoms that before the treatment, b) appearance of symptoms during the day, c) an implication of other parts of the body, normally the arms od) an increase in the severity and the possibility of developing even shortly after the start of levodopa therapy. The incidence of increase seems to be higher in patients with severe RLS and with higher levodopa dosages. In some ways, the increase in patients with RLS can be described as an increase in the severity of RLS symptoms during the day followed by a decrease in symptoms during the night, after the typical drug administration treatment in the evening. More generally, the increase can refer to any increase in RLS symptoms that follows an initial decrease in symptoms after drug administration. This can appear in a patient who responds well in the first days or weeks of treatment but who later has an increase rather than a decrease in the severity of the symptoms. The increase and / or rebound have often been observed when the RLS patient is treated with a drug that is a dopaminergic agent such as levodopa or some dopamine agonists such as pergolide, bromocriptine, etc. It has been reported that the increase occurs in treated patients P1114 with L-dopa in 27% proportions in a 12-week study, see, Callado-Seidel U., Krazenwadel J., Wetler TC, Kohnen R. et al., Neurology 1999; 52: 285-290 and 82% of patients with RLS in a different study, see Alien RP., Earley CJ. , Sleep 1996; 3: 205-213. In the latter study, the increase occurred in 31% of patients with PLMS (periodic limbic movements during sleep) and 82% of patients with RLS. 50% of RLS patients with augmentation needed a change of medication. Of 22 RLS patients with an increase, 100% of these reported an increase in the severity of 3 important symptoms. The symptoms that increased included: temporary expansion, symptoms that occurred at bedtime, now appeared earlier in the afternoon. In some they were prolonged by the hours, b) increase in intensity, mild symptoms at bedtime or in the afternoon, became agonizing, c) decrease in rest time when symptoms occurred and 7% patients reported increased movements in other parts of the body. The rebound phenomenon is similar to the increase with the appearance of RLS symptoms in the morning hours, shortly after awakening. Some physicians attempt the treatment by switching to a sustained release preparation of the drug and / or adding a morning dose of levodopa. It should be noted that the bounce problem is P1114 different from a simple loss of effectiveness during the night, which is also observed in some patients especially affected in severe form. There are reports that the dopamine agonist, pergolide, had some effect in patients who developed an increase with levodopa, in an open study of 6 months. On the other hand, the increase was also reported in patients treated with pergolide (again sensitive to dopaminergic agents) but to a lesser degree and with less severity, in two open studies with a follow-up period of 6 to 28 and 2 to 39 months , respectively. In one study 15% of patients treated with pergolide experienced an increase, see, Earley CJ. , Alien RP. Pergolide and the carbidopa / levodopa combination were used in the treatment of restless leg syndrome and periodic movements of the leg during sleep in a consecutive series of patients. In this study, 21 of 51 patients responded to levodopa, 26 of 51 changed to pergolide, 19 of 26 patients with pergolide responded well, however 4 out of 26 patients with pergolide had an increase. It seems that patients with PLMS responded well to L-dopa, those on RLS responded to pergolide. It is not clear why some patients develop the augmentation or rebound phenomenon and others do not. It is evident that what is needed is a medication in which the P1114 patients and the attending physician have some assurance that the increase will not occur. While in the present, the authors do not guarantee that the increase will never occur with the treatment of cabergoline, it is much less likely that the increase or rebound occurs in patients treated with cabergoline than in those treated with others. dopaminergic agents such as levodopa or pergolide. It seems that cabergoline has fewer side effects of increase or rebound, which is known to worry patients who follow other drug treatments. The side effects of increase or rebound can be most unpleasant, for a patient who knows that the price you have to pay for having at first a relief of their symptoms, may be to suffer them later with greater intensity. A patient who experiences an increase or rebound can achieve relief at night, possibly allowing him to sleep, only to suffer the next day two or three times the usual number of periodic movements of the legs. Instead of this, it is likely that the patient who experiences increase or rebound effects, would prefer to be treated with cabergoline than with a treatment in which he has to "steal Peter to pay Paul" for a satisfactory night's sleep. III) We also report here that the cabergoline P1114 can be very useful in the treatment of RLS symptoms that last after treatments with other dopamine agonists and dopamine agonists, such as L-dopa that has become ineffective due to the patient's tolerance to treatment with the drug. Tolerance in patients with RLS can be described as an adaptation to drug therapy. This means either that more and more drug is needed to alleviate the same symptoms that were previously treated with smaller amounts of drug or that the same amount of drug provides less and less relief of the symptoms being treated. It is known that tolerance occurs with the treatment of levodopa in patients suffering from RLS. Tolerance to the drug is usually evident after 4 to 6 months of treatment. Tolerance to levodopa is common. Unlike previously known dopamine agonists, treatment with cabergoline provides more lasting relief of RLS symptoms and poor tolerance. This means that an effective treatment can be maintained without large increases in the amount of drug that needs to be provided to the patient. In most cases, once the cabergoline titre demonstrates a clinical effect, it is not necessary to increase the medication.

P1114 IV) Cabergoline provides improved sleep patterns in patients with abnormal sleep patterns. Cabergoline is especially useful for normalizing the sleep patterns of patients with RLS. Many patients with RLS have abnormal sleep patterns and the more severe the RLS symptoms are, the worse these patients sleep. Perhaps the greatest benefit that cabergoline can provide to these patients with RLS is a good night's sleep. Thus, it is observed that cabergoline provides an improved and long-lasting treatment, with a convenient and infrequent dosage, without the unpleasant side effects that are generally observed with other treatments for RLS. Often, cabergoline can be administered as a monotherapy, as opposed to having to combine it with other dopaminergic agents, as is often done. Note, however, that for some patients, we also discuss here the use or preparation of a drug or treatment comprising the combination of cabergoline and a dopaminergic agent, which include levodopa and / or the other dopamine agonists mentioned in the document, included in the background section, combinations of drugs used in pharmacologically acceptable quantities and with greater preference, in the amounts for cabergoline P1114 alone as described above for cabergoline and for levodopa, as would be ordinarily administered by one skilled in the art, when administering levodopa or a dopaminergic agent with another dopaminergic agent.

Expected Results In a pilot study, open for 12 weeks, the effects of a single evening dose of cabergoline on the RLS symptoms were investigated in 9 patients and the results were presented. See also, Stiasny K., Oertel W.H. , Schüler P. (1998), Cabergoline in RLS, ENS, Nice, Abstract. To evaluate the efficacy and tolerability of this long-acting dopamine agonist (DI) / D2, cabergoline, (half-life> 65 hours), we investigated 9 patients who had previously been treated insufficiently with this and who partially developed increase with levodopa, in an open pilot test. Efficacy was assessed by polysomnography and subjective ratings. All patients had previously experienced the partial benefit of a levodopa therapy (either standard or slow-release) and in part had developed an increase with levodopa therapy. Upon entering the study, all patients were coadministered domperidone (20 mg three times a day) and five were still on therapy.

P1114 levodopa (400-800 mg). At the end point, all patients were on cabergoline monotherapy (mean dose 2.1 mg, range 1 to 4 mg). Domperidone was discontinued in all patients due to its excellent tolerability. The polysomnographic data showed a significant reduction in the number of periodic leg movements (PLM) during bed time, PLM excitations and PLM awakenings. Total sleep time was prolonged, sleep latency was reduced and sleep efficiency increased. All patients reported significant relief or were freed from RLS symptoms. These results indicate that cabergoline administered as a simple vespertine dose is effective and well tolerated in restless legs syndrome, especially in patients with severe RLS and in those who developed an increase with levodopa therapy. In addition to the relief of the RLS symptoms reported above, there is another significant benefit with the administration of cabergoline for the treatment of RLS. Many patients receiving L-Dopa or L-Dopa plus decarboxylase inhibitor have benefited from the short-term relief of RLS symptoms, although often with the augmentation and rebound effects mentioned above, but they soon become " tolerant "to treatment and then P1114 of a period of time, generally 6 months or less, no longer respond well to treatment. This could be represented visually by means of a graph that represents the relief of the symptomatic events of the RLS against time, with a zero-time treatment. As the time reaches 6 months or more after treatment with L-Dopa, the data would provide a graph that would show a line that decreases gradually, from a high point at the start of treatment to a low point after 6 months or more of treatment. Conversely, as the time reaches 6 months or more after cabergoline treatment, the data would provide a graph that would show a line that has a much lower slope with cabergoline than with L-Dopa, from a high starting point with the treatment to a low point after 6 months or more of treatment. This lack of tolerance in the treatment with cabergoline is most surprising and unexpected. The cabergoline for the treatment of RLS can be administered in the dose range of 0.1 and more preferably 0.25 to 6 mg per person per day, preferably 1-4 mg / person per day and more preferably 1-2 mg. Also with some patients, cabergoline can be administered every third day, at these dosages and still provide relief of RLS symptoms.

P1114 A method for the preparation of a medicament useful in the treatment of RLS is described herein. The medicament can be prepared using cabergoline as the active ingredient plus excipients, formulations and standard preparations, known to those skilled in the art. Cabergoline can be given to patients who have never been treated before to relieve RLS, or it can be given to patients treated in advance with some other medications, especially those mentioned in the Background section of this document. Cabergoline is useful especially for patients suffering from the symptoms of the disease, who have previously been treated with a D2 agonist or levodopa or L-dopa or who are currently treated with such compounds. Patients with RLS who experience 2 to 8 Periodic Leg Movements (PLM) per hour, while asleep, are especially good candidates for cabergoline therapy and patients who experience 3 to 7, 4 or 5 PLM / hour they are also preferred candidates for the drug. The above description should fully describe this invention and allow one skilled in the art to carry it out. The obvious variants and combinations of the invention are assumed and described herein.

P1114 with the treatments mentioned in the Background section. In addition, an example is provided to further illustrate the invention. The descriptions would serve as a guide for the similar studies that could be carried out and the expected results. The obvious variations of this example should be apparent to one skilled in the art.

Example After a baseline period of 2 weeks, all patients were treated with cabergoline in an open 12-week study. In addition to levodopa, two weeks before the baseline, all patients had to stop taking any medication known to have positive or negative effects on the RLS, (for example, other dopamine agonists, benzodiazepines, opioids, or others). psychotropic agents). Patients who were on levodopa therapy were either allowed to stop levodopa before entering the study or continue, decrease or discontinue levodopa during the same. To avoid the well-known peripheral dopaminergic side effects such as nausea, vomiting, vertigo and arterial hypotension, domperidone was coadministered at the beginning (not available in the United States) and also when possible it was decreased. It started with 0.5 mg of cabergoline as a simple afternoon dose, administered two hours before P1114 and increased in amounts of 0.5 mg until the symptoms of RLS "clearly improved or disappeared, according to the opinion of patients." In patients treated with levodopa, it was gradually decreased and, if possible, discontinued. carried out the history of the neurological case, examination, electrocardiogram, chest x-ray and polysomnography to ensure that the selection criteria were met.We performed a PSG (polysomnography) of two nights (including one night of adaptation), to evaluate the diagnosis and the inclusion / exclusion criteria without taking into account whether or not patients were without levodopa After a 12-week treatment period the patients were studied again for one night in the sleep laboratory. at the baseline, at week 4, week 8 and at the end point after 12 weeks, in addition patients were monitored by telephone calls s to take note of any adverse events and determine when to increase the dosage of the study drug, decrease levodopa and domperidone. The program of telephone calls was variable and the frequency almost always depended on the presence of simultaneous therapy with levodopa. Inclusion criteria. The patients were included if they met the minimum criteria of P1114 diagnosis according to the International Group for the EPIRB Study. After rating the clinical symptoms in the baseline, patients were sent to polysomnography without any specific treatment for RLS other than levodopa. Patients were included if they had more than five PLM per hour of bed time (PLM index) and an index of sleep efficiency (total sleep time per bed time) less than 85%. Exclusion criteria. We excluded patients with signs of some other disorder in PSG, especially sleep apnea syndrome (respiratory disturbance index >5 per hour of total sleep time). We also excluded subjects who received neuroleptics, antidepressants or other psychotropic medications or with any other severe additional disease (with special consideration for pulmonary fibrosis). Patients with established or suspected hypersensitivity to ergot derivatives and patients who presented significant clinical changes in routine laboratory studies were not included. Pregnant or lactating women or women without safe contraception were not allowed to participate in this study. Dosage. The study medication was P1114 available in tablets containing 0.5 mg, 1 mg or 2 mg of Cabergoline (Cabaseril®, Pharmacia &Upjohn, Erlangen, Germany). The medication was taken 2 hours before going to bed. The initial therapy consisted of a 0.5 mg tablet. Patients were able to increase the dose in steps of 0.5 mg if they considered that their RLS symptoms, including sleep deterioration, had not improved enough in the first 3 days. When necessary, the increased dose can be reduced again. At the beginning, all patients were coadministered domperidone to 20 mg three times a day, which could be reduced and stopped when possible. Subjects who were previously treated with levodopa were asked to decrease levodopa simultaneously, when possible. Polysomnographic studies. At the baseline and at the end of the study after 12 weeks, PSG records were performed for one night (11 PM to 7 AM) to evaluate the inclusion and / or exclusion criteria and obtain primary and secondary efficacy parameters. The studies included electroencephalogram (EEG) monitoring (C3-A2, C4-A1), electro-oculogram, electromyogram (EMG) of the chin, electromyogram (EMG) of the two anterior tibial muscles and electrocardiogram (ECG). The PSG methods used standard procedures such as Pollmacher and Schuitz. In the baseline, they were monitored using methods P1114 standard, oronasal airflow, breathing effort and oxygen saturation. The sleep rating was also performed with methods. PLMs were scored if they were part of a series of at least four consecutive movements lasting 0.5 to 5 seconds, with an event interval of 4 to 90 seconds. The PLM index was calculated as the PLM number per hour of bed time and the PLM excitation index as number of PLM excitations per hour of total sleep time. Sleep efficiency was calculated as total sleep time per hour of bed time and the beginning of sleep as the time point of the first NREM period (by the acronym of Non Rapid Eye Movement, without Eye Movements) 2 that lasts minus 3 minutes Subjective ratings After each night of registration and at each visit to week 2 and 4, patients rated the severity of their illness (normal to extremely ill), the therapeutic effects by rating their overall improvements through the use of Global Patient Impressions (status general from much worse to much better), the severity of RLS symptoms during the time they fell asleep, during the night and during the day (scale: 0 = not present at 10 = very strong) and satisfaction with sleep (very dissatisfied to very satisfied). In addition, the patients rated their quality as P1114 life, related to welfare and complaints during the previous week, using the modified scale of 50 mm "Hamburger Visual Analogue Scale". Patients also filled in a sleep diary at each study visit, rating the following symptoms: overall assessment of sleep (very bad to very good night), sleep latency, sleep time, frequency of awakenings and impulse to move the legs at the time of falling asleep, during the night and during the day (scale: 0 = not present at 10 = very strong). Qualification of the Physician. The doctor rated the severity of the disease in the baseline (normal to extremely sick), the overall improvement (general condition much worse to much better) and the side effects, through the use of Clinical Global Impressions (CGI, for short) in English) . Security. The safety of cabergoline was evaluated by type and frequency of the adverse event, clinically significant changes in laboratory or ECG data or premature discontinuation of participation in the study. Adverse events were classified as serious versus non-serious and were characterized by intensity, relationship with the treatment drug, frequency, course and therapeutic intervention. Statistic analysis. The statistical evaluation P1114 was performed as an attempt to treatment analysis using descriptive statistics. The real results of this example are the following: Subjects. Nine patients (seven women and two men, with mean ages between 54.1 + 8.7, interval (38.1 - 64.3 years) with idiopathic RLS for 23.1 + 13.7 years (range 5 - 47 years), were treated. levodopa despite several adjustment attempts At the time of study entry, five patients were taking levodopa with dosages ranging from 400 to 800 mg.All had developed an increase with levodopa.The remaining four patients did not have any specific medication for RLS during the investigation Baseline: Two patients had previously been treated with other dopamine agonists, one developed severe hypotension with low dosage of bromocriptine (5 mg) .In baseline conditions the doctor considered that patients were extremely ill (2), Very sick (4) or notably sick (3) Medication and dosage At the end of the study (range 84-89 days) all patients were on Cabergoline monotherapy (mean dosage 2.1 mg) with doses ranging from 1.0 to 3.0 mg in 8 patients (1 mg in 2, 1.5 mg in 1, 2 mg in 3; mg in 1; 3 mg in 1). A P1114 patient who entered the study with 800 mg of levodopa finally required 4.0 mg of Cabergoline. Cabergoline was administered daily in the afternoon, between 7 and 9 PM. All patients who initially took levodopa, discontinued levodopa treatment during the study. Domperidone was discontinued in all patients due to good tolerability. Effectiveness. Polysomnography: Analysis of the two primary end points showed a greater effect of Cabergoline compared to baseline measurements for the following parameters: 1) the total number of PLM during bed time was significantly reduced by 195.8 + 109.1"to 26.4 + 40.2 and 2) the total sleep time was extended by more than one hour from 302.7 ± 50.7 minutes to 379.4 + 59.8 minutes.The secondary polysomnographic efficacy parameters revealed a pronounced increase in sleep efficiency ( 63.1 +, 10.5% to 79.1 + 12.5%) and sleep latency was reduced by almost half an hour (42.4 + 49.1 vs. 16.3 + 22.8 minutes) Other PLM parameters revealed a significant reduction in the PLM index (27.7 ± 17.1 vs. 3.6 + , 5.3), the PLM excitations (51.7 + 42.3 versus 6.4 + 11.2), the PLM excitation index (10.4 + 7.8 against 1.0 + 1.7) and the number of PLM awakenings (9.6 + 4.9 against 1.0 + 2.0) (See Table 1 ).

P1114 Subjective sleep ratings and RLS. With cabergoline monotherapy, the severity of the disease was rated as much less pronounced, since the patients rated themselves as normal (5) or borderline (2) according to PGI (Global Impressions of the Patient), only two as moderately patients, compared to the baseline when patients rated themselves as extremely (2), very (4) or markedly (3) sick. With the cabergoline, the general state was rated as much better (6) or much better (3) according to PGI. Overall ratings of the severity of RLS for the last week of each study visit showed that RLS symptoms improved significantly at the time of falling asleep (4.9 +, 4.3 vs. 0.4 +, 0.7), during the night (6.7). +. 2.7 versus 1.6 +. 2.6) and during the day (5.1 + 3.4 versus 0.8 +. 1.7). All patients reported significant relief or were freed from RLS symptoms. At the end point, patients were much more satisfied with their sleep, since 2 were very, 4 remarkably, 1 moderately satisfied and only 2 were moderately dissatisfied, compared to baseline conditions when all patients were very (1) , notably (6) or moderately (2) dissatisfied with their dreams. In dream diaries, the overall quality of the P1114 previous night was rated much higher in the final point (6.9) than in the baseline (3.1) on a scale of zero (very bad) to 10 (very good). Patients also woke up less frequently (0.6 times) with cabergoline therapy (versus 2.1 times per night at the baseline). Subjective qualifications of the quality of life. The scales "Hamburger Visual Analogue Scales" can be subdivided into six scales that measure satisfaction and six that measure negative sensations and complaints. Patients rated their quality of life as much better than under baseline conditions on a four / five point list. Qualification of the doctor for the severity of RLS. The qualification of the doctor showed a significant overall improvement. With the cabergoline the general condition of the patients was rated as much better in 5, much better in 3 and very little better in 1. Safety. Adverse events . A total of 8 adverse events, probably related to the study drug, were reported in 5 patients. The side effects probably related were vertigo (2), dizziness (2), headache (2), diarrhea (1) and nausea in 1 patient, which later led to reduce the dose of cabergoline, temporarily. There were no effects P1114 serious and no patient withdrew from the study. All side effects were temporary and were considered mild to moderate. No significant changes were detected in the laboratory or ECG data. Since overall tolerability was excellent, all patients were able to decrease and eventually discontinue domperidone. Analysis . The results of this open pilot test show, for the first time, that cabergoline, a long-acting agonist (Dl) / D2, is very effective and well tolerated in the treatment of restless legs syndrome. A treatment period of 12 weeks with a single afternoon dose of 1 to 4 mg (mean dose 2.1 mg) of cabergoline resulted in a total or significant relief of RLS symptoms and a marked improvement in subjective sleep parameters and objectives, in all patients who had previously been treated with levodopa. In two patients who had total relief of the subjective symptoms of RLS, they improved their sleep quality, but were still moderately dissatisfied. The reduction in the dosage of cabergoline in these patients could then improve sleep, without worsening the symptoms of RLS, which suggests the well-known warning effect of dopamine agonists as an underlying cause. The increase in RLS symptoms caused by levodopa was reversible with cabergoline, in all of our patients. Due to good tolerability, domperidone was decreased and eventually discontinued in all patients. There were no serious adverse events and no patient discontinued the study because of side effects. In addition, we did not observe other dopaminergic or peripheral side effects with the monotherapy of 4 mg of cabergoline. Some recent studies that include double-blind, placebo-controlled trials have indicated that levodopa provides an effective treatment for restless legs syndrome and therefore its acceptance is increasing as the treatment of choice for RLS. Due to its short half-life (2 to 4 hours) regular release formulas often do not maintain therapeutic coverage overnight. Attempts have been made to solve this difficulty, making a sustained release formula for levodopa. The main problems can further complicate levodopa therapy, especially in patients with severe RLS. In this relatively short treatment period, we did not observe an increase in our patients. Although the sample size is limited, our results showed that 1) cabergoline is effective in the treatment of RLS, 2) that it is also effective in patients with severe RLS and most P1114 important 3) that it is effective in patients who develop increase with levodopa therapy. Cabergoline is the first chemical agent that provides 24 hours of efficacy in RLS therapy. Table 1: Results of polysomnographic data in the baseline (five of nine patients were on levodopa therapy) compared to the endpoint of cabergoline therapy.

Baseline Week 12 Sleep latency (min) 42.4 ± 49.1 16.3 ± 22.8 Total sleep time (min) 302.7 ± 50.7 379.4 + 59.8 Sleep efficiency (%) 63.1 + 10.5 79.1 ± 12.5 PLM No. 195.8 + 109.1 26.4 + 40.2 PLM index 27.7 + 17.1 3.6 + 5.3 Excitations PLM 51.7 + 42.3 6.4 + 11.2 index of excitations PLM 10.4 + 7.8 1.0 ± 1.7 Awakenings PLM 9.6 + 4.9 1.0 + 2.0

Claims (31)

1. CLAIMS; A method for treating restless leg syndrome (RLS) in patients who suffer from it and who need an effective treatment for it, comprising: the administration of an effective amount of cabergoline or a pharmacologically acceptable salt thereof.
2. 2. A method according to claim 1, wherein the dose of cabergoline is approximately between 0.1 and 6 mg per patient per administration, depending on the need.
3. 3. A method according to claim 2, wherein the dose of cabergoline is administered once a day.
4. 4. A method according to claim 2, wherein the dose of cabergoline is administered 4 or 5 times a week in amounts of approximately 0.25 to 6 mg per administration.
5. 5. A method according to claim 2, wherein the dose of cabergoline is administered 2 or 3 times a week in amounts of approximately 0.25 to 6 mg per administration.
6. 6. A method according to claim 5, wherein the dose of cabergoline is administered once a week in amounts of approximately 0.25 to 6 mg per administration.
7. 7. A method according to claim 1, in P1114 where the dose of Cabergoline is approximately between 0.25 and 4 mg / day.
8. 8. A method according to claim 1, wherein the dose of Cabergoline is approximately between 0.25 and 2 mg / day.
9. 9. A method for treating Restless Legs Syndrome (RLS) in patients who suffer from it and who have previously been treated or concurrently treated with one or more of: a dopamine agonist, a benzodiazepine or a psychotropic agent, which comprising: administering an effective amount of cabergoline or a pharmacologically acceptable salt thereof.
10. A method according to claim 9, wherein the previous or concurrent treatment is or was with a dopamine agonist and the dose of Cabergoline is approximately between 0.1 and 6 mg / day.
11. 11. A method according to claim 9, wherein the dopamine agonist is or was levodopa.
12. 12. A method according to claim 11, wherein the dose of Cabergoline is approximately

    0. 25 and 4 mg / day.
13. 13. A method according to claim 9, wherein the previous or concurrent treatment is or was with benzodiazepines and the dose of Cabergoline is approximately between 0.25 and 4 mg / day. P1114
14. 14. A method according to claim 13, wherein the benzodiazepine is clonazepam (Klonopin).
15. 15. A method according to claim 9, wherein the prior or concurrent treatment is or was with the psychotropic agent, wherein the psychotropic agent is an opioid and the dose of Cabergoline is approximately between 0.1 and 4 mg / day.
16. 16. A method to treat Restless Legs Syndrome (RLS) in patients who suffer from it, where the patient has suffered or is considered to be susceptible to the effects of an increase or rebound from a previous RLS treatment, where the previous treatment it consists in treating with one or more of: a dopaminergic agent, a dopamine agonist, a benzodiazepine or a psychotropic agent, comprising: the administration of an effective amount of cabergoline or a pharmacologically acceptable salt thereof.
17. 17. A method for treating patients who do not sleep well, comprising the administration of an effective amount of cabergoline or its pharmaceutically acceptable salts.
18. 18. A method according to claim 17, wherein the patients have abnormal sleep patterns as measured by standard sleep tests.
19. 19. A method according to claim 16, in P1114 where the effective amount of cabergoline is approximately between 0.25 and 5 mg per patient per day.
20. 20. A method according to claim 16, wherein the pretreatment consisted of treating with a dopamine agonist, wherein the dopamine agonist is levodopa and the effective amount of cabergoline or the salt thereof is between 0.25 and 4 mg per patient per day.
21. 21. A method to treat Restless Legs Syndrome (RLS) in patients who suffer from it, wherein the patient has experienced tolerance with a previous treatment of RLS, wherein the previous treatment consisted in treating with one or more of: a dopaminergic agent, a dopamine agonist, a benzodiazepine or a psychotropic agent, comprising: administration of an effective amount of cabergoline or a pharmacologically salt thereof.
22. 22. A method according to claim 21, wherein the pretreatment consisted in treating with a dopamine agonist, wherein the dopamine agonist is levodopa and the effective amount of cabergoline or the salt thereof is between 0.1 and 4 mg per patient per day.
23. 23. A method to treat Restless Legs Syndrome (RLS) in patients who suffer from it and who need an effective treatment for it, comprising: the administration of an effective amount of cabergoline or a P1114 pharmacologically acceptable salt thereof in combination with an effective amount of levodopa or its pharmacologically acceptable salts.
24. 24. A once-a-day method for treating restless legs syndrome (RLS) in patients who suffer from it and who need an effective treatment for it, comprising: administering to the patient an effective amount of cabergoline or a pharmacologically acceptable salt thereof, once a day.
25. 25. A method for treating Restless Legs Syndrome (RLS) in patients who suffer from it and who need an effective treatment for it, comprising: administering an effective amount of cabergoline or a pharmacologically acceptable salt thereof; but without the administration of another dopaminergic agent.
26. 26. A method for treating restless leg syndrome (RLS) in patients who suffer from it and who need an effective treatment for it, which in essence consists of: the administration of an effective amount of cabergoline or a pharmacologically acceptable salt of the same .
27. 27. Any of the treatments according to claims 1 to 26, wherein the cabergoline is administered to the patient once a day.
28. 28. Any of the treatments according to P1114 claims 1 to 26, wherein the cabergoline is administered to the patient every third day.
29. 29. Any of the treatments according to claims 1 to 26, wherein the cabergoline is administered to the patient approximately 2 to 3 times per week.
30. 30. The use of cabergoline or its pharmaceutically acceptable salts, in the manufacture of a medicament for treating RLS and any of the RLS symptoms described herein.
31. 31. A pharmaceutical composition that is used as a treatment for RLS and for any of the RLS symptoms described herein, comprising cabergoline and its pharmaceutically acceptable salts. P1114