MXPA00006716A - Methods of treating tardive dyskinesia and other movement disorders - Google Patents

Abstract

The present invention describes novel treatments for movement disorders, including tardive dyskinesia and tardive dystonia, tic disorders, Tourette's syndrome, and blepharospasm, and other focal dystonias. The treatments of the present invention utilize agents that simultaneously act as NMDA-type glutamate receptor antagonists. Additionally, the treatments of the present invention utilize agents that simultaneously act as NMDA-type glutamate receptor antagonists and GABA-A receptor agonists. Preferably these two activities are characteristic of a single agent, for example acamprosate. Alternatively, separate agents having these activities can be combined and administered together. The invention also provides a third agent that can be used in combination with a treatment for movement disorders, that acts as a non-competitive NMDA-receptor blocking agent or ion channel blocker that augments the effect of the primary treatment. A particularly preferred ion channel blocking agent is magnesium. Alternatively, magnesium can be administered alone for prevention and treatment of movement disorders.

Description

METHODS TO TREAT LATE DISCINESIA AND OTHER MOVEMENT DISORDERS DESCRIPTION OF THE INVENTION This invention relates to the treatment of three main types of movement disorder 1) tardive dyskinesia (TD), late dystonia and related movement disorders, induced by exposure to neuroleptic drugs (antipsychotics); 2) focal dystonias not related to medications, which include blepharospasm, Meige syndrome, torticollis, spasmodic dysphonia, and writer's cramps; and 3) tics, which includes multiple tics and Gilles de la Tourette syndrome (TS). Movement disorders affect a significant portion of the population, causing disability as well as stress. Tardive dyskinesia (TD) is a chronic disorder of the nervous system, characterized by irregular rhythmic involuntary movements of the mouth, tongue and facial muscles. The upper extremities may also be involved. These movements can be accompanied, to a varying degree, by other involuntary movements and movement disorders. These include rocking, twisting or contorting movements of the trunk (late dystonia), impulsive closing of the eye (late blepharospasm), an irresistible urge to move continuously (tardive tardy), jerking movements of the neck (delayed spasmodic torticollis), and respiratory movements disorganized (respiratory dyskinesia). The vast majority of TD cases are caused by prolonged use of antipsychotic (neuroleptic) drugs. A relatively small number is caused by the use of other medications, such as metoclopramide, which, like neuroleptics, blocks dopamine receptors. TDs often manifest or worsen in severity after neuroleptic drug therapy is discontinued. The resumption of neuroleptic therapy will temporarily suppress involuntary movements, but may aggravate them in the long run. TD is also associated with a variable degree of cognitive impairment. Cognitive dysfunction associated with TD may also involve attention, concentration, memory, or executive functions such as judgment or abstract reasoning. (See, for example, Sachdev et al., Acta Psychia tr Scand 93: 451, 1996, Waddington &Youssef, Psychol Med 26: 681, 1996, S artz, Neuropsychobiology 32: 115, 1995). Cognitive impairment associated with TD is usually seen as a marker of underlying differences in brain function that predispose the patient to TD. However, it may also be due to the TD itself, and may be irreversible, or partially reversible if the TD is successfully treated.

Tardive dyskinesia (TD) affects approximately 15-20% of patients treated with neuroleptic drugs (Khot et al., Neuroleptics and Classic Tardive Dyskinesia, in Lang AE, Weiner WJ (eds.): Drug Induced Movement Disorders, Futura Publishing Co., 1992, pp. 121-166). Neuroleptics are used to treat various common psychiatric disorders including schizophrenia and related psychoses (estimated prevalence 1%), mood disorders with psychotic features (estimated minimum prevalence 0.5%), and Alzheimer's disease with psychosis or agitation (Estimated minimum prevalence at 0.5%). Assuming that half of those who need neuroleptic treatment or receive it, it turns out that TD affects hundreds of thousands of people in the United States alone. The cumulative incidence of TD is substantially higher in women, the elderly, and those who are treated with neuroleptics for conditions other than schizophrenia, such as bipolar disorder (manic-depressive illness). (see, for example, Hayashi et al., Clin. Neuropharmacol., 19: 390, 1996; Jeste et al., Arch. Gen. Psychia try, 52: 756, 1995). Unlike the acute motor side effects of neuroleptic drugs, TD does not respond in general to antiparkinson drugs (Decker et al., New Eng. J. Med., October 1, p.861, 1971). Focal dystonias are a group of movement disorders that involve the intermittent sustained contraction of specific muscle groups, resulting in recurrent abnormal postures of some parts of the body. The most common is spasmodic torticollis, which involves the neck turning. Other examples are blef rospasmo, which involves involuntary eye closure or excessive compulsive blinking, and writer's cramp, which involves contraction of the hand muscles. Another less common focal dystonia involves the muscles of the larynx, (spasmodic dysphonia). Other relatively rare dystonias involve groups of muscles specific to a particular occupation, such as playing the violin. The prevalence of focal dystonias in a United States county was estimated at 287 per million (Monroe County Studey); this suggests that at least 70,000 people are affected only in the United States. Blepharospasm only affects more than 25,000 people (Source: US FDA Web Site, page on Orphan Drug Act). It is estimated that tics affect 1% to 13% of boys and 1% to 11% of girls, with the male-female ratio being less than 2 to 1. Approximately 5% of children between the ages of 7 and 11 are affected with tic behavior (Lec man et al., Neuropsychia try of the Bas. Gang, December, 20 (4): 839-861, 1997). The estimated prevalence of multiple tics with vocalization, ie Tourette syndrome, varies between the different reports, ranging from 5 per 10,000 to 5 per 1,000. Tourette syndrome is 3-4 four times more common in boys than in girls and 10 times more common in boys and adolescents than in adults (Leckman et al., Supra; Esper et al, Tenn. Med., January, 90: 18-20, 1997). A tic is an abrupt repetitive movement, gesture, or expression that often mimics a normal type of behavior. Motor tics include movements such as eye blinking, head twitching, or shrugging of the shoulders, but may vary to complex behaviors that appear purposefully such as facial expressions of emotion or significant gestures of the arms and head. In extreme cases, the movement may be obscene (copropaxy) or self-injurious. Phonic or vocal tics range from sounds of throat clearing to complex language and vocalizations, sometimes with coprolalia (obscene language) (Leckman et al., supra). The tics are irregular in time, although they are consistent with the group of muscles involved. Characteristically, they can be suppressed for a short time by voluntary effort. Gilles de la Tourette syndrome (TS) is the most severe tic disorder. Patients with TS have multiple tics, which include at least one vocal tic (phonic). TS becomes apparent in early childhood with the presentation of simple motor tics, for example, eye blinking or head twitching. Initially, the tics may come and go, but over time the tics become persistent and severe and begin to have adverse effects on the child and the child's family. Phonic tics occur, on average, from 1 to 2 years after the start of motor tics. At the age of 10, most children have developed an awareness of premonitory urgencies that often precede a tic. Such premonitions can enable the individual to voluntarily suppress the tic, however the premonition unfortunately adds to the discomfort associated with having the disorder. In advanced adolescence / young adult tics disorders can improve significantly in certain individuals. However, adults who continue to suffer from tics frequently have particularly severe debilitating symptoms (Leckman et al., Supra). The pathophysiology of movement disorders, specifically TD, has not been definitively established. It is well known that blocking dopamine receptors will lead to an increase in the number of dopamine receptors, and therefore to an increased sensitivity to dopamine of neurons in the striatum. (See, for example, Andrews, Can J Psych 39: 576, 1994, Casey, in Psychopharmacology: The Fourth Generation of Progress, Raven Press, 1995). The first major hypothesis about the pathophysiology of TD was that TD was the result of this hypersensitivity of striatum neurons to dopamine. In support of the hypothesis of "dopamine supersensitivity", it is noted that dopamine agonists can aggravate the disorder (Bezchibnyk-Butler &Remington, Can J. Psych., 39:74, 1994). However, the hypothesis of dopamine supersensitivity is not compatible with the observation that TD and Parkinsonism (a state of dopamine deficacy) frequently exist together in the same patient. Other studies have suggested that irreversible cases of TD can be related to excitotoxic damage to the basal ganglia (Andreassen &Jorgensen, Pharmacol, Biochem, Behav., 49 (2): 309-312, 1994, Tsai et al.,: JAm J Psych, September 155: 9, 1207-13, 1998). An acquired deficiency of the inhibitory neurotransmitter GABA has also been implicated in the development of TD (Delfs et al., Experimental Neurol., 133: 175-188, 1995). A widely studied animal model of TD, that of empty chewing movements (VCM), has also produced evidence for an excitotoxic mechanism based on glutamate in the development of the disorder (Eshul et al., Psychopharmacology (Berl), 125: 238-47). , June 1996; Andreassen et al; Br J Pharmacol, 199: 751-1, October 1996). When administered to rats with MCV, ethanol sharply decreases the orofacial movements of the animal. This effect is avoided if the rats are pre-treated with a benzodiazepine inverse agonist, suggesting that it is mediated by the stimulation of the GABA-A receptors by ethanol (Stoessl, Pharmacol, Biochem, Behav, July, 54: 541-6). , July 1996). Stoessl suggests that "GABAergic stimulation" deserves further investigation in the treatment of TD. However, it does not advance the idea of treating TD with NMDA antagonists, nor does it suggest using memantine as a treatment for TD. The physical manifestations of TD may resemble movement disorders associated with degenerative diseases such as Huntington's disease and Parkinson's disease. Patients with TD may show chorea (irregular rapid movements of the extremities) indistinguishable from those seen in cases of Huntington's disease. The movements of the neck, trunk and extremities of the TD can be indistinguishable from those of the dyskinesia associated with the peak dose with the prolonged treatment of Parkinson's disease with levodopa. The physical manifestations of late dystonia are almost identical to the manifestations of idiopathic dystonias, that is, those unrelated to the exposure of dopamine antagonists. (See further discussion below). It is evident that similar mechanisms may be involved in the pathophysiology of late movement disorders and idiopathic focal dystonia. Positron emission tomography has shown that a specific dystonia, torticollis, is associated with neuronal hypermetabolism in the basal ganglia. It has been hypothesized that the hyperactivity of a motor control loop involving the cerebral cortex, basal ganglia, and thalamus is responsible for abnormal postures and movements (ie, movements in and out of abnormal postures) characteristic of dystonia ( Galardi et al., Acta. Neurol Scand, September, 94: 172-6, 1996). Other studies have shown dopaminergic transmission or abnormal receptor function in patients with dystonia (see, for example, Perlmutter et al, J Neurosci, January 15, 17: 843-50, 1997). It should be noted that much or little dopamine may be associated with dystonia, since patients with Parkinson's disease and dystonia may have the problem at peak and depressed levels of levodopa (Hallett, Arch. Neurol., May 55: 601-3, 1998). Although memantine has dopamine antagonist activity, memantine has not been suggested as a treatment for focal dystonias. The pathophysiology of tic disorders like that of TD has not yet been definitively established, although several plausible hypotheses have been established. The pathophysiology of tic disorder resembles the mechanism that may be involved in the pathophysiology of TD and focal dystonias. Excessive activity of a cortical-thalamic-pallidal sensorimotor handle of the cortical striatum has been implicated in the lack of motor impulse control associated with tic disorders (Zambian et al., Am. J. Psychiatry, Vol. 154, September , 1997; Leckman et al., Supra). This hyperactivity may reflect excessive dopaminergic activity in the striatum, or a relative deficacy of inhibitory transmission. While basal ganglia dysfunction or its connections may be present, the basal ganglia, thalamus, and motor cortex are anatomically normal in most cases. TD Treatment Recent research suggests that Vitamin E can reduce TD symptoms briefly (Lohr &Caliguiri, J Clin Psychia try 57; 167, 1996; Dabiri et al. Am. J. Psychia try, June, 151 (6 ): 925-926, 1994). GABA antagonists such as baclofen and various benzodiazepines have also been the subject of some positive reports and are widely used in practice to improve the symptoms of TD, probably because their low toxicity justifies their use despite their limited efficacy (Gardos &Cole, Psychopharmacology: The Fourth Generation of Progress, eds Bloom and Kupfer, pp. 1503-1510, 1995). This review cites reports of various benefits associated with other agents that include propranolol, clonidine, cholinergic agonists, buspirone, and calcium channel blockers. However, none of these has become a generally accepted treatment for movement or cognitive disorders associated with TD. (The author has had some success treating TD as nimodipine, a calcium channel antagonist with particularly good CNS penetration). In US Pat. No. 5,602,150, by Lidsky et al., It is proposed that the occurrence of TD in patients receiving neuroleptics can be prevented by simultaneously administering taurine or taurine derivatives. Lidsky bases his invention on the theory that TD is due to excitotoxic damage, and that taurine and taurine derivatives protect patients against this damage. The taurine recommendation is based on studies of a simple animal model. The reported experiments do not deal with any therapeutic effect of taurine in established movements, neither in the presence of continued neuroleptic administration or in any other way. Neither the patent nor the experiments cited therein predict or imply that taurine or derivatives will be beneficial for the disorders of the established movement. In addition, the mechanism proposed by Lidsky et al.,. { supra) is based on long-term neuroprotection. It does not infer, affirm or suggest that taurine or taurine derivatives can have any immediate effect in the short term in movement disorders. Memantine is a drug approved in Europe for the treatment of Parkinson's disease. Memantine, a congener of amantadine, is a N-methyl-D-aspartate glutamate receptor blocker ("NMDA antagonist receptor" or "NMDA receptor blocker") as well as a dopamine agonist. Although it has been reported that memantine relieves some of the dyskinetic movements that can be seen in Parkinson's disease treated, there are no reports of its use in humans to treat tardive dyskinesia, and at least one widely renowned expert in the field of TD expresses surprise that any anti-Parkinson's drug is an effective agent against TD (Dilip Jeste, MD, personal communication, 1997). In US Pat. No. 4,122,193, it is reported that 1, 3, 5-trisubstituted adamantane, including 1-amino-3,5-dimethyladamantane, is useful in the treatment of hyperkinesis in rats. The agent is generally also recommended as a treatment for hyperkinesis, in the context of Parkinson's disease, head tremors, thalamic tension conditions, and spastic conditions, and for "the activation of patients with brain-organic to kinetic conditions". It is notable that, unlike TD, it is thought that none of the underlying conditions described in that patent according to the context of hyperkinesis to be treated, is aggravated by dopamine agonists. In addition, there is no recognition in the reference that l-amino-3,5-dimethyladamantane acts as a blocker of the NMDA receptor. Instead, the discussion indicates that the trisubstituted 1, 3, 5-adamantane compounds influence the catecholamine metabolism, for example by releasing dopamine or by stimulating the receptors. The latter aspect suggests that the authors did not recognize that memantine could be effective in the treatment of TD, for whose administration of dopamine agonists in general goes against expert opinion. In co-pending applications commonly owned Nos. Nos. 08 / 861,801 and 09 / 006,641, incorporated herein by reference, treatments with memantine (a congener of amantadine and a receptor blocker (NMDA) type N-methyl-D -aspartate as well as a dopamine agonist), and acamprosate (a calcium salt of an amino acid derivative taurine and an indirect NMDA antagonist and GABA-A agonist), were proposed as effective treatments for the associated cognitive and movement disorders with TD, and reported to be dramatically effective in various severely accepted individuals. The cases described in those patent applications contain the first reports of the use of memantine for the treatment of TD. 5 Treating focal dystonia As noted above, a focal dystonia is a movement disorder that involves the recurrent abnormal posture of a part of the body. The spasms of focal dystonia can last many seconds at a time, causing a major disorganization of the function of the affected area. Some of the focal dystonias are precipitated by repetitive movements; the best known example is the writer's cramp. Focal dystonia may involve the face (eg, blepharospasm, mandibular dystonia), neck (torticollis), extremities (for example, writer's cramp), or trunk. Dystonia may occur spontaneously or may be precipitated by exposure to neuroleptic drugs and other dopamine receptor blockers (late dystonia). No drug therapy • Systemic is generally effective, but some drugs give partial relief to some patients. The most frequently prescribed drugs are anticholinergics, baclofen, benzodiazepines, and dopamine agonists and antagonists. The most consistently effective treatment is the injection of botulinum toxin inside the affected muscles.

The various focal dystonias tend to respond to the same drugs (ie, the treatments that are helpful for a focal dystonia are generally helpful for others). (Chen, Clin Orthop, June, 102-6, 1998, Esper et al, Tenn. Med, January, 90: 18-20, 1997, De Mattos et al., Arq. Neuropsychia try, March 54: 30-6 , nineteen ninety six). The clinical experience published so far suggests that a new treatment that reduces the involuntary movements of a focal dystonia would be likely to do the same for the involuntary movements of others. In addition, the common symptoms, signs, and responses to the medication of spontaneous dystonia (idiopathic) and neuroleptic-induced dystonia suggest that an effective treatment for a drug-induced focal dystonia will be effective for the same dystonia that occurs spontaneously. Blepharospasm, one of the focal dystonias, is a condition that involves the continuous recurrence of involuntary eye closure or compulsive blinking. Blepharospasm is one of the most common disorders of oculomotor function. It is considered variably as a facial dyskinesia or a facial dystonia. When presented together with dystonia of the oral and mandibular regions, with or without involvement of the neck, it is referred to as Meige syndrome. Blepharospasm can significantly impair visual function. Patients may become unable to read, drive a car, or do any skilled work that requires visual control. Blepharospasm can occur spontaneously (idiopathic blepharospasm) and with a prevalence that increases with increasing age; the majority of cases arise in the fifth and sixth decade of life (Holds et al., Am. Fam. Physician, June, 43: 2113-20, 1991). It can also be presented as a sequel to the neuroleptic drug treatment (Ananth et al., Am. J. Psychia try, April, 145: 513-5, 1988; Kurata et al., Jpn. J. Psychia try. Neurol., December; , 43: 627-31, 1989; Sachdev et al., Med. J. Aust., March 20, 150: 341-3, 1989) and perhaps treatment with other classes of psychotropic drugs (Mauriello et al., J Neuropa thol, June, 18-153-7, 1998), either alone or together with tardive dyskinesia or other forms of late dystonia. Another report of 19 patients with severe tardive dyskinesia states that the frequent blinking of the eyes was the most frequent prodromal sign of the disorder (Gardos et al., Supra, 1988). The oculomotor phenomenon of idiopathic blepharospasm and Meige syndrome are identical with those seen in cases induced by neuroleptic treatment. The differences between idiopathic blepharospasm and late blepharospasm do not imply eye movements themselves. (The differences observed have involved the history of the family and the possibility that other non-ocular involuntary movements are present).

Although many substances have been tested for their ability to relieve blepharospasm, the injection of the botulinum toxin into the orbicularis oculi muscles is the support of the treatment (Mauriello et al., Br. J. Oph thalmol. December, 80: 1073-6, 1996). These injections weaken the muscles responsible for closing the eye, thereby mitigating the involuntary movements of those muscles. They can also indirectly influence oculomotor control by the central nervous system, altering the entry of motor nerve afferents. Botulinum toxin injections have become the treatment of choice because they improve symptoms in approximately 80% of patients-a much larger proportion than the benefit of the numerous systemic drug treatments tested to date. The movements associated with blepharospasm do not respond well to the treatments of systemic drugs used to date. In a large series of cases, only 22% of patients with blepharospasm treated with systemic medications achieved marked and persistent relief (Jankovic et al., Mov. Disord., May 9: 347-349, 1983). In another report, of the 13 blepharospasm patients who did not do well with the botulinum toxin injections, only 2 showed some improvement when given systemic drug therapy (Mauriello et al., Cl in.

Neurol. Neurosurg. , August, 98: 213-6, 1996). Even botulinum toxin injections are not always effective. Surgery is sometimes recommended for patients who do not get relief from botulinum toxin injections (Elston et al., J. Neurol, January, 239: 5-8, 1992). Of the numerous systemic treatments tested for the treatment of blepharospasm, (see, for example, Arthurs et al., Can. J. Ophthalmol, February, 22: 24-8, 1987, Casey et al., Neurology, July, 30: 690-5, 1980, Jacoby et al., Invest. Ophthalmol, Vis. Sci, March, 31: 569-76, 1990, Michaeli et al., Clin. Neuropharmacol., June, 11: 241-9, 1988; Ransmayr et al., Clin. Neuropharmacol., February, 11: 68-76, 1988) clonazepam, a GABA agonist, was the only drug found to be consistently useful (Jankovic et al., Ann. Neurol., April, 13: 402-11, 1983). A combination of two GABA agonists, valproate and baclofen, was effective in a simple case (Sandyk, et al., S Afr Med J. December, 64: 955-5, 1983). Tetrabenacin, an agent that depletes dopamine, relieved involuntary movements in 4 out of 6 patients with Meige syndrome, but patients had many undesirable side effects including drowsiness, drooling, and Parkinsonism (Jankovic, et al., Ann Neurol., January , 11: 41-7, 1982). Due to such unpleasant side effects, tetrabenazine has not become a widely used treatment for blepharospasm, tics or even tardive dyskinesia, despite the absence of other treatments generally effective for these conditions. Neuroleptics sometimes relieve blepharospasm symptoms, but they do less well than tetrabenazine, and patients treated with them are at risk of developing TD or other late-onset disorders. In sum, although drugs that reduce dopamine transmission and GABA agonists have been used with some benefit in the treatment of idiopathic blepharospasm, these types of medications have proven to be generally satisfactory treatments. Treatment of tics and Tourette syndrome It is likely that patients with moderate to severe motor and vocal tics require drug therapy. Many kinds of neurological and psychiatric medications have been tried, although only neuroleptic alpha-2 adrenergic agonists and clonazepam have attained standard treatment status. (For recent reviews see Chappell et al., Neur. Clin, of North Am., 15 (2), May 1997; Kurlan, Neurol. Clin., May, 15: 403-409, 1997; Lichter et al., J Child Neur., 11 (2), March, 1996, Leckman et al., Supra, Esper et al., Tenn. Med., January, 90: 18-20, 1997; Scahill et al., J. Child Adolesc Phychopharmacol, 7 (2), 1997, incorporated herein by reference). Unfortunately, the three treatments commonly used for TS have significant disadvantages. The most commonly used therapies for the treatment of tic disorders are neuroleptics (ie dopamine antagonist antipsychotic drugs). Within this category, haloperidol and pimozide are the most commonly used in the United States. Neuroleptic treatment will normally suppress involuntary movements of tic disorders, with up to 85% of patients experiencing relief (Esper et al., Supra). Side effects of neuroleptic drugs include sedation, depression, parkinsonism, cognitive decline and tardive dyskinesia. Other late-onset disorders may develop with prolonged use. The intolerable side effects frequently lead patients to discontinue neuroleptic therapy for TS, while the risk of TD means that most doctors do not want to use them in light cases. Those with more severe TS should frequently make an unpleasant selection between tension symptoms and stress side effects. People with simple tic may experience emotional stressshame, deteriorated self-esteem, or physical harm if their tics are sufficiently violent. However, they will not usually be treated with neuroleptics due to their side effects and long-term toxicity that is not acceptable in the treatment of relatively light cases. Other drug treatments for TS do not carry the risk of TD. But they are less effective than neuroleptics. The most common non-neuroleptic alternatives are alpha-2 adrenergic agonists such as clonidine. Unfortunately, less than 50% (perhaps as few as 25%) of patients treated with clodinide show significant clinical improvement of tic-related symptoms (Esper et al., Supra).; Chappell et al., Supra). In addition, many patients whose tics do not respond to clonidine will have side effects that limit their use, most often in hypotension or sedation. Another non-neuroleptic treatment, clonazepam, a benzodiazepine with GABA-A and serotonergic actions, has some efficacy in the treatment of Tourette's syndrome (Steingard et al., J. Am. Acad Child Adolesc Psychia try, March-April, 33: 394-9, 1994). Sedation and ataxia limit the dosage of clonazepam; the tolerable dose is often below what is needed to suppress the patient's tics. A new class of compounds that act as antagonists of 5-HT2 brain receptors initially showed promising results, although children and adolescents experienced increased sensitivity to side effects (Chappell et al., Supra). Additional alternatives that have received recent attention include treatment with antioxidants (Rotrosen et al., Prost. Leuk and Ess. Fatty Acids, 55 (1 & 2), 1996), transcranial magnetic stimulation (Ziemann et al., Supra), nicotine treatment (Sanberg et al., Pharmacol. Ther., 74 (1)., 1997; Silver et al., J. Am. Acad. Adol esc.

Psychia try, Vol 35, December 1996) and treatment with botulinum toxin. While each of these treatments has offered significant clinical relief to individual patients, none has replaced neuroleptics as the preferred treatment. There is clearly a need for additional treatments for tics and TS that do not carry the side effects and long-term results of neuroleptics. It has been suggested, on theoretical grounds, that future therapies for Tourette syndrome might include glutamate antagonists, although a recent article proposing its use does not mention any specific drugs that could fill this role (Chappell et al., Neurol. Clin, May 15 (2): 429-450, 1997). Magnesium Disorders and Movement There is considerable evidence of abnormalities in magnesium status in a patient with severe mental illness (See, for example, Athanassenas et al., J. Clin. Psychopharma col. August, 3: 212-6, 1983; Alexander; et al., Br.

J. Psychia try, August, 133: 143-9, 1978, Kirov et al., Neuropsychobiology, 30 (2-3): 73-78, 1994; Wang et al. 1997; Yassa et al., Int. Pharmacopsychia try, 14 (1): 57-64, 1979). Alexander et al. . { supra, 1978) found that those schizophrenic patients who develop extrapyramidal side effects of neuroleptics had, on average, lower magnesium levels than those who did not have such side effects. Neuromuscular excitability and anxiety are common acute manifestations of magnesium depletion, and there are theoretical reasons to speculate that magnesium deficacy may contribute to a wide range of neurodegenerative disorders (Durlach et al., 1997, supra). Because magnesium deficacy can cause neuromuscular excitability (Durlach et al, Magnes Res, June, 10: 169-95, 1997), it could potentially cause or aggravate movement disorders. Ploceniak,. { Communications Libres, 91, suppll, 1990) reported, without details, that he had found the magnesium supplement useful in patients with bruxism (teeth grinding) and the facial tics associated with tetany (susceptibility to muscle cramps typical of hypocalcemia). ). However, he did not suggest that magnesium supplementation would help patients with Tourette syndrome, or those with tics not due to magnesium deficacy. There has been no suggestion that magnesium deficacy is a cause of tardive dyskinesia, other delayed movement disorders, blepharospasm, or other focal dystonias, or that magnesium supplementation can be used to successfully treat or prevent movement disorders, in the absence of apparent magnesium deficacy manifested by tetany. Although the current pharmacopoeia offers a variety of agents to treat the movement disorders described above, none of these agents can prevent or cure these conditions. In addition, the most effective systemic drug treatments are often associated with intolerable side effects. Botulinum toxin injections can be unpleasant, they must be repeated frequently, and often lose their effectiveness over time. In addition, when used to treat dystonia of an upper extremity, they can weaken the muscles that are needed for optimal function of the hands. There remains a well-defined need for new systemic treatments for TD, other delayed movement disorders, blepharospasm, and other focal dystonias, which have greater efficacy and fewer side effects than those currently available. The present invention provides a method for treating movement disorders including TD, other late movement disorders, tic disorders, blepharospasm, and other focal dystonias in humans. The present invention also provides a method for reducing the involuntary movements characteristic of patients with movement disorders by administering a pharmacological agent that decreases the neurotransmission of NMDA-type glutamate. In one aspect, a pharmaceutical agent is selected from the group of agents that has the ability to reduce post-synaptic excitation potentials induced by glutamate in striatum cells. Specific cases include memantine, dextromethorphan and congeners or derivatives thereof with similar pharmacodynamic effects on NMDA-like glutamate neurotransmission, and prodrugs that are metabolized in the liver, blood, or brain to produce metabolites and active derivatives with similar pharmacodynamic effects. In another aspect, the invention provides a method for reducing the characteristic involuntary movements of patients with hyperkinetic or dyskinetic movement disorders by administering a pharmacological agent, which (i) acts directly or indirectly as an agonist at the GABA-A receptors and (ii) ) decreases the neurotransmission of NMDA-type glutamate by an indirect or modulatory mechanism. Specific cases include calcium N-acetylhomotaurinate (acamprosate), magnesium N-acetylhomotaurinate, other N-acetylhomotaurinate salts, N-acetylhomotaurinate derivatives with similar pharmacodynamic effects on GABA and NMDA-like glutamate neurotransmission, and prodrugs that are metabolized in the liver, blood or brain to provide N-acetylhomotaurinate or a derivative with similar pharmacodynamic effects. In another aspect, the present invention provides methods for reducing characteristic involuntary movements of patients with hyperkinetic or dyskinetic movement disorders by administering more than one pharmacological agent which, in combination, act to increase the activity of the GABA-A receptor and decrease neurotransmission. of NMDA-type glutamate. The present invention also provides a method for treating movement disorders by combining magnesium or a non-competitive NMDA receptor antagonist with memantine or another compound or mixture thereof (including specifically those listed in the preceding paragraphs) that decrease the post-challenge response. synaptic to glutamate in NMDA type receptors. For example, dextromethorphan can be combined with memantine and magnesium for the treatment of movement disorders. In another aspect the present invention provides a combination of magnesium or a NMDA receptor antagonist uncompetitive with memantine or another compound or mixture thereof that simultaneously decreases the post-synaptic response to glutamate at NMDA-like receptors and also directly or indirectly increases the transmission of GABA-A. In preferred embodiments, magnesium is used as a non-competitive NMDA receptor antagonist. (Memantine works as an NMDA receptor antagonist by blocking the calcium ion channels). The present invention demonstrates that magnesium can increase the effect of the pharmacological agents used to treat movement disorders including tics and TD, and, by extension, TS and blepharospasm and other focal dystonias, whether used or not by neuroleptic exposure. Synergistic activity is shown between magnesium and other pharmacological agents that act as NMDA receptor antagonists and also agents that act as NMDA receptor antagonists and simultaneously as enhancers of GABA-A transmission. In one embodiment, any combination of agents that act as NMDA receptor antagonists, with or without magnesium, are used for the treatment of movement disorders. Alternatively, magnesium is only used to reduce the symptoms associated with movement disorders. In another preferred embodiment, magnesium supplementation is used to prevent movement disorders in persons already at risk thereof, reducing the risk, or delaying the onset of the movement disorder for which they are at risk. In particular, it is confirmed that magnesium deficiency is a risk factor for the development of DT in patients receiving neuroleptics, and that magnesium supplementation can prevent the development of TD, particularly in patients prone to magnesium deficiency, which includes elderly women, alcoholics, diabetics, people taking diuretics and malnourished individuals. In other embodiments, any combination of agents that act as an NMDA receptor antagonist together with one or more agents that facilitate the neurotransmission of GABA-A (acting as GABA-A receptor agonists, increasing the release of GABA-A, or increasing the post-stic response to stimulation of the GABA-A receptor), with or without magnesium is used for the treatment of movement disorders. A pill that combines one or more agents that act as antagonists of the NMDA-type glutamate receptor and magnesium with or without an agent acting as a GABA agonist is proposed as a specific vehicle for the delivery of this combination therapy. In addition, other oral preparations are suggested; The mixture can be supplied in a syrup, elixir, or extended-release capsule. The latter is suggested as a method to prolong the duration of the action of a dose of the mixture. 2. 3 Definitions "Tardive dyskinesia": As used herein, "Tardive dyskinesia" means that it includes late dystonia and other movement disorders related to the long-term use of neuroleptics. The abbreviation TD may be used in place of the term "tardive dyskinesia". Also, the set of conditions encompassed by TD in this application can also be referred to as "tardive dyskinesia and late related movement disorders". "Blepharospasm": As used in this, "Blepharospasm" includes Meige syndrome, which is a combination of blepharospasm and dystonia of the face and / or neck. "Focal dystonia": As used herein, "focal dystonia" includes blepharospasm and Meige syndrome, spasmodic torticollis, spastic dysphonia, writer's cramp, musician's cramp, and other occupational dystonia. "Tourette's syndrome": "Tourette's syndrome" as used herein is synonymous with "Gilles de la Tourette syndrome", "Tourette syndrome", "disorder of Tourette ", and similar expressions The abbreviation TS may be used in place of any of these terms" NMDA receptor antagonist ": As used herein," NMDA receptor antagonist "is any molecule that inhibits or decreases the Post-synaptic response of glutamate-like glutamate receptors to glutamate "NMDA-like glutamate neurotransmission": "NMDA-like glutamate neurotransmission" is widely used herein, to refer to anything that decreases the transmission of NMDA glutamate, whether it acts - before the synapse, at the glutamate receptor binding site, at the modulator site such as the glycine modulator site, within the ion channel, within the cell membrane, or within the neuron This also includes any substance that reduces the release of glutamate at the synapse with NMDA receptors, alters the binding of glutamate to NMDA receptors, or alters the number or types of receptors. s NMDA. "Acamprosate": As used herein, "Acamprosate" refers to calcium N-acetylhomotaurinate. These two terms can be used interchangeably. "N-acetylhomotaurinate" and "acetylhomotaurinate" are also used interchangeably. "Acamprosate and related compounds": "Acamprosate and related compounds" refers to calcium acetylhomotaurinate, magnesium acetylhomotaurinate, other salts of N-acetylhomotaurinate, acetylhomotaurine base, salts of homotaurine base and homotaurine, derivatives of homotaurine or acetylhomotaurine having similar pharmacodynamic activity with respect to the transmission of glutamate type GABA-A and NMDA, and prodrugs that are metabolized in the blood, liver, or brain to produce acetylomotaurinate or derivative with similar pharmacodynamic activity with respect to the transmission of glutamate GABA-A and NMDA type. Acamprosate decreases the intracellular response of neurons stimulated by glutamate and the NMDA receptor, and increases GABA-A transmission, at least in part by an antagonistic effect on pre-synaptic GABA inhibitory autoreceptors. For ease of expression it refers to acamprosate and similar compounds as: "GABA agonists and NMDA antagonists", "GABA-A agonists and NMDA antagonists", "agents that increase the transmission of GABA and decrease the transmission of NMDA glutamate. "," GABA agonists and glutamate antagonists ", and" upstream regulators of GABA transmission and downstream regulators of NMDA-type glutamate transmission ". "Transmission of GABA-A": "Transmission of GABA-A" refers to the pharmacodynamic phenomenon associated with the activation of GABA-A receptors by GABA. Increased GABA-A transmission may involve increasing the release of GABA, decreasing its metabolism, increasing the receptor binding, or increasing the cellular effects of the receptor link.

"GABA-A receptor agonist": "GABA-A receptor agonist", as used herein refers to molecules that are capable of binding to active or modulatory sites on the GABA-A receptor to increase the transmission of GABA-A. (as defined above). "Effective": "Effective" as used herein with reference to the dosage of a medication, refers to the administration of a specific amount of a pharmacologically active agent made to the measure of each individual patient that manifests the symptoms of a disorder of the particular movement (eg, TD, other disorders of late movements, tic disorder, blepharospasm, and other focal dystonias) sufficient to cause a reduction or improvement in the patient's involuntary movements or any of the other symptoms associated with the disorder of the patient. movement, with tolerable adverse effects. The symptoms of movement disorder, as referred to herein, refers not only to involuntary movements, but also to any and all impairments of physical, instrumental, social and occupational functioning, which includes visual function, cognitive function , and the use of the hands, which are attributable to the involuntary movements, or to the brain dysfunction that supports them. Experimentally, doses of memantine in a range of 10 mg to 30 mg have been shown to be effective, as doses having dextromethorphan in a range of 30 mg four times a day to 60 mg four times a day. The doses of acamprosate in a range of 333 mg to 666 mg administered three or four times a day are effective. A person skilled in the art will recognize that the optimum dosage of the pharmaceutical agent to be administered will vary from one individual to another. Dosing in individual patients should take into account the height • of the patients, weight, absorption rate and metabolism of the drug in question, the stage of the disorder to be treated, and what other pharmacological agents are administered concurrently. "Disorder of movement": "Disorder of movement", as used herein, is used to refer to all forms of abnormal and involuntary movements. Movement disorders include, for example, tardive dyskinesia (TD), tics, Gilles de la Tourette syndrome (TS), Parkinson's disease, Huntington's disease, and focal dystonias such as blepharospasm. The disorders of the specific movement that are the subject of this application include, without limitation, TD, other late movement disorders. Blepharospasm and other focal dystonias, whether or not the latter are associated with exposure to neuroleptic drugs or other dopamine antagonists.

"Tic Disorder": "Tic Disorder" as used herein, refers to any abrupt repetitive movement, gesture, or expression that frequently mimics a fragment of intended behavior. Tics are characterized by stereotyped, repetitive, but irregularly rhythmic involuntary movements. They include motor tics and vocal tics (phonic). Tic disorder includes, for example, simple tics, multiple tics, and Gilles de la Tourette syndrome, defined as multiple tics with vocalizations. The present invention relates to the treatment of movement disorders and including, without limitation, TD, other disorders of late movement, tics, Tourettes, blepharospasm and other focal dystonias, whether or not the latter are associated with drug exposure. neuroleptics or other dopamine antagonists. These movement disorders probably involve some of the same physiological mechanisms and therefore will probably be sensitive to the same treatments. In one aspect of the present invention, it has been discovered that memantine, a drug used in the treatment of Parkinson's disease, although not contemplated for use in the treatment of tardive dyskinesia, late dystonia, or focal dystonia is or is not Related to neuroleptics or other drugs, it is effective in reducing involuntary movements, cognitive symptoms, and functional impairment associated with tardive dyskinesia. It has also been discovered that memantine is an effective treatment of tics and disorders related to tic. In another aspect of the present invention, it has been discovered that an agent used in the treatment of abstinent alcoholics, not contemplated for use in treatment of tardive dyskinesia or other movement disorders, which include Tourette's syndrome and tics, is effective for reduce hyperskinesia and dyskinesia of patients with movement disorders. Several years ago, it was hypothesized that TD represents a non-linear form of oscillation in neural circuits that involves the basal ganglia, and that oscillation can be reduced by agents that block excitatory neurotransmission. PET scintigraphy studies have demonstrated increased metabolism in the globus pallidus and the primary motor cortex in schizophrenic patients with TD, but not in those without TD, (Phal et al., < J. Neuropsych Clin Neurosci 7: 457, 1995 ). This suggests that TD is associated with hyperactivity in a motor control circuit, which may be part of the putative nonlinear oscillator. As previously observed, the hypothesis has been proposed that the agents that act to reduce the gain in a motor control circuit through the striatum, can have a beneficial action on the TD and the related movement disorders that include the disorders of late movement, focal dystonia, tics and Tourettes. For example, GABA is an inhibitory neurotransmitter in striatum. Thus the support for the hypothesis comes from the animal evidence that the agents that directly or indirectly stimulate the GABA receptors can decrease the neuroleptic-induced dyskinesias (Gao et al., J Neural Transmission 95:63, 1993; Stoessl, Pharmacol. Biochem. Behav., 54: 541, 1996). Rats with neuroleptic-induced dyskinesia demonstrate decreased levels in the glutamic acid decarboxylase striatum, the enzyme that limits the rate of GABA production (Delfs et al., Exp. Neurol., 133: 175, 1995). Without limiting the biochemical mechanism of the invention to that described herein, it appears that drugs that act to reduce the gain in the hypothesized oscillator circuit reduce the involuntary movements of tardive dyskinesia. GABA glutamate, and dopamine, are the main neurotransmitters in the circuit. Other neurotransmitters, which include norepinephrine, serotonin, acetylcholine, and endogenous opiates, hypothesized that they have indirect actions on the oscillator circuit. In co-pending patent application, Serial No. 08 / 861,801, and the teachings of which are incorporated herein by reference. reference, it is described that certain excitatory neurotransmitter antagonists (and agonists) are effective in treating movement and cognitive disorders associated with TD, late dystonia, tics, and movement disorders that share a similar biochemical mechanism. Acamprosy In the present invention, it is described that acamprosate, a GABA receptor agonist also decreases the post-synaptic response of NMDA-like receptors to glutamate can improve TD as well as related involuntary movements and cognitive symptoms. For example, in accordance with the theory of the present invention, a GABA agonist with concurrent effects on the transmission of glutamate reduces the severity of the involuntary movements associated with TD. Such a GABA agonist alleviates focal dystonias, for example blepharospasm associated with TD and by extension idiopathic blepharospasm which is likely to share a common mechanism, in light of the response of both to dopamine antagonists, to agonists of GABA and injections of butulinum toxin. To support this point, an expert in blepharospasm, Dr. Gary Borodic of the Harvard Medical School, states that neuroleptic-induced (delayed) blepharospasm is generally less sensitive to medications than the spontaneous type (Borodic, personal comunications, 1998). If this is the case, an effective treatment for late blepharospasm is especially likely to be useful for spontaneous blepharospasm. In the same way, treatment with acamprosate will probably improve symptoms associated with Meige syndrome, which is blepharospasm accompanied by dystonic movements of the neck and lower face. It is also described in the present application that acamposate dramatically decreases the dyskinetic movements associated with tic disorders including both simple and multiple tics. In addition, it is proposed that acamprosate and other agents that (i) decrease the neurotransmission of NMDA-type glutamate, and (ii) increase the neurotransmission of the GABA-A receptor are useful in the treatment of a * tic disorder of the common type and Severe, Tourette syndrome, which is characterized by multiple motor and phonic tics. Acamprosate (calcium N-acetylhomotaurinate) is the calcium salt of homotaurine, a derivative of the amino acid taurine. It is used clinically in the treatment of abstinent alcoholics to reduce or inhibit their craving for alcohol. Acamprosate, which is chemically similar to the inhibitory neurotransmitter GABA, is a GABA agonist, particularly in GABA receptors. In addition, it reduces the post-synaptic response of NMDA-like glutamate receptors and reduces calcium influxes through voltage-operated channels (Wilde &Wagstaff, Drugs, 53: 1039-53, 1997). Acamprosate is a particularly attractive drug for the treatment of chronic movement disorders, due to its very low toxicity. In controlled trials for the treatment of alcoholism involving 3,338 patients, acamprosate had no severe medical or neurological side effects. Certainly, the rate of separation of the subject was identical in the group receiving acamprosate treatment and the group receiving a placebo (Wilde &Wagstaff, Drugs, June, 53 (6): 1038-53, 1996). This is in complete contrast to the existing systemic treatments for TD and TS. For these, as noted above, intolerable side effects are common, and impose a major limitation to their clinical utility. The previous hypothesis regarding the motor control circuit involving GABA (by means of GABA-A receptors) and glutamate (by means of NMDA receptors) implies that any drug that is a GABA agonist and an NMDA-like glutamate antagonist can improve the dyskinesia movements. Acamprosate (N-acetyl-ohomotaurinate calcium) is a specific example of such a drug for which direct evidence is offered in humans of the efficiency in the treatment of dyskinesia.

Other examples of such drugs include other salts of N-acetylhomotaurine, derivatives of taurine and homotaurine with similar effects on the transmission of glutamate of the NMDA and GABA type and prodrugs that are metabolized in the liver, blood, or brain to produce N-acetylhomotaurinate or compounds related to similar pharmacodynamic properties. Accordingly, a preferred embodiment of the present invention provides an effective dose of homotaurine and N-acetylhomotaurine derivatives to a patient for the treatment of movement disorders. Particularly preferred are the acamprosate derivatives which are readily absorbed from the gastrointestinal tract. Acamprosate is regularly absorbed from the Gl tract, in part due to the hydrophilic polar character of the acetylhomotaurinate ion. It is well known in the art that certain drug derivatives can be absorbed better and more reliably because they are more lipophilic. For example, the prepared esters of the acetylhomotaurinate ion would be more lipophilic, and therefore could have greater and more predictable absorption through the membranes of the intestinal mucosa. If such an ester were toxic and naturally metabolized in the body for example, cleaved by enzymes in the blood, liver or brain, it would be particularly preferred as a vehicle to reliably deliver the acetylhomotaurinate ion to the brain. In addition, such derivatives as described above would have, in appropriate doses, equal or greater efficiency in the treatment of any acamprosate-sensitive movement disorder. Generally, any prodrug with improved delivery of acamprosate would be a preferred means of delivery in accordance with the present invention. Additionally, a particularly preferred form of acamprosate would be an acamprosate derivative with a prolonged half-life. Such acamprosate derivative would be clinically superior to acamprosate because it could be taken once daily, instead of three or four times a day, as necessary when acamprosate is used. An additional approach to prolong the half-life of acamprosate or a related medication is to provide it in a prolonged-release capsule. In other preferred embodiments, these derivatives are used to treat dyskinetic movement disorders associated with prolonged exposure to neuroleptic medications. Additionally, the above compositions can be used to treat tardive dyskinesia in abstainers abusing alcohol who are treated with neuroleptics for concurrent mental disorders, for example bipolar disorder or schizophrenia. More particularly, current treatments reduce the severity and duration of the various disorders related to movement. Another preferred embodiment of the present invention provides agents that act as GABA agonists and NMDA antagonists as a treatment for focal dystonias. An example of a focal dystonia, blepharospasm, is a target for treatment of the present invention. As mentioned earlier, blepharospasm is a condition that involves involuntary forced closure of the eye. How I know # mentioned above, the blepharospasm can be presented spontaneously (idiopathic blepharospasm) or it can be a form of late movement disorder. The eye movement disorder of idiopathic blepharospasm is clinically identical to that arising after neuroleptic exposure and therefore can be expected to respond to the same treatments that are effective for late movement disorders. In fact, both disorders are improved, at least in the short term, by neuroleptic drugs and other dopamine antagonists, and both are sensitive to injections of the muscles orbicularis oculi. with botulimun toxin (Casey, Neurology, July, 30: 690/5, 1980). The present invention demonstrates the relief of blepharospasm associated with tardive dyskinesia by acamprosate treatment, suggesting that acamprosate and compounds and derivatives related to combined action on NMDA and GABA type glutamate receptors will benefit people with idiopathic blepharospasm and all other focal dystonias, either spontaneous or induced by exposure to neuroleptic medications. In a preferred embodiment of this aspect of the invention, a pharmaceutical agent is selected from the group of agents that act as GABA receptor agonists and also act to decrease the function of the NMDA receptor by an indirect or modulatory mechanism such as, in a non-selective manner. limiting, acamprosate calcium (calcium N-acetylhomotaurinate), other salts of N-acetylhomotaurinate (for example magnesium N-acetylhomotaurinate or lithium N-acetylhomotaurinate), acetylhomotaurine base, other homotaurine derivatives, with similar pharmacodynamic actions on GABA and the transmission of glutamate and prodrugs that are metabolized in the liver, blood or brain to produce N-acetylhomotaurinate or compounds related to similar pharmacodynamic actions on GABA and the transmission of glutamate. In another preferred embodiment, a pharmaceutical agent is selected from the group of agents that have the ability to reduce excitatory post-synaptic potentials produced by glutamate in striatum cells including acamprosate and the range of similar compounds and prodrugs described previously). In, other preferred embodiments, a combination of two or more pharmaceutical agents are selected such that the combination acts concurrently to increase the transmission of GABA (particularly by means of GABA-A receptors) and to attenuate the transmission of NMDA-like glutamate ( for example by non-competitive inhibition and by modulatory or indirect effects on NMDA receptors). A fourth embodiment involves the combination of such compound or mixture of compounds with memantine or a similar non-competitive NMDA receptor blocking agent described in detail below. The combination may be mixtures, covalently bound portions with combined action, or prodrugs metabolized in the blood, liver or brain to release each member of the combination. Risk factors for TD include advanced age, diabetes, alcoholism and a primary psychiatric diagnosis of a mood disorder instead of schizophrenia. Each of these risk factors is associated with a high prevalence of magnesium deficiency (Durlach, et al., Magnes Res, March, 1998, G'amez et al., Sci. Total, Environ., September 15, 203 (3): 245-51 1997, Gullestad et al., J Am Coil Nutr , February, 13: 45-50, 1994, De Leeu et al, Magnes, Res., June, 10: 135-41, 1997, Lipski et al, Age Aging, July 22: 244-55, 1993, Martin et al. al., J. Trace, Elem. Electrolytes Healt Dis, September, 5: 203-11, 1991, Shane et al., Magnes, Trace Elem., 10: 263-8, 1991-1992, Zorbas et al. ., Biol. Trace, Elem. Res., July-August, 58: 103-16, 1997). Because people who adjust the profile of being at risk of developing TD have an increased risk of magnesium dyskinesia, I have hypothesized that magnesium deficiency (per se) is also a risk factor for tardive dyskinesia and other movement disorders. Therefore, it is further confirmed that magnesium supplementation can alleviate or prevent movement disorders and enhance the action of other treatments whether or not the individual treated shows tetany or other signs of magnesium deficiency. (See Report on Case 4, in which the treatment of a patient with tardive dyskinesia was improved by adding a magnesium supplement). The risk of developing a movement disorder can be assessed, in accordance with the present invention, by administering to a patient a sufficient and non-toxic dose of the magnesium ion (ie a "magnesium load") subsequently measuring the amount of the magnesium excreted in the patient's urine. More specifically, the risk of developing a movement disorder caused by dopamine or neuroleptic receptor blocker can be assessed by standard tests of total magnesium status. If magnesium deficiency is present, there is a higher than normal retention of the magnesium load, and decreased excretion of magnesium in the urine. If an abnormally low proportion of magnesium is recovered in a 24-hour sample in the patient's urine, the patient is magnesium deficient and at risk of developing a movement disorder. The present invention demonstrates that magnesium supplementation can reduce the symptoms associated with a simple tic and increases the action of acamprosate in the treatment of a single tic (See Report on Case 5). In addition, magnesium administered along with acamprosate reduces the symptoms associated with simple tic better than magnesium or acamprosate alone. Together, Cases 4 and 5 suggest that magnesium ion supplementation can be used to successfully treat other types of movement disorders. In preferred embodiments of the present invention, magnesium is used for the treatment of movement disorders (eg TD, Tourette's Syndrome, and focal dystonias particularly blepharospasm). In addition, magnesium supplementation can be used to develop a movement disorder followed in a preferred embodiment, movement disorders can be prevented by magnesium supplementation. In another modality, magnesium supplementation may delay the onset of a movement disorder in a person identified as being at risk of developing a movement disorder. In yet another modality, magnesium supplementation will reduce the symptoms associated with the various movement disorders. According to the present invention, magnesium supplementation will increase the therapeutic effects of other NMDA receptor antagonists and downstream regulators (See Report on Case 5). In a preferred embodiment, magnesium is administered with acamprosate (calcium N-acetylhomotaurinate, to treat TD and other movement disorders resulting from the use of neuroleptic drugs, tics, Tourette's syndrome, blepharospasm, other focal dystonias, and peak dose of Parkinson's disease dyskinesia In a particularly preferred embodiment the magnesium salt of N-acetylhomotaurine and the magnesium salts of those N-acetylhomotaurine derivatives that similarly improve GABA transmission and decrease NMDA glutamate neurotransmission are Effective treatments for movement disorders It will be recognized by those skilled in the art that all the conditions for which N-acetylomotaurine is an effective treatment, the magnesium salt of N-acetylhomotaurine, and the magnesium salts of those N derivatives. -acetylhomotaurine that have similar effects on GABA neurotransmission and neurotransmission d and NMDA glutamate will also be effective treatments. Alternatively, any magnesium salt can be administered with any salt of those N-acetylhomotaurine derivatives to treat hyperkinetic and dyskinetic movement disorders. In a non-limiting example, a pill containing the appropriate dose of acamprosate together with the appropriate dose of magnesium can be formulated and administered to a patient with a movement disorder. In other preferred embodiments, an agent having NMDA antagonist activity and GABA agonist activity is combined with the appropriate dose of magnesium in a pill. In yet another preferred embodiment, an NMDA antagonist with a GABA agonist and an appropriate dose of magnesium in the form of a pill. One of ordinary experts in the art will recognize that the composition of the administration is not limited to a pill, it can also be a syrup, an elixir, a liquid, a tablet, a prolonged-release capsule, an aerosol or a transdermal patch. . The acamprosate to magnesium ratio can be varied to optimize the therapeutic synergy of the two ingredients. Magnesium N-acetylhomotaurinate (Durlach, supra1980), with a magnesium: acetylhomotaurinate ratio of approximately 1:20 by weight, does not optimize the therapeutic effects of the two components. In typical therapeutic doses of acetylhomotaurinate, the amount of magnesium is too low to have therapeutically relevant effects on glutamate transmission. In the experience, excellent therapeutic results have been obtained from the combination of 2 grams of daily dose of acamprosate with one gram of elemental magnesium, given as a salt or chelate. This combination gives better relief of TD and tics than the 2 degrees of acamprosate alone. I have also shown (See Report on Case 5 below) that a single dose of 300 mg of magnesium will increase the therapeutic effect of a single dose of 666 mg of acamprosate. Allowing variations in the individual response and variations in the intestinal absorption of acamprosate and magnesium, it was confirmed that the optimal ratio of mg: acetylhomotaurinate for an individual patient will be somewhere between 1: 6 and 1: 1. It is unlikely that lower magnesium to acamprosate ratios will significantly increase the therapeutic effect of acamprosate, and higher ratios of 1: 1 are likely to produce magnesium toxicity (or at least Gl intolerance) at a typical daily dose of acamprosate. grams. Although magnesium N-acetylhomotaurinate may be slightly more efficient than calcium N-acetylhomotaurinate for the treatment of tic disorders, in the present application the magnesium content of acamprosate in the related compounds is effectively increased by administering the magnesium ion (as a salt or chelate) in combination with a salt of N-acetylhomotaurinate, because there is a significant benefit to administer a higher ratio of magnesium to acamprosate than that which is present in the magnesium salt of acamprosate. The effects of acamprosate are carried out within hours after the administration of acamprosate. This observation is critically important to the hypothesized mechanism of acamprosate action in the treatment of movement disorders. In 1997, Lidsky et al., (US Patent Number 5,602,150) described the use of taurine and taurine derivatives, including acamprosate, for the prevention of tardive dyskinesia in people taking neuroleptic drugs. In a rodent model the neuroleptic animals were given with or without taurine. For several months, animals that received taurine were less likely to develop empty chewing movements (VCM), a movement disorder with similarity to TD in humans. The mechanism proposed to explain the effect was a long-term neuroprotective action of taurine, in which taurine blocks the long-term effect of glutamatergic overstimulation of striatum neurons. One of ordinary skill in the art would not expect that an agent with neuroprotective activity against glutamate-induced excitotoxicity necessarily be effective in the treatment of severe established cases of movement disorder, and produce benefit within hours of administration. Currently, there are well-known situations in neurology where an effective preventive agent can actually aggravate an established case of the condition to be prevented. For example, antiparkinson drugs dopamine agonists may delay the onset of dyskinesia in patients treated with levodopa for Parkinson's disease. However, dopamine agonists can aggravate dyskinetic movements once they have been established. Magnesium ions also act as neuroprotective agents, particularly in models of neuronal damage mediated by NMDA-like glutamate receptors (Erna et al., Alcohol, February, 15; 95-103, 1998; Greensmith et al., Neuroscience, October, 68 : 807-12, 1995; Heat et al., J. Neurotrauma, March, 15: 183-9, 1998; Hoane et al., Brain, Res. Bull., 45: 45-51, 1998; Muir et al. , Magnes, Res., March, 11: 43-56, 1998; Vanick'y et al., Brain, Res., April, 798: 347-50, 1998). However, the virtually immediate benefit of magnesium in the treatment of established movement disorders can not be based on neuroprotection. Rather, the immediate and direct effects of magnesium on neural transmission, which include glutamatergic transmission, must be involved. In this connection, note that the magnesium dosages used for neuroprotection in humans are usually well above 1 gram per day which was the highest dose used here in the treatment of movement disorders. Certainly, magnesium, administered at doses well below those used when magnesium is a single agent, can increase the beneficial effects of other treatments, as described herein. Another aspect of the invention forms a method that uses agents that act as antagonists and NMDA agonists to improve memory and cognition in humans with TD. A particularly preferred embodiment of the present invention is to develop methods for improving cognitive function in patients who have TD, specifically to increase memory, concentration span, and daily functional performance in activities that are particularly dependent on cognition. These improvements to the function are measured subjectively and objectively. Memory improvement can be demonstrated by standard neuropsychological tests. The improvement in cognition is shown by the performance in neuropsychological tests that include, without limitation, the King Verbal-Auditory Learning Test, and the measurement of the Reaction Time of Selection, and by subjective indicators of performance of tasks highly dependent on cognitive processes. . It will be obvious to the person skilled in the art that numerous different neuropsychological tests could be used to demonstrate improved cognitive function in patients in a treatment regimen including acamprosate or any of the other agents described above, including without limitation: Other salts of derivatives of acetylhomotaurine of homotaurine and acetylhomotaurine with similar pharmacodynamic effects on NMDA glutamate and GABA neurotransmission, prodrugs that are metabolized in the blood, liver, or brain to produce acetylomotaurinate or derivatives with similar pharmacodynamic effects on NMDA glutamate and GABA neurotransmission, and mixtures of the two or more compounds having, taken together, NMDA glutamate antagonist effects and GABA agonist. All of these entities may have neuroprotective actions against excitotoxic damage induced by glutamate, but their beneficial effects, virtually immediate, on movement disorders and cognition, which are reversible if the medication is discontinued, can not be due to such neuroprotective actions. Another preferred embodiment of the present invention is the development of methods to improve tics and, as a consequence, reduce the stigma and improve the quality of life of patients with tic or tic disorders such as TS. In yet another embodiment of this aspect and the present invention is the development of methods to improve blepharospasm, and the impairment of visual function involved by involuntary, convulsive and frequent eye closure. A final embodiment of this aspect of the invention provides methods for treating all focal dystonias, either spontaneous or precipitated by exposure to neuroleptic drugs and other dopamine receptor blockers. One of ordinary skill in the art will recognize that the present invention is not limited to a method of treating TD and other tic disorders with agents that reduce the neurotransmission of glutamate NMDA and increase GABA neurotransmission by means of direct effects on GABA receptors and NMDA. In addition to direct effects on receptor sites, agents can modify the transmission of glutamate NMDA and GABA through indirect effects on receptors (ie, by means of pre-synaptic effects on neurotransmitter release, allosteric modulation of the receptor site or effect on the intracellular response to the binding of the transmitter to the receptor), presynaptic effects on the release of transmitter, or any of a variety of mechanisms. It will be obvious to the person skilled in the art that a range of all derivatives and prodrugs should be therapeutically effective. Anything that shares the effects on glutamate in hypothesized GABA transmission to support the therapeutic effects of acamprosate is within the scope of the claimed invention. No matter how a drug, prodrug or mixture thereof decreases NMDA glutamate neurotransmission and increases GABA neurotransmission, it only improves the symptoms associated with TD and the tics at tolerable nontoxic doses (ie unaffected side effects free from toxicity) . As discussed previously, the current inventive treatment can be used to treat any movement disorder characterized by any form of abnormal or involuntary movement. In addition, the inventive treatment can be used to ameliorate or eliminate non-movement related symptoms that are consequences of movement disorder, for example, cognitive dysfunction or motivational abnormalities, mood, or impulse control. The latter includes anxiety, depression, apathy, aggression, and obsessive-compulsive behavior. The basal ganglia, which include the striatum, are a point of intersection of motor, cognitive and emotional circuits. Basal ganglia diseases frequently involve cognitive, emotional, motivational behavior changes as well as motor dysfunction. It is expected that effective drug treatments for TD, tics, and other movement disorders may alleviate some or all of the non-motor symptoms. In general, treatments for basal ganglia diseases have non-motor effects. For example, antiparkinson drugs dopamine agonists not only slow the movement of patients with Parkinson's diseaseIt also improves the speed of mental processing. When the addition of magnesium increases the effect of a drug treatment on the motor manifestations of a movement disorder it can also increase the effect of that treatment on non-motor manifestations. In another aspect of the present invention, it is described that memantine, an NMDA-like glutamate receptor antagonist, which also acts as a dopamine agonist, can improve TD as well as related involuntary movements and cognitive symptoms. In particular, it has been shown in two patients that memantine can improve blepharospasm associated with a more extensive late-onset movement disorder. As discussed above, according to the theory of the present invention, NMDA receptor antagonists reduce the severity of the involuntary movements associated with TD. Such NMDA receptor antagonists will probably alleviate focal dystonias and idiopathic focal dystonias, whether or not they are accompanied by other symptoms of TD and whether or not they are related to neuroleptic exposure or other dopamine receptor antagonists, based on the hypothesis that the common response to various v.

Therapies involve a common physiology. For example, NMDA receptor antagonists will relieve symptoms of blepharospasm associated with TD and by extension of drug-induced blepharospasm without TD, and idiopathic blepharospasm, which are likely to share a common mechanism, in light of their response to dopamine antagonists, GABA agonists and to botulinum toxin injections. In the same way, treatment with memantine will likely improve symptoms associated with Meige syndrome, which is blepharospasm accompanied by dystonic movements of the neck and lower face. One of the two patients described above (Report on Case 1) with TD not only had blepharospasm, but also dystonic movements of the face and neck, allowing the diagnosis of late Meige syndrome. As with blef rospasmo only Meige syndrome not associated with neuroleptics can be expected to respond at least also as memantine in late Meige syndrome. The previous hypothesis regarding the motor control circuit involving glutamate (via NMDA receptors) suggests that any drug that is an NMDA-like glutamate antagonist with a relative lack of toxicity at effective doses may improve blepharospasm, Meige syndrome, and disorders of late movement. Memantine is a specific example of such a drug for which direct evidence of efficiency in humans is offered (See Report on Cases 1 and 6). As noted above, single GABA-A agonists are not particularly potent therapies of tics. Therefore, NMDA antagonism is probably a necessary part of the therapeutic effect of acamprosate. In addition, NMDA antagonism itself is sufficient in the treatment of tardive dyskinesia and late dystonia, suggesting that with respect to late movement disorders, the NMDA antagonist activity of memantine is more important than its agonism. of dopamine. The evidence described here suggests that movement disorders, such as tics and Tourettes will respond in a manner similar to late movement disorders, to drug therapies that have NMDA antagonist activity. The hypothesis of a common response to various therapies involves a common physiological mechanism with reference to tic and Tourettes is supported by the fact that: 1) acamprosate relieves tardive dyskinesia, late dystonia and tics; and 2) memantine relieves tardive dyskinesia and delayed dystonia; and 3) acamprosate and memantine are NMDA receptor antagonists. Thus, it is logical to expect that memantine will also be useful in the treatment of tics, v. which includes Tourettes. Indeed, it is described in the present application that memantine dramatically decreases the dyskinetic movements associated with tic disorders that include simple and multiple tics. In addition, it is proposed that memantine and other agents (and congeners and derivatives thereof) with similar pharmacokinetic action, that both (i) decrease the neurotransmission of NMDA-like glutamate and (ii) increase the neurotransmission of the dopamine receptor they are useful in the treatment of a tic disorder of the common and severe type, Tourette's syndrome, which is characterized by multiple motor and phonic tics. The Report on Case 5 demonstrates that a patient with a simple tic experience a significant reduction in the frequency of tic with the administration of memantine. Other examples of drugs with similar effects on NMDA-like glutamate transmission include extramethorphan, memantine and dextromethorphan derivatives, and prodrugs that are metabolized in the liver, blood, or brain to produce biologically active compounds with similar pharmacodynamic properties. Dextromotorphan, like memantine and amantadine, is an NMDA receptor antagonist. In a preferred embodiment of the present invention, dextromethorphan (and congeners and derivatives thereof), is administered to patients for the treatment of movement disorders. There have been no reports of the use of i. dextromethorphan in the treatment of tardive dyskinesia, • dystonia or other movement disorders. A preferred embodiment of the present invention provides memantine and dextromethorphan derivatives at effective doses to a patient for the treatment of movement disorders. Additionally, the particularly preferred zones of memantine and dextromethorphan would be derived with long duration action, for example obtained through • of the longest elimination half-lives. Such derivatives of memantine or dextromethorphan would be clinically superior to memantine or dextromethorphan, because it could be taken once daily, instead of two to four times per day, as is necessary when using memantine or dextromethorphan. An additional proposal to the lengthening of The duration of the action of memantine, dextromethorphan or related medications is to deliver them in a prolonged-release capsule. In other preferred embodiments, these memantine and dextromethorphan derivatives are used to treat disorders of dyskinesia and dystonia associated with prolonged exposure to neuroleptic medications. Additionally, the compositions described above can be used to treat tardive dyskinesia in patients who continue to be treated with neuroleptics for mental disorders chronic or persistent, for example bipolar disorder or schizophrenia. More particularly, the memantine and related compounds reduce the severity and duration of various related movement disorders. Another embodiment of the present invention provides memantine, dextromethorphan derivatives and congeners thereof as a treatment for focal dystonias. An example of a focal blepharospasm dystonia is an objective for treatment in the present invention. The present invention demonstrates blepharospasm relief associated with tardive dyskinesia by treatment with memantine, suggesting that this and related compounds and derivatives with similar action on NMDA-like glutamate will benefit people with idiopathic overuse and all other spontaneous focal dystonias. or induced by exposure neuroleptic medications. In a preferred embodiment of this aspect of the invention, a pharmaceutical agent is selected from the group d agents that acts to decrease the function of the NMDA receptor either as non-competitive antagonists, blocking the ion channel, or modulators of the function of the receptor. of NMDA. These include, in a non-limiting form memantine, dextromethorphan and dextrofan, a dextromethorphan derivative with known NMDA antagonism and acceptable toxicity for administration in humans. One of ordinary skill in the art will recognize that the above embodiments include congeners and derivatives of memantine, dextromethorphan and dextrofan with similar pharmacodynamic actions on the transmission of glutamate, and prodrugs that are metabolized in the liver, blood or brain to form compounds related to pharmacodynamic actions similar on the transmission of glutamate. In yet another preferred embodiment, a pharmaceutical agent is selected from the group of agents that have the ability to reduce excitatory post-synaptic potentials produced by glutamate in striatum cells, (which includes memantine, dextromethorphan, and the range of similar compounds and prodrugs described. previously) . In other preferred embodiments, a combination of two or more pharmaceutical agents is selected such that the combination acts concurrently to attenuate the transmission of NMDA-like glutamate (eg, by noncompetitive inhibition, by indirect or modulatory effects on NMDA receptors). or by a combination or sequence of actions). A fifth embodiment involves the combination of such compounds or mixtures of compounds with a similar non-competitive NMDA receptor blocking agent described in detail below. The combinations can be either mixtures, covalently linked portions with combined action or prodrugs metabolized in the blood, liver or brain to release each member of the combination. As mentioned above, the risk factors for developing TD include magnesium deficiency. Thus, it has been hypothesized that magnesium deficiency is also a risk factor for other movement disorders and that magnesium supplementation can alleviate or prevent movement disorders alone or in combination with other therapies. The Report on Case 2 showed that the administration of magnesium in combination with acamprosate and memantine increases the therapeutic action of memantine and acamposate in the treatment of TD. The Report on Case 5 showed that the administration of magnesium in combination with memantine alone increases the therapeutic action of memantine alone for the treatment of simple tic. Thus, it is proposed that magnesium will increase treatment when used in combination with memantine or dextromethorphan alone for the treatment of tics and Tourettes as it does when used in combination with acamprosate, given the common physiological actions of these compounds. Additional support for this hypothesis is the fact that tics and Tourette, like late movement disorders, are temporarily suppressed by neuroleptics. Magnesium supplementation may be beneficial whether or not the treated individual shows clinical signs of magnesium deficiencies, (See Report on Cases 2 and 4 and Copending Patent Application Serial No. 09 / 193,892, filed on November 18. of 1992 entitled "Methods of Treating Tardive Dyskinesia and Other Movement Disorder", for full details, These cases demonstrated that patients whose tardive dyskinesia, which improved with the administration of NMDA receptor antagonists, improved further with the addition of magnesium) . In preferred embodiments of the present invention, magnesium is used to increase the efficiency of memantine, dextromethorphan, or other agents with similar effects on NMDA glutamate neurotransmission, in the treatment of movement disorders (eg, tardive dyskinesia, late dystonia). and idiopathic focal dystonias, particularly blepharospasm). According to the present invention magnesium supplementation will increase the therapeutic effects of other NMDA receptor antagonists and down regulators. In a preferred embodiment, magnesium is administered with memantine to treat TD and other movement disorders resulting from the use of neuroleptic drugs, as well as various focal dystonias. Also in accordance with the preferred embodiments of the present invention, magnesium is administered with memantine to treat tics, Tourettes and other disorders related to tics. In another modality, magnesium is administered with dextromethorphan and memantine to treat TD, tics, Tourettes and other movement disorders resulting from the use of neuroleptic drugs, as well as diverse focal dystonias. In a final modality, magnesium is administered with both memantine and dextromethorphan for the treatment of movement disorders. It will be recognized by those skilled in the art that all conditions for which memantine and dextromethorphan are effective treatments, derivatives and congeners of memantine and dextromethorphan that have similar effects on NMDA glutamate neurotransmission will also be effective treatments. In a non-limiting example, a pill containing the appropriate dose of memantine together with the appropriate dose of magnesium can be formulated and administered to a patient with a movement disorder. Alternatively, a pill containing the appropriate dose of dextromethorphan together with the appropriate dose of magnesium can be formulated and administered to a patient with a movement disorder. One can also combine the appropriate dose of memantine, dextromethorphan and magnesium in a simple pill for administration to a patient for the treatment of a movement disorder. In another preferred embodiment, an agent having NMDA antagonist activity is combined with the appropriate dose of magnesium in a pill. In other preferred embodiments, an NMDA antagonist is combined with a dopamine agonist and an appropriate dose of magnesium in the form of a pill. One of ordinary skill in the art will recognize that the composition of the administration is not limited to a pill, although it may also be a syrup, an elixir, a liquid, a tablet, a prolonged-release capsule, an aerosol or a transdermal patch. The ratio of memantine and / or dextromethorphan to magnesium can be varied to optimize the therapeutic synergy of the two ingredients. Typically a combination of 5-10 mg of memantine and 250-300 mg of magnesium is administered three times a day to a patient with a movement disorder. This dose of magnesium is below the pharmacological doses used for neuroprotection or treatment of eclampsia. The recommended administration regimen for dextromethorphan is four times per day at a dose of 30-60 mg with 250-300 mg of magnesium for the treatment of movement disorders. One skilled in the ordinary art can experiment with different variations in the individual response and intestinal absorption to find the optional ratio of memantine or dextromethorphan to magnesium. The skilled artisan will also recognize that optimal doses may vary if magnesium is administered with dextromethorphan and memantine simultaneously. (Because magnesium is excreted by the kidney, the magnesium dose would be much lower in patients with kidney failure, in addition to their movement disorder). Memantine, dextromethorphan and magnesium have all been proposed as neuroprotective agents, particularly in models of neuronal damage mediated by NMDA-like glutamate receptors (Representative quotes for memantine: (Wenk GL, et al., Behav Brain Res, 83: 129-33 , 1997 February; Kornhuber J. et al .: J Neural Transm Suppl, 43: 91-104, 1994; Weller M et al .: Eur J Pharmacol, 248: 303-12, 1993 December 1; Krieglstein J et al. Neuropharmacology, 35: 1737-42, 1996). Representative quotes for dextromethorphan: (Duhaime AC, et al., J Neurotrauma, 13: 79-84, 1996 February, Steinber GK et al., Neurol Res, 15: 174-80, 1993 June; Britton P et al .: Life Sci, 60: 1729-40, 1997). Representative quotes for magnesium: Erna et al., Alcohol, February, 15; 95-103, 1998; Greensmith et al., Neuroscience, October, 68: 807-12, 1995; Heath et al., J. Neurotrauma, March, 15: 183-9, 1998; Hoane et al., Brain. Res. Bull. , 45: 45-51, 1998; Muir et al., Magnes. Res. , March, 11: 43-56, 1998; Vanicky et al., Brain. Res. , April, 789: 347-50, 1998). However, as previously mentioned for acamprosate, the immediate, short-term benefits of memantine, dextromethorphan and magnesium for disorders v. of late movement can not be due to their neuroprotective actions, since the excitotoxic neuronal damage due to neuroleptics is thought to occur gradually from months to years while the therapeutic action of the treatments proposed here is virtually immediate. One of ordinary skill in the art will recognize that the present invention is not limited to treatment with drugs that directly block NMDA-like glutamate receptors. It will be obvious to the person skilled in the art that a whole range of derivatives and prodrugs will be therapeutically effective. If a drug decreases the transmission of glutamate NMDA by a mechanism other than that which is effected directly on the recipient, or if the active substance is a metabolite of a prodrug that is administered, it lies within the scope of the invention currently claimed as it improves symptoms associated with TD, late dystonia and other dystonias that include blepharospasm, in acceptably non-toxic doses (ie dose without severe side effects). The present invention will now be illustrated by the following non-limiting examples. Report on Case 1 A 45-year-old woman who had TD for a long time, originally induced by 7 years of exposure to amoxapine, an antidepressant drug with neuroleptic effects. The patient's irregularly rhythmic movements consisted of forced eye blinking (blepharospasm), tongue thrust forward and side to side, tongue twisting, gestures, shrugging shoulders, tension of the platysma muscles of the neck. (If the patient's symptoms had not been associated with exposure to neuroleptics, a subset of their movements could be characterized as Meige syndrome of oromandibular dystonia with blepharospasm). The patient is a semi-professional musician; dyskinetic movements were accompanied by significant occupational disability, including difficulty reading music or text and difficulty in playing wooden wind instruments. Much of his reading impairment was due to frequent involuntary blinking and closing of the eye. He had impaired attention, concentration, and memory compared to how it worked before the start of TD. He had significant fatigue, and usually required rest at some point during each day. The patient with TD was diagnosed by a widely certified neurologist with extensive experience in the evaluation of side effects induced by neuroleptics. The patient's dystonia and dyskinesia worsened after the amoxapine was discontinued. Another palliative treatment was prescribed with alprazolam (an anxiolytic v and GABA agonist by modulation, in doses of 0.25 mg four times a day) and trihexyphenidyl (an anticholinergic antiparkinson drug that inhibits the reuptake of dopamine in the synapse; 2 mg dose twice a day). This combination produced a minimal improvement. The patient began treatment in the winter of 1992 and was maintained on trihexyphenidyl for an additional 18 months. Trihexyphenidyl was then discontinued without any change in its involuntary movements. During 1993, alprazolam was increased to 0.5 mg four times a day, to treat mild symptoms of anxiety; the change in dose did not have a detectable effect on the involuntary movements of the patient. The treatment trials with buspirone, sertraline, verapamil, and vitamin E in 1992 produced little benefit or were not tolerated in doses that only slightly reduced their involuntary movements. None of these drugs significantly improved the patient's daily function, that is, their functioning when reading text or music, their istamine or their ability to concentrate. The first drug that provided significant and sustained benefits was nimodipine, a calcium channel blocker type L, which indirectly reduces dopaminergic activity (Bonci et al.; J. Neurosci. , September 1, 18 (17): 6693-703 1998) In early 1993, nimodipine was administered at a dose of 30 mg four times a day. Initially, his other medications remained unchanged. This regimen reduced "involuntary movements of the patient by approximately 50%." Unfortunately, the patient experienced adverse effects, including dizziness, lightheadedness, and palpitations, and there was no symptomatic improvement in cognitive function.There was a significant improvement in his ability to Reading and playing music, however, even with this improvement, he could read text or music for no more than 30 minutes at a time, before fatigue or blepharospasm prevented him from continuing.In 1995, memantine attracted attention as a relatively non-toxic NMDA receptor antagonist In view of the hypothesis about the pathophysiology of tardive dyskinesia, it was thought that memantine could be beneficial in its treatment, nimodipine was discontinued, and the patient started with memantine at a dose of 10 mg twice daily The involuntary movements of the patient's TD were reduced within 24 hours of the administration of the memantine, to a degree substantially greater than that observed with minodipine. Adverse effects included a sense of mild intoxication. Adjustments were made to the therapeutic regimen so that the drug was reduced to 5 mg three times a day, with the result that the therapeutic benefits were maintained without noticeable side effects. In addition, the patient reported improved energy, attention, and concentration. Memantine was the patient's primary treatment for TD for the next 1 1/2 years, until acamprosate was discovered as an indirect NMDA antogist with the added benefit of GABA agonism. Before treatment with acamprosate, the patient's involuntary movements (in an optimal dose of memantine) consisted of blinking of the eye, puckering of the cheeks, twisting of the tongue and tension of the platysma. These involuntary movements were usually light and occasionally moderate in intensity. The movements had been substantially more severe in the past, but had been significantly reduced during the course of the two-year treatment. In addition, the patient's movements are accompanied by a slight but definite cognitive impairment. The patient's most prominent cognitive symptom was the difficulty in sustaining concentration enough to read more than a few pages of the text. The patient withdrew memantine and was treated with acamprosate at a dose of 333 mg four times a day. With acamprosate, the involuntary movements of the patient (forced blinking of the eye (blepharospasm), tongue thrust forward and side to side, tongue twisting, gestures, shrug and tension of the platysma muscles of the neck) became imperceptible. In addition, the cognitive function of the patient was significantly improved when measured subjectively and objectively. With acamprosate, the patient was able to sustain the concentration for prolonged periods. For example, he could now read a book for an hour at that time, with a good memory of what he had read. The cognitive improvement of the patient was also assessed using formal neuropsychological measurements. The patient was tested on the drug, after the drug was withdrawn and tested two days later. With the drug, the patient was able to recall 13 of the 15 items after a short period of time as well as 13 of the 15 items after a long period of time, as measured by the King Auditory Verbal Learning Test. This was compared with the patient's ability, while without the drug, to remember only 7 of the 15 articles after a short period of time as well as 8 of the articles after a long period of time in the tests performed. further, the patient was able to recognize the 15 articles despite acamprosate although he was without the drug (and while having been without memantine for two months) the patient could only recognize 10 of the articles. The order of the test would give advantage of familiarity to the condition without the drug. However, the difference in favor of the drug condition was substantial. The comparison with other neuropsychological tests showed that the improved cognitive discoveries showed that while the patient was with acamprosate they were not clarified by a non-specific lack of effort or concentration during the drug-free condition. These additional tests, which reflect basic attention and psychomotor speed, showed that the patient currently had slightly better results without acamprosate. Tests that show such results included the Simple Reaction Time, the Evidence Making Signs (both parts) and the Addition Test in the Auditory Series in March (PASAT). The selection reaction time, a test that requires basic attention and concentration on a specific task that should be remembered, was slightly better with acamprosate, consistent with the hypothesis that the general cognitive function, as opposed to simple attention, improves with the treatment of Acamprosate The following tables report the results on neuropsychological tests (drug 1 is memantine and drug 11 is acamprosate): TABLE 1: REACTION TIME, PSYCHOMOTOR SPEED, AND FUNCTIONING FOR DRUG I (MEMANTIN) AND DRUG II (ACAMPROSATE) Note: »lower marker indicative of better performance b upper marker indicative of better performance TABLE 2: TASKS EMPLOYED, ATTENTION, VISOCONSTRUCTION AND VISUAL MEMORY FOR DRUG I (MEMANTIN) AND DRUG II (ACAMPROSATE) Note: a lower marker indicative of better performance b upper marker indicative of better performance TABLE 3: MEMORY TEST FOR DRUG I (MEMANTIN) DRUG II (ACAMPROSATE) Note: «inferior marker indicative of better functioning superior bmarker indicative of better functioning In addition to increasing cognitive ability, the patient also experienced an increase in vigor when taking acamprosate. Before the start of the acamprosate regimen the patient became fatigued at the end of the afternoon, requiring rest to be alert at night. This fatigue decreased significantly while in the acamprosate regimen, with a corresponding improvement in cognitive function related to fatigue. With acamprosate, the patient does not need to rest more during the day to be alert and active during the night. To verify that the acamprosate was related to the improvement of the patient, to control movement disorders, cognitive function and vigor, the acamprosate regimen (as well as the memantine regimen) was withdrawn from the patient for a period of four weeks. . During the initial two-week period without acamprosate the patient's involuntary movements gradually returned to their pre-acamprosate base line, with no memantine baseline. (Since the baseline without the patient's drug was less severe than when it started with memantine two years earlier, its movements were still severe enough to significantly interfere with its daily functioning). From that point on, until the acamprosate was reinstituted, he showed continuous medium to moderate gestures, tension of the platysma, and forced closure of the eye. These involuntary movements worsened even more during periods of tension or fatigue. In addition, the patient became fatigued much more easily, to a degree that markedly reduced his daily functioning. Subjectively, the patient reported that concentration and memory decreased. Within two days of the reinstitution of the acamprosate treatment, the patient reported that his energy, vigor, concentration and memory had improved to the level experienced during the previous treatment with aco prosanto. Two months after the restitution of acamprosate, the involuntary movements of the patient were absent except for very light movements during times of stress. In July 1998, this patient participated in a magnesium supplementation test as an adjunct to his treatment with acamprosate. During a baseline period of seven days in Campral Cacamprosato 333 mg four times a day plus 0.25 mg alprazolam four times a day, he observed six involuntary movements involving the face and neck, 2 moderate and 4 light. During the next 10 days, he added 250 mg three times a day of chelated magnesium. During the period of magnesium supplementation, he did not notice any involuntary movements. On a separate occasion, the patient was treated again with memantine. Subjectively, the patient reported that his daily function had improved to a greater degree during treatment with memantine than that experienced during treatment with mimodipine. He was able to read or play his instrument for longer periods with less need for rest during the day. Objectively, its cognitive functioning, which includes the attention span, the lapse of concentration and memory improved as indicated by the neuropsychological test. Discontinuation of memantine resulted in obviously increased dyskinesia within 24 hours, to the point where movements interfered with reading and musical activities, and they caused subjective tension to the patient. After restarting memantine, the involuntary movements were reduced to their level with the previous treatment within 24 hours. The patient's excellent response to memantine supported the hypothesis that NMDA receptor blockers might be useful in tardive dyskinesia. To support this hypothesis, the patient was treated with dextromethorphan, an NMDA receptor blocker that is thought to act at a different site on the NMDA receptor than was observed with memantine. In addition, dextromethorphan is not a dopamine agonist such as memantine or amantadine. Memantine was discontinued and the patient was started on dextromethorphan, 30 mg four times a day. Within 24 hours, the patient's involuntary dyskinetic movements were reduced to the levels seen while the patient was on memantine. However, the patient felt sedated, and felt that his attention span was shorter and his concentration worsened than that experienced with memantine. The administration of dextromethorphan was continued for a week and the reduction of involuntary movements continued during this period. The increase in dyskinesia was seen shortly after the discontinuation of dextromethorphan administration. Again, memantine was administered, with the result that the dyskinetic movements were reduced to the same extent as during the previous administration of memantine. Summary: This example demonstrates that effective treatments for TD include memantine and acamprosate. Both treatments improve cognition and function as well as involuntary movements. In addition, memantine and acamprosate relieve blepharospasm and Meige syndrome associated with more extensive late-onset disorders. Finally, the oral administration of magnesium, given together with acamprosate in a ratio of 1: 1.8 by weight, increases the therapeutic effect of acamprosate on the involuntary movements of TD. Case Report 2 A 79-year-old woman who has had TD for a long time after decades of treatment with the neuroleptic drug ferfenazine. Their involuntary movements included bilateral chorea of the upper extremities, as well as twisting of the tongue and biting of the tongue. The last movements led to a very painful tongue. In addition, the patient experienced deterioration of his short-term memory, which was attributed mainly to zero-vascular disease. After treatment with memantine the patient's voluntary movements improved, but continued at a medium to moderate level. She also continued to have a sore tongue. His congestive symptoms did not improve. In addition to memantine, the patient regularly took anti-epileptic drugs (gabapentin and lamotrigine), antiplatelet agents (aspirin and ticlopidine), as well as medications for hypertension, glaucoma and gastrointestinal symptoms (isosorbide mononitrate, metoprolol, timolol, eye drops and olsalazine). These various drugs did not affect the patient's involuntary movements or cognitive symptoms; there was no noticeable change in either of them at the time each of the aforementioned drugs was instituted. v.

The patient was placed on a treatment regimen that included the administration of 666 mg of acamprosate, three times a day. In this case, acamprosate was added to the patient's regimen, which continued to include memantine. Once the patient started taking acamprosate, his chorea and tongue bite stopped completely, and the writhing movements of the tongue decreased substantially. Subjectively, the patient's memory improved to the extent that his longtime bridge partner declared that the patient was remarkably better at remembering cards during the bridge game in pairs. Despite past evidence of formal evidence that the patient had impaired short-term memory, he usually performed on a two-sentence memory task, which involves testing the patient's recall ability using two sentences containing 13 separate details. In the two-sentence memory task, within three attempts, the patient was able to recall 9 details and, using a multiple-choice format, was able to recall a total of 11 details. The memory of 9 details on the third attempt would be normal for a middle-aged adult, and even less so in his 80s at the time of the test. After a full year with emantine and acamprosate, memantine was discontinued, with little change in the patient's symptoms. With acamprosate 666 mg three times a day, persistent symptoms included lighthearted movement in the hands, light involuntary movements of the tongue and jaw, and pain of the tongue disproportionate to visible involuntary movements. 250 mg of magnesium oxide was added three times a day, each dose being taken together with acamprosate. The movements and pain of the tongue improved further. The effect was defined: the movements worsened when the magnesium oxide stopped and improved when it was restarted.

After one month with magnesium, the acamprosate dose was increased to 666 mg four times a day, with 250 mg of magnesium oxide given along with each dose. With this regimen, the movements of the tongue and the pain of the tongue were completely eliminated. The only residual sign of TD was a slight degree of involuntary hand movement.

Summary: Magnesium and acamprosate are effective treatments for tardive dyskinesia when given alone. More specifically, the Case Report 2 demonstrated that acamprosate can improve the involuntary movements associated with TD as well as the associated cognitive deterioration, in a patient whose memantine improves involuntary movements but not cognition. In addition magnesium, when administered with acamprosate can increase the efficiency of acamprosate in the treatment of TD. In this case, the acamprosate and magnesium combination was effective in a magnesium: acamprosate ratio of 1: 2.66. It is logical to infer that treatment with memantine and magnesium would be better than treatment with memantine alone. Case Report 3 A 56-year-old nursing professor had Parkinson's disease from her late 30s. The Parkinson's disease of the patient was treated using levodopa / carbidopa and bromocriptine. The patient's profession requires a high level of mobility and physical exertion, but taking a sufficient dosage of levodopa / carbidopa to allow adequate physical functioning in the outcome of work in the patient demonstrating severe dyskinesia at peak doses. The patient's manifestations of peak dose dyskinesia consisted of upper trunk torsional movements, rotational and lateral jerking movements of the neck, and chorea of both upper extremities. The patient accepted these involuntary movements because lower doses of levodopa-carbidopa left her too rigid or hypokinetic to do her job. Before starting acamprosate treatment, the patient was on a regimen of antiparkinson treatment consisting of 1 mg of pergolide three times a day, 5 mg of selegiline twice daily, and a combination of levodopa / carbidopa consisting of 550-600 mg of levodopa and 125-150 mg of carbidopa administered in divided doses. Concurrent medications that did not appear to affect Parkinsonism or dyskinesia consisted of betanecol, sertraline, carbamazepine, conjugated estrogens, and medroxyprogesterone. (As with the additional medications mentioned in Case 2, there was no discernible change in the patient's dyskinesia or Parkinsonism after the introduction of each of the listed drugs). The patient also received 10 mg of memantine three times a day, which had previously reduced his dyskinesic movements from severe to medium to moderate. The patient started acamprosate as an addition to the antiparkinson regimen described above. Initially, the patient received 666 mg of acamprosate administered three times a day. Two weeks later the regimen was adjusted in such a way that the patient received 333 mg of acamprosate four times a day, taking a 333 mg pill with each daily dose of 100 mg of levodopa and 25 mg of carbidopa. The patient's dose of controlled-release levodopa-carbodopa (200 mg of levodopa and 50 mg of carbidopa) was continued at bedtime but was given without acamprosate. As soon as acamprosate was added to his regimen, the patient's severe peak dose dyskinesia was reduced from moderate to light intensity, and there were periods of up to two hours of each dose during which there was no dyskinesia completely. There was no decrease in the efficiency of the levodopa-carbidopa treatment of its hypokinesia and rigidity. With acamprosate, the patient experienced longer periods of good motor function, and had no more periods at all where his motor function was inadequate for work or social activity. The reduction of the dyskinesia to a minimum level led to a substantial improvement in the intentional motor function of the upper extremities. To confirm that the patient's improvement was due to the administration of acamprosate, acamprosate was withdrawn from the patient. In the course of a day of acamprosate suspension, the patient's dyskinetic movements were as severe as they had been before acamprosate was first given. With the reinstitution of acamprosate, the patient experienced an immediate reduction in his dyskinetic movements. During the acamprosate-free period, an attempt was made to replace acamprosate with blacofen (a GABA receptor agonist) at a total daily dose of 30 mg, and then with baclofen at a daily dose of 60 mg. These doses of blacofen were high enough to produce sedation and nausea, but did not have a beneficial effect on the patient's dyskinesia. Subsequently, an additional improvement in the dyskinesia obtained was obtained by replacing the pergolide with 1 mg of pramipexole administered three or four times a day. Several months later, magnesium (300 mg of elemental magnesium, as a mixed chelate) was added to the regimen. It was taken three times a day, along with one of the regular doses of the levodopa / carbidopa patient. There was an immediate reduction in the severity of dyskinesia. To establish if the improvement was due to magnesium, the magnesium stopped after several weeks. Within two days, the dyskinesia was definitely worse. Summary: The Case Report 3 shows that memantine and acamprosate can improve dyskinesia at peak doses of Parkinson's disease treated. The efficiency of memantine and acamprosate in the treatment of peak dose dyskinesia of Parkinson's disease can be further increased by the co-administration of magnesium in a ratio of 1: 1.48 by weight with acamprosate. Case Report 4 A 37-year-old man had extremely severe tardive dyskinesia and dystonia, as a result of 15 years of treatment of bipolar disorder with lithium and an assortment of neuroleptics. Their involuntary movements consisted of forced extension of the trunk, torsion of the lower legs, plantar flexion of the left foot, chorea of both arms, twisting of the tongue and gesticulation. In addition, he had profuse sweating associated with involuntary movements. To sit motionless in a chair, I had to forcefully grab both arms. In the chair, the forced extension of the trunk practically lifted him out of the chair. His movements of trunk and legs led to a deteriorated balance with a wobbly step and often about to fall. Continuous severe movements were associated with deterioration in concentration which made his work less efficient. By virtue of talent and intelligence, however, he was able to work competitively with a software engineer. Because his bipolar disorder remained an active problem, it was necessary to continue the neuroleptic treatment to maintain his mental health. It was maintained with 300 mg of lithium carbonate three times a day, and 4 mg of respiridone per day. His movement disorder had been treated with benzodiazepines, anticholinergics and dopamine agonists, all without any significant benefit. He was then treated with acamprosate, first at a dose of 333 mg three times a day, and then at a dose of 666 mg three times a day. The acamprosate therapy was then increased with magnesium sulfate, 300 mg three times a day. After several weeks, 10 mg of memantine was added three times a day, but the memantine was discontinued after a few days because it aggravated its movement disorder. At one point during his treatment, the patient was left without acamprosate, and was without him for three days in a row. After 24 hours without acamprosate, his movement disorder returned to his baseline (severe). 72 hours after resuming acamprosate, he regained his previous level of benefit. The patient maintained a weekly symptom log, which is reproduced in the present as Table 4. Table 4 shows that: 1) Acamprosate therapy was associated with the improvement of all its symptoms. For several of its symptoms - trunk movement, balance, and sweating 666 mg of acamprosate three times a day were more efficient than 333 mg three times a day. 2) The addition of magnesium was associated with the additional improvement of various symptoms, that is, movements of the face and tongue, neck and extremities; 3) The benefits of acamprosate increased with continued therapy; 4) Mental function, indicated by subjective memory, improved along with involuntary movements; 5) The addition of memantine aggravated the involuntary movements. The patient's self-ratings say less than the degree of improvement noted by three physicians (two neurologists and one psychiatrist) who examined the patients before and after the acamprosate and magnesium treatment. Before treatment, he was unable to sit in a chair without grabbing his arms, wriggling and rocking wildly. After the treatment, I was able to cross a room with a cup of coffee and not spill anything. - TABLE 4: ATTACHMENT OF THE PATIENT OF THE EFFECTS OF THE TREATMENT DE DT - CASE 4 Diet 1. 333 mg of acamprosate three times a day 2. 666 mg of acamprosate three times a day 3. 666 mg of acamprosate three times a day + 300 mg of magnesium sulfate three times a day 4. 666 mg of acamprosate three times a day + 10 mg of memantine three times a day Symptoms Severity of face and tongue movements (10 is the worst) Severity of trunk movements (10 is the worst) Difficulty in maintaining balance (10 is worse) Sweating (10 is the worst) General well-being (10 is the best) Side effects (10 is none) * The only significant side effect was nausea and vomiting, which the patient experienced during the first day after starting acamprosate, the first day after increasing the dose of acamprosate, and the first day after adding memantine. Summary: Acamprosate is effective in the treatment of severe tardive dyskinesia and dystonia. The administration of magnesium with acamprosate increases the therapeutic action of acamprosate in the treatment of severe TD and late dystonia.

In the reported case, a good effect was obtained in a mangnesium: acamprosate ratio of 1: 2.22. Memantine, although frequently effective in the treatment of tardive dyskinesia, can actually aggravate it in certain individuals, such as the one described in Case 4. Treatment with acamprosate, with or without magnesium, can help alleviate a movement disorder that is aggravate by memantine. Additionally, this case report demonstrates that acamprosate, administered with or without magnesium, can relieve involuntary movements and other symptoms in patients with late-onset disorders who continue to receive neuroleptics for their mental disorder. Finally, Case 4 illustrates the point at which a treatment that prevents the development of involuntary movements in an animal model of TD (ie, memantine, see Andreassen et al., Supra) may not be of any benefit in the treatment of humans with TD established. Case Report 5 A 46-year-old man had a simple neck tic that involved compulsive extension and turning the neck to the right. The tic had begun in the context of depression therapy with dextroamphetamine and pramipexole, a dopamine agonist drug. The tic was presented 20-50 times per hour, with a higher frequency when he was tired or under tension.

It was initially treated with 666 mg of acamprosate three times a day. Within 24 hours after the start of acamprosate therapy, the frequency and severity of the tic decreased dramatically, at a rate of less than 5 per hour. The patient was frequently completely free of tics for two or three hours after each acamprosate dose, after which the tic returned very gradually. The dose was then increased to 666 mg four times a day. With this dose, speeds of more than 5 per hour were presented only under initially stressful circumstances, and there were frequent tick-free periods of 4 hours or more. If acamprosate was omitted for a full day, the frequency of tics increased rapidly, to 10 for one hour. On the second day without acamprosate, the tick rate was again 20 for one hour. Chelated magnesium was then added at a dose of 300 mg of elemental magnesium 3 times a day. With magnesium supplementation, the average frequency of tics fell to 6 per hour or less. When 666 mg of acamprosate was given three times a day along with 300 mg of magnesium three times a day, the usual tic-free period after each acamprosate dose increased from about 3 hours to about 5 hours. The acamprosate treatment was subsequently replaced with memantine, 10 mg twice daily, with two doses of supplemental magnesium (300 mg). The amemantine with magnesium resulted in a tic free interval of 6-7 hours. Then, 10 mg of memantine was administered twice a day for two doses without supplemental magnesium. Administration of memantine without magnesium produced a tick-free period of only 4-5 hours beginning approximately 30 minutes after each dose. Summary: Acamprosate is effective in the treatment of a simple tic. The efficiency of acamprosate is increased by the concurrent administration of magnesium. In this case, a good effect was obtained in a magnesium: acamprosate ratio of 1: 2.22. By extension, acamprosate should be effective in the treatment of multiple tics and Gilles de la Tourette syndrome. In addition, this study demonstrates that memantine is an effective treatment for tics and the efficiency of memantine is increased by the concurrent administration of magnesium in a manner similar to that of acamprosate. Case Report 6 A therapist from the United Kingdom recently reported on the treatment of a 47-year-old woman with chronic schizophrenia and severe tardive dyskinesia. As in Case 1, the involuntary movements of the patient included severe blepharospasm. In addition, he had involuntary rhythmic movements and movements, and chorea-like movements of both hands, as in the patient in Case 2. He had no cognitive complaints, nor were cognitive abnormalities observed in the routine psychiatric analysis. The patient had developed symptoms of paranoid schizophrenia in 1991, at the age of 40 years. Symptoms of psychosis included auditory hallucinations, bizarre delusions, and persecutory fears. He started with oral haloperidol as an outpatient in July 1992 and had an acute dystonic reaction to the drug. Subsequently he was hospitalized and stabilized with flupenthixol decanoate, a deposit of neuroleptic given by intramuscular injections. The symptoms of TD were developed in November 1994 after 28 months of neuroleptic therapy. The patient's change to an atypical neuroleptic, olanzapine or risperidone, did not eliminate his TD. At the beginning of October 1997 the patient was treated for his schizophrenia with 2 mg risperidone alone. At this modest dose of an atypical neuroleptic, he had severe symptoms of TD for which I seek treatment anxiously. Memantine was started on November 28, 1997 at a dose of 5 mg per day, increased after 7 days to 5 mg twice a day, and after another 7 days until mg three times a day. After the first two weeks of memantine treatment (one with 6 mg twice a day) there was marked improvement in blepharospasm, although the movements started to return just before the second dose of the day was fulfilled. Two weeks later, with 5 mg three times a day, the improvement was sustained more, with no apparent involuntary movement noted at the peak of a given dose of memantine, and only slight movements were noted when a dose was to be met. Additional increments of dose were attempted to completely abolish involuntary movements. The maximum dose obtainable without side effects was 10 mg twice daily; Above that level the patient had complaints of dizziness. That dose of memantine was maintained during May 1997. At that point, after 6 months of treatment with memantine, the patient had no blepharospasm or chorea of extremities, and only slight peri-oral movements. In May 1998, the patient started acamprosate, seeking the complete elimination of his involuntary movements. Initially, 333 mg of acamprosate was added three times a day to 10 mg of memantine twice a day. With the addition of acamprosate, the peri-oral movements were eliminated, and the patient was essentially free of involuntary movements. Memantine was discontinued in August 1998; the patient continued free of involuntary movements only with acamprosate.

Summary: Memantine and acamprosate can alleviate the involuntary movements of TD in patients with chronic schizophrenia who continue to require neuroleptic therapy. Both drugs can relieve blepharospasm induced by severe neuroleptics. Acamprosate can alleviate involuntary TD movements that do not respond to memantine at doses tolerated by the patient. The response of drug-induced blepharospasm to these two agents suggests that memantine and acamprosate will be useful in the treatment of idiopathic (spontaneous) blepharospasm. By extension, they can be expected to be useful in the treatment of other focal dystonias. Discussion: All the patients discussed in the presented cases exhibited a marked decrease in the frequency and severity of dyskinetic movements in response to acamprosate or memantine treatment. Relief symptoms began within 48 hours of treatment administration, and, if a patient discontinues treatment, symptoms return immediately. This evidence supports the novel hypothesis that pharmacological agents such as acamprosate, memantine, and dextromethorphan, or derivatives with similar pharmacodynamic actions, will be useful in the treatment of late-onset disorders, including TD, late dystonia, tic disorders (including Tourette), and focal dystonia. In particular, Reports from Cases 1 and 6 demonstrate that memantine can relieve blepharospasm and Meige syndrome associated with more extensive late-onset disorders. By extension, it is predicted that memantine (with or without magnesium) and related agents will also be successful treatments for the idiopathic blepharospasm of Meige syndrome, as well as other focal dystonias such as spasmodic torticollis, scribal cramps, and other occupational dystonia. In addition, evidence has been presented elsewhere (see co-pending application Serial No. 09 / 193,892, filed on November 18, 1998, entitled "Methods of Treating Tardive Dyskinesia and Other Movement Disorders") that magnesium, an NMDA glutamate neurotransmitter antagonist by means of Ion channel blockade may increase the therapeutic action of other JsTMDA receptor antagonists in movement disorders including tics, tardive dyskinesia, and tardive dystonia. One can infer from this work, and it is demonstrated in the present, that magnesium will increase the therapeutic effect of acamprosate, memantine and dextromethorphan for tics and late movement disorders, as well as for spontaneous movement disorders that closely mimic late movement disorders, including without limiting blepharospasm and Meige syndrome, as well as other focal dystonias such as spasmodic torticollis , writer's cramp and other occupational dystonias. It was proved that the administration of elemental magnesium would improve the efficiency of acamprosate in the treatment of simple tics. In Case 5, it is shown that the supplementation of memantine or acamprosate with magnesium salts relieves tics better than memantine or acamprosate alone. Therefore, magnesium can be combined with any other agents that increase the transmission of GABA and / or decrease the transmission of NMDA glutamate to further suppress simple tics. The salts or chelates of acetylhomotaurinate calcium and magnesium are safe medications when given in an appropriate dose. Because magnesium acetyl homotaurinate produces the same magnesium ions and homotaurinate ions when dissociated in the Gl tract as does the mixture of acamprosate and magnesium salts. It is inferred that magnesium acetylomotaurinate will also be a safe medication. Therefore, magnesium N-acetylhomotaurinate would be a safe and effective drug, with a potentially greater efficiency for movement disorders than acamprosate (calcium), due to the blocking action of the NMDA receptor of the magnesium ion. However, as noted above, it does not have the ideal molar ratio of magnesium to N-acetylhomotaurinate for the maximum therapeutic effect. Therefore, a magnesium salt or chelate combined with an N-acetylhomotaurine salt or a derivative is likely to be more effective as a treatment for movement disorder. The combination of magnesium ion with acamprosate and related compounds is likely to alleviate the symptoms of various hyperkinetic, dyskinetic and dystonic movement disorders, for example multiple tics, Tourette's syndrome, tardive dyskinesia and blepharospasm, and other focal dystonias. After starting treatment with acamprosate, those patients who previously exhibited cognitive disorders showed a functionally significant improvement in cognitive function (See Cases 1, 2 and 4). This evidence supports the novel hypothesis that acamprosate, or a derivative with similar pharmacodynamic actions, will be useful in the treatment of hyperkinetic movement disorders, including dyskinesias and dystonias, and the cognitive impairment associated with them. Acamprosate and similar drugs have simultaneous actions on GABA neurotransmission and NMDA-like glutamate neurotransmission that can be synergistic with respect to the therapy of hyperkinetic, dyskinetic and dystonic movement disorders. To the extent that other related compounds and mixtures of compounds have similar simultaneous effects on GABA and glutamate neurotransmission, these related compounds may have the same or similar action on movement disorders and their associated cognitive impairments. Related compounds include, but are not limited to, other salts of N-acetylhomotaurinate (e.g., magnesium N-acetylhomotaurinate), acetylhomotaurinate base, homotaurine, derivatives of these compounds, and prodrugs metabolized in the liver, blood, or brain to produce acetylhomotaurinate or analogs with similar pharmacodynamic effects in GABA and in NMDA-like glutamate neurotransmission. Additionally, any derivatives or pro-drugs that are readily absorbed after oral administration, or that have a long half-life are particularly desirable. Acamprosate also has benefits for treating other hyperkinetic or dyskinetic movement disorders other than TD. Case 3 shows that it is useful for relieving dyskinesia at peak doses of Parkinson's disease treated with levodopa. Case 1 shows that acamprosate can be used successfully to treat blepharospasm (a focal dystonia) and Meige syndrome when these are associated with TD, and suggests that it can be used successfully to treat idiopathic blepharospasm and Meige syndrome. Case 4 suggests that acamprosate is efficient for treating simple tic and, by extension, multiple tics and Gilles de la Tourette syndrome. By extension, acamprosate will probably benefit patients with movement disorders not induced by neuroleptics, which show an identical clinical symptomatology with those neuroleptic-induced (late) movement disorders. In particular, as mentioned above, it may be effective in treating any of the focal dystonias, and in the treatment of the involuntary movements of Huntington's disease. Patients with Huntington's disease also have a deficiency of GAD in striatum, and are thought to suffer from neuronal death due to NMDA-receptor-mediated excitotoxicity (DE Riley and AE Lang: Movemen t Disorders, in WG Bradley et al., editors, Neurology in Clinical Practice, Boston: Butterworth-Heinemann, 1991, p.1568). These characteristics of the disorder favor a positive response to acamprosate, a drug with co-actions on the NMDA and GABA receptors. Therefore, one can predict that patients will be alleviated, at least in part, by acamprosate, memantine and dextromethorphan, alone or in combination with magnesium. As mentioned above, one aspect of the method of the characteristics of the invention is improved in the cognitive disorder associated with TD. The improvement in daily cognitive and functional functioning seen during TD treatment makes acamprosate particularly attractive for patients with cognitive impairment that frequently accompanies TD. The relationship between tardive dyskinesia and cognitive impairment is not completely understood. It is known that pre-existing cognitive impairment increases the risk of developing TD in the event that a patient receives neuroleptics during a long-term period. It is also known that schizophrenics treated with TD are more likely to show deficient cognitive impairment than those without TD. However, it is not known if TD treatment will improve the cognitive deficits associated with TD. Cases 1, 2 and 4 discussed above suggest that at least some TD treatments can improve such cognitive deficits. The prior art does not report that the administration of acamprosate, when used as a treatment for alcoholism, improves the patients' cognition, it is inferred that the improvement in cognition seen in Cases 1, 2 and 4 is related to the improvement in his movement disorders. This is consistent with the well-established involvement of basal ganglia in cognitive processes (Sano et al., Basal Ganglia Diseases, in Fogel et al., (Eds.), Neuropsychiatry, Williams and Wilkins, 1996).

However, the fact that acamprosate is known as an agent used in the treatment of alcoholism makes acamprosate particularly suitable for the treatment of patients who have a history of alcoholism in addition to a hyperkinetic movement disorder. A group of such patients with schizophrenia and alcoholism (called "double diagnosis" patients), who have TD, for which alcoholism is a risk factor. Based on the foregoing, the following is claimed:

Claims (159)

1. CLAIMS 1. A method for treating hyperkinesis characterized in that it comprises: administering an effective dose of an agent which is a GABA receptor agonist and which decreases the response of NMDA-like glutamate receptors.
2. 2. The method of compliance with the claim 1, characterized in that the agent is selected from the group consisting of acamprosate, calcium N-acetylhomotaurinate, salts of N-acetylhomotaurinate, acetylhomotaurinate base, homotaurine and derivatives thereof.
3. 3. The method of compliance with the claim 2, characterized in that the method for treating hyperkinesia also improves cognition or memory in humans who exhibit signs of tardive dyskinesia when the response is determined using a standard neuropsychological test.
4. 4. The method of compliance with the claim 3, characterized in that the standard neuropsychological test is selected from the group consisting of established clinical tests, established bedside tests of cognition or memory, and observation of the performance history of daily activities that are highly dependent on cognitive processes.
5. 5. The method according to claim 1, characterized in that the administration step comprises oral administration.
6. 6. A method for treating a hyperkinetic movement disorder characterized in that it comprises the steps of: selecting at least a first pharmacologically active agent that acts as a GABA receptor agonist and at least a second pharmacologically active agent that acts as an antagonist of the receptor NMDA type glutamate; and administer the first and second agents.
7. 7. The method of compliance with the claim 6, characterized in that it additionally comprises the steps of: selecting a first dose of the first agent; selecting a second dose of the second agent in such a way that the administration of the first and second doses improves the movement disorder at non-toxic doses.
8. 8. The methods according to claims 6 and 7, characterized in that the first agent and the second agent are the same agent.
9. 9. The method of compliance with the claim 6, characterized in that the movement disorder is tardive dyskinesia or comprises involuntary movements similar to those seen in tardive dyskinesia.
10. 10. The method according to claim 6, characterized in that the movement disorder is peak dose dyskinesia associated with Parkinson's disease or comprises involuntary movements similar to those seen in peak dose dyskinesia.
11. 11. The method according to claim 6, characterized in that the movement disorder is associated with Huntington's disease.
12. The method according to claim 6, characterized in that the method further improves the cognitive response in humans that exhibit movement disorder when the response is measured using standard neuropsychological tests.
13. 13. The method according to claim 12, characterized in that the standard neuropsychological test comprises established chemical tests, established bedside tests, of cognition and memory, and observation of a registry of defined changes in the functioning of daily activities highly dependent on the cognitive processes.
14. 14. The method according to claim 6, characterized in that the movement disorder is related to a GABA deficiency in the basal ganglia.
15. 15. The method according to claim 6, characterized in that the movement disorder is related to the NMDA-based excitotoxicity.
16. The method according to claim 6, characterized in that it comprises the additional steps of: selecting a third pharmacologically active agent that is a non-competitive antagonist at the NMDA receptors; and administer the third agent together with the first and second agents.
17. 17. The method according to claim 16, characterized in that the third agent is memantine or a derivative thereof.
18. 18. A method for treating movement disorders characterized in that it comprises: administering an effective dose of an agent that increases GABA-A neurotransmission and decreases the neurotransmission of NMDA glutamate to a patient with a movement disorder.
19. 19. The method according to claim 18, characterized in that the movement disorder is selected from the group consisting of simple tics, multiple tics, Tourette's syndrome, focal dystonias, blepharospasms, and Meige's syndrome.
20. The method according to claim 18, characterized in that the agent is selected from the group consisting of acamprosate (calcium N-acetylhomotaurinate), magnesium N-acetylhomotaurinate, lithium N-acetylhomotaurinate, salts of N-acetylhomotaurinate, acetylhomotaurinate base and derivatives thereof that share the pharmacodynamic effects of acamprosate on the transmission of glutamate and GABA-A improving GABA-A transmission and reducing the transmission of NMDA-like glutamate.
21. 21. The method according to the claim 18, characterized in that the agent is available in the blood.
22. 22. The method according to claim 18, characterized in that the agent is available in the brain.
23. 23. The method according to claim 18, characterized in that the agent is a prodrug metabolized in the body to release the acetylhomotaurinate ion within the body.
24. 24. The method of compliance with the claim 23, characterized in that the agent released within the body is selected from the group consisting of any derivative of homotaurinate or acetylhomotaurinate with similar pharmacodynamic effects on GABA and the neurotransmission of glutamate as acetylhomotaurinate.
25. 25. The method according to claim 23, characterized in that the pro-drug is metabolized in the liver, blood or brain.
26. 26. The method according to claim 23, characterized in that the pro-drug comprises an ester of acetylhomotaurinate or a derivative of homotaurine or acetylhomotaurine with similar pharmacodynamic effects on GABA or the transmission of glutamate.
27. 27. The method according to claim 18, characterized in that the agent comprises a derivative of calcium acetylhomotauxinate, homotaurine or acetylhomotaurine with similar pharmacodynamic effects on GABA or the transmission of glutamate.
28. 28. The method according to claim 27, characterized in that the derivatives have a longer half-life than acamprosate.
29. 29. The method according to claim 27, characterized in that the derivatives are better absorbed from the gastrointestinal tract.
30. 30. The method of compliance with the claim 27, characterized in that the derivatives are more reliably absorbed from the gastrointestinal tract.
31. 31. The method according to claim 18, characterized in that the treatment of movement disorders reduces the cognitive symptoms of movement disorder when the symptoms are determined by subjective functioning, examination of the mental status, or through the use of neuropsychological tests.
32. 32. The method according to claim 18, characterized in that the administration step comprises oral administration.
33. 33. The method according to claim 18, characterized in that the movement disorder is related to a GABA deficiency in the basal ganglia.
34. 34. The method of compliance with the claim 18, characterized in that the movement disorder is related to glutamate-based excitotoxicity.
35. 35. A method for treating movement disorders characterized in that it comprises the steps of: selecting a first pharmacologically active agent that acts as a GABA-A receptor agonist and selecting a second pharmacologically active agent that acts as an antagonist of the glutamate receptor type NMDA; and administering the first and second agents to a patient with a movement disorder.
36. 36. The method according to claim i 35, characterized in that the movement disorder is selected from the group consisting of simple tics, multiple tics, Tourette's syndrome, focal dystonias, blepharospasms, and Meige's syndrome.
37. 37. The method according to the claim 36, characterized because blepharospasm is idiopathic blepharospasm.
38. 38. The method according to claim 36, characterized in that the blepharospasm is associated with a movement disorder induced by neuroleptics.
39. 39. The method according to claim 35, characterized in that the administration step comprises the selection of doses of the first and second agents in such a way that the administration of the first and second doses reduce the symptoms of movement disorder to non-toxic.
40. 40. The methods according to claim 35, characterized in that the step of selecting, the first agent and the second agent are the same agent.
41. 41. The method according to claim 35, characterized in that the movement disorder comprises involuntary movements similar to those seen in Tourette's syndrome, focal dystonias, blepharospasm and tics.
42. 42. The method according to claim 35, characterized in that the movement disorder is associated with Huntington's disease.
43. 43. The method according to the claim 35, characterized in that the treatment of Tourette's syndrome, focal dystonias, blepharospasm or tics reduces the cognitive symptoms associated with the movement disorder when the symptoms are terminated by subjective report, by examination of the mental status, or through the use of neuropsychological tests standard.
44. 44. The method according to claim 35, characterized in that the movement disorder is related to a GABA deficiency in the basal ganglia.
45. 45. The method according to the claim 35, characterized in that the movement disorder is related to glutamate-based excitotoxicity.
46. 46. The method according to claim 35, characterized in that the selection step further comprises the selection of a third pharmacologically active agent that is an NMDA receptor antagonist or an ion channel blocker in the channels linked to the NMDA receptors. .
47. 47. The method according to claim 35, characterized in that the administration step further comprises administering the third agent together with the first and second agents.
48. 48. The method according to claim 47, characterized in that the third agent is memantine.
49. 49. The method of compliance with the claim 47, characterized in that the third agent is a derivative of memantine with pharmacodynamic effects similar to NMDA receptors:
50. 50. The method according to claim 47, characterized in that the third agent is magnesium.
51. 51. A method for assessing the risk of developing a movement disorder caused by dopamine receptor blocker or neuroleptic characterized in that it comprises: performing standard tests on the status of total body magnesium.
52. 52. The method according to claim 51, characterized in that it comprises measuring the retention of magnesium after a load of oral or parenteral magnesium.
53. 53. The method of compliance with the claim 51, characterized in that the administration step comprises selecting a dose of magnesium which is sufficient to assess magnesium retention and is non-toxic.
54. 54. A method for preventing movement disorders induced by dopamine receptor blocker or neuroleptic characterized in that it comprises: reducing the risk of movement disorders by administering to a patient at risk of developing a movement disorder, an effective dose of the magnesium ion.
55. 55. The method of compliance with the claim 54, characterized in that it additionally comprises: delaying the onset of movement disorder induced by the dopamine receptor blocker or neuroleptic by administering to a patient at risk of developing a movement disorder, an effective dose of the magnesium ion.
56. 56. A method for treating movement disorders characterized in that it comprises: reducing the symptoms of the movement disorder by administering to a patient at risk of developing a movement disorder, an effective dose of the magnesium ion.
57. 57. The method according to claim 56, characterized in that it additionally comprises: increasing the therapeutic effects of NMDA receptor antagonists and down regulators in patients with movement disorders by administering to the patient an effective dose of the magnesium ion.
58. 58. The method according to claim 56, characterized in that the movement disorder is selected from the group consisting of de_tics, multiple tics, Tourette's syndrome, focal dystonias, blepharospasms, and Meige's syndrome.
59. 59. The method according to claim 56, characterized in that it additionally comprises: administering to a patient with a movement disorder an effective dose of N-acetylhomotaurine of magnesium sufficient to decrease the symptoms of the movement disorder.
60. 60. The method according to claim 56, characterized in that the magnesium N-acetylhomotaurine administered is a magnesium salt of any N-acetylhomotaurine derivative which shares its property of improving the GABA-A neurotransmission and attenuating the neurotransmission of glutamate of NMDA.
61. 61. The method of compliance with the claim 59, characterized in that the administration step comprises administering the magnesium salt of any N-acetylhomotaurine derivative which is an effective treatment.
62. 62. A method for treating a movement disorder characterized in that it comprises: administering to a patient in combination, a simple pill at an effective dose, (i) an NMDA receptor antagonist (ii) an agonist of GABA-A (iii) ion of magnesium.
63. 63. The method according to claim 62, characterized in that the NMDA receptor antagonist and the GABA-A agonist is the same agent.
64. 64. The method according to claim 62, characterized in that the magnesium ion is in the form of a magnesium salt.
65. 65. The method of compliance with the claim 62, characterized in that the NMDA antagonist and the GABA-A agonist is selected from the group consisting of acamprosate (calcium N-acetylhomotaurinate), magnesium N-acetylhomotaurinate, salts of N-acetylhomotaurinate, acetylhomotaurinate base homotaurine and derivatives of the same with similar pharmacodynamic effects on GABA and glutamate neurotransmission.
66. 66. The method of compliance with the claim 65, characterized in that the derivative is available in the blood.
67. 67. The method according to claim 65, characterized in that the derivative is available in the brain.
68. 68. The method according to claim 65, characterized in that the derivative is a prodrug metabolized in the liver, blood, or brain to release the acetylhomotaurinate ion.
69. 69. The method of compliance with the claim 65, characterized in that the derivative is a prodrug metabolized in the liver, blood or brain to release any ion derived from the acetylhomotaurinate ion with similar pharmacodynamic effects on GABA and glutamate neurotransmission.
70. 70. The method according to claim 65, characterized in that the pro-drug comprises an acetylhomotaurinate ester, or any derivative of acetylhomotaurine or homotaurine with similar pharmacodynamic effects on GABA and neurotransmission of glutamate.
71. 71. The method according to claim 62, characterized in that the derivative has a longer half-life than acamprosate.
72. 72. The method according to claim 62, characterized in that the derivative is absorbed from the gastrointestinal tract better than acamprosate.
73. 73. The method according to claim 62, characterized in that the derivatives are better absorbed from the gastrointestinal tract.
74. 74. The method of compliance with the claim 62, characterized in that the pill is used to treat Tourette's syndrome.
75. 75. The method according to claim 62, characterized in that the pill is used to treat multiple tics.
76. 76. The method according to claim 62, characterized in that the pill is used to treat simple tics.
77. 77. The method according to claim 62, characterized in that the pill is used to treat blepharospasm or Meige syndrome.
78. 78. The method according to claim 62, characterized in that the pill is used to treat focal dystonias.
79. 79. The method according to claim 62, characterized in that an effective dose of (i) an NMDA receptor antagonist (ii) an agonist of GABA-A (iii) magnesium ion is supplied in the form of a delivery agent that it comprises a syrup, an elixir, a liquid, a tablet, a prolonged-release capsule, an aerosol or a transdermal patch.
80. 80. A pill for treating movement disorders characterized in that it comprises: (i) one or more agents that increase the neurotransmission of GABA-A one or more agents that decrease the neurotransmission of glutamate NMDA; and the magnesium ion.
81. 81. The pill in accordance with the claim 80, characterized in that the NMDA receptor antagonist and the GABA-A agonist is the same agent.
82. 82. The pill according to claim 80, characterized in that the magnesium ion is in the form of a magnesium salt.
83. 83. The pill in accordance with the claim 80, characterized in that the NMDA antagonist and the GABA-A agonist is selected from the group consisting of acamprosate (N-acetylhomotaurinate calcium), magnesium N-acetylhomotaurinate, salts of N-acetylhomotaurinate, acetylhomotaurinate base, homotaurine and derivatives thereof with similar pharmacodynamic effects on GABA and neurotransmission of glutamate.
84. 84. The method according to claim 83, characterized in that the derivative is available in the blood.
85. 85. The method according to claim 83, characterized in that the derivative is available in the brain.
86. 86. The method of compliance with the claim 83, characterized in that the derivative is a prodrug metabolized in the liver, blood, or brain to release the acetylhomotaurinate ion.
87. 87. The method according to claim 83, characterized in that the derivative is a prodrug metabolized in the liver, blood or brain to release any ion derived from the acetylhomotaurinate ion with similar pharmacodynamic effects on GABA and glutamate neurotransmission.
88. 88. The method of compliance with the claim 83, characterized in that the pro-drug comprises an acetylhomotaurinate ester, or a compound related to similar pharmacodynamic effects on GABA and glutamate neurotransmission.
89. 89. The method according to claim 80, characterized in that the derivative has a longer half-life than acamprosate.
90. 90. The method according to claim 80, characterized in that the derivative is absorbed from the gastrointestinal tract better than acamprosate.
91. 91. The method according to claim 80, characterized in that the derivative is more reliably absorbed from the gastrointestinal tract.
92. 92. The pill according to claim 80, characterized in that the pill is used to treat Tourette's syndrome.
93. 93. The pill according to claim 80, characterized in that the pill is used to treat simple tics.
94. 94. The pill in accordance with the claim 80, characterized in that the pill is used to treat multiple tics.
95. 95. The method according to claim 80, characterized in that the pill is used to treat blepharospasm.
96. 96. The method according to claim 80, characterized in that the pill is used to treat focal dystonias.
97. 97. The method according to claim 80, characterized in that an effective dose of (i) an NMDA receptor antagonist (ii) an agonist of GABA-A (iii) magnesium ion is supplied in the form of a delivery agent that it comprises a syrup, an elixir, a liquid, a tablet, a prolonged-release capsule, an aerosol or a transdermal patch.
98. 98. A composition characterized in that it comprises at least two agents, the composition has activities of: (i) improving the neurotransmission of GABA-A (ii) decreasing the neurotransmission of NMDA-type glutamate.
99. 99. The composition according to claim 98, characterized in that the composition is a compound.
100. 100. The composition according to claim 98, characterized in that the composition is a mixture.
101. 101. The composition according to claim 58, characterized in that no agent has both activities.
102. 102. A composition characterized in that it comprises: (i) acamprosate (ii) an inorganic salt or magnesium chelate.
103. 103. The composition according to claim 102, characterized in that the ratio of acamprosate to the inorganic magnesium salt or chelate is ben 1: 2 and 6: 1 by weight.
104. 104. The composition according to claim 102, characterized in that the inorganic salt or magnesium chelate is any inorganic salt or magnesium chelate.
105. 105. The composition according to claim 102, characterized in that the inorganic salt or magnesium chelate comprises magnesium chloride, magnesium oxide, magnesium sulfate, and magnesium chelated with any of the various amino acids.
106. 106. A method for treating the symptoms of a movement disorder in a subject characterized in that it comprises: administering to the subject a receptor antagonist NMDA selected from the group consisting of dextromethorphan, memantine, and derivatives and congeners thereof, which have similar pharmacodynamic effects with respect to NMDA-like glutamate neurotransmission.
107. 107. The method according to claim 106, characterized in that the movement disorder is selected from the group comprising tics, Tourette, blepharospasm, Meige syndrome, cervical dystonia, spasmodic torticollis, spasmodic dysphonia, writer's cramp, musician's cramp, and other occupational dystonia.
108. 108. The method according to claim 106, characterized in that the NMDA receptor antagonist is available in the blood.
109. 109. The method according to claim 106, characterized in that the NMDA receptor antagonist is available in the brain.
110. 110. The method of compliance with the claim 106, characterized in that the NMDA receptor antagonist is a prodrug metabolized in the body to release the active compound within the body.
111. 111. The method according to claim 110, characterized in that the compound released within the body is selected from the group consisting of any derivative or congener of memantine or dextromethorphan with pharmacodynamic effects on the neurotransmission of NMDA-like glutamate similar to those of memantine or dextromethorphan.
112. 112. The method according to claim 111, characterized in that the congener derivative is a prodrug metabolized in the liver, blood or brain to release any derivative with similar pharmacodynamic effects on the neurotransmission of glutamate.
113. 113. The method according to claim 111, characterized in that the derivatives or congeners have a longer duration of action than memantine or dextromethorphan.
114. 114. The method of compliance with the claim 106, characterized in that the administration step comprises oral administration.
115. 115. A method for treating movement disorders characterized in that it comprises the steps of: selecting a first pharmacologically active agent that acts as an antagonist of the NMDA-like glutamate receptor; and administer the first agent to a patient with a movement disorder.
116. 116. The method of compliance with the claim 115, characterized in that the movement disorder is selected from the group comprising tics, Tourettes, focal dystonias that include, without limitation, blepharospasm, Meige syndrome, cervical dystonia, spasmodic torticollis, spasmodic dysphonia, writer's cramp, musician's cramp, and other dystonia. occupational
117. 117. The method of compliance with the claim 116, characterized because blepharospasm is idiopathic blepharospasm.
118. 118. The method according to claim 116, characterized in that blepharospasm is induced by exposure to neuroleptics or other dopamine receptor antagonists, or is associated with a more extensive neuroleptic-induced movement disorder.
119. 119. The method of compliance with the claim 115, characterized in that the administration step comprises selecting the dose of the first agent in such a way that the administration of the first dose reduces the symptoms of the movement disorder to non-toxic doses.
120. 120. The method of compliance with the claim 115, characterized in that the movement disorder comprises involuntary movements similar to those seen in tardive dyskinesia, late dystonia, or focal dystonias not associated with the use of neuroleptic drugs.
121. 121. The method of compliance with the claim 115, characterized in that the movement disorder is associated with Huntington's disease.
122. 122. The method according to claim 115, characterized in that the selection step further comprises selecting a second pharmacologically active agent that is an NMDA receptor antagonist., or an ion channel blocker in the channels linked to NMDA receptors.
123. 123. The method according to claim 115, characterized in that the administration step further comprises administering the second agent together with the first agent.
124. 124. The method according to claim 122, characterized in that the second agent is memantine or a derivative or congener of memantine with similar pharmacodynamic effects at NMDA receptors such as memantine.
125. 125. The method according to claim 122, characterized in that the second agent is magnesium.
126. 126. A method for treating movement disorders characterized in that it comprises: increasing the therapeutic effects of memantine in patients with movement disorders by administering to the patient an effective dose of the magnesium ion.
127. 127. A method for treating movement disorders characterized in that it comprises: increasing the therapeutic effects of dextromethorphan in patients with movement disorders by administering to the patient an effective dose of the magnesium ion.
128. 128. The method according to claim 126 or 127, characterized in that the movement disorder is selected from the group consisting of the focal dystonias, which include without limitation tics, Tourettes, blepharospasm, Meige syndrome, spasmodic torticollis, spasmodic dysphonia, scribe's cramp, musician's cramp, and other occupational dystonias.
129. 129. A method for treating a movement disorder characterized in that it comprises: administering to a patient in combination, a simple composition at an effective dose, (i) an NMDA receptor antagonist; and (ii) magnesium ion.
130. 130. The method according to claim 129, characterized in that the NMDA antagonist is selected from the group consisting of memantine, dextromethorphan, and derivatives and congeners thereof with similar pharmacodynamic effects on glutamate neurotransmission as memantine or dextromethorphan.
131. 131. The method according to claim 129, characterized in that the NMDA antagonist is available in the blood.
132. 132. The method of compliance with the claim 129, characterized in that the NMDA antagonist is available in the brain.
133. 133. The method of compliance with the claim 130, characterized in that the congener derivative is a prodrug metabolized in the liver, blood, or brain to release any derivative with similar pharmacodynamic effects on glutamate neurotransmission.
134. 134. The method according to claim 130, characterized in that the derivative or congener has a longer effective duration of action than memantine or dextromethorphan, the elimination half-life or being absorbed over a longer period.
135. 135. The method of compliance with the claim 129, characterized in that the pill is used to treat blepharospasm or Meige syndrome.
136. 136. The method according to claim 129, characterized in that the pill is used to treat other focal dystonias, including without limitation spasmodic torticollis, spastic dysphonia, writer's cramp, musician's cramp, and other occupational dystonias.
137. 137. The method according to claim 129, characterized in that the composition administered to a patient is administered in the form of a pill, a syrup, an elixir, a liquid, a tablet, a prolonged-release capsule, an aerosol or a transdermal patch.
138. 138. A composition for the treatment of movement disorders characterized in that it comprises: one or more agents that decrease the neurotransmission of NMDA glutamate; and the magnesium ion.
139. 139. The composition according to claim 138, characterized in that the composition is a compound.
140. 140. The composition according to claim 138, characterized in that the composition is a mixture.
141. 141. The composition according to claim 138, characterized in that the magnesium ion is in the form of a magnesium salt.
142. 142. The composition according to claim 138, characterized in that the magnesium ion is in the form of a chelate.
143. 143. The method according to claim 138, characterized in that the composition is available in the blood.
144. 144. The method according to claim 138, characterized in that the composition is available in the brain.
145. 145. The composition according to claim 138, characterized in that the composition that decreases the NMDA glutamate neurotransmission is selected from the group consisting of memantine, dextromethorphan, and derivatives and congeners thereof with similar pharmacodynamic effects on glutamate neurotransmission as the memantine or dextromethorphan.
146. 146. The method according to claim 143, characterized in that the derivative or congener is a prodrug metabolized in the liver, blood or brain to release any derivative with similar pharmacodynamic effects on the neurotransmission of glutamate such as memantine or dextromethorphan.
147. 147. The composition according to claim 143, characterized in that the derivative or congener has a longer effective duration of action than memantine or dextromethorphan.
148. 148. The composition according to claim 143, characterized in that the congener derivative is absorbed for a longer period of time than memantine or dextromethorphan.
149. 149. The composition according to claim 143, characterized in that the derivative or congener has a longer elimination half-life than memantine or dextromethorphan.
150. 150. The composition according to claim 138, characterized in that the composition is used to treat blepharospasm or Meige syndrome.
151. 151. The composition according to claim 138, characterized in that the composition is used to treat focal dystonias.
152. 152. The composition according to claim 138, characterized in that the composition is supplied in the form of a delivery agent comprising a pill, a syrup, an elixir, a liquid, a tablet, a prolonged-release capsule, an aerosol or a transdermal patch.
153. 153. A composition for the treatment of movement disorders characterized in that it comprises: (i) memantine (ü) an inorganic salt or magnesium chelate.
154. 154. A composition for the treatment of movement disorders characterized in that it comprises: (i) dextromethorphan (ii) an inorganic salt or magnesium chelate.
155. 155. A composition for the treatment of movement disorders characterized in that it comprises: (i) memantine (ii) dextromethorphan (iii) an inorganic salt or magnesium chelate.
156. 156. The composition according to claims 48, 49 or 50, characterized in that the inorganic salt or magnesium chelate comprises magnesium chloride, magnesium oxide, magnesium sulfate, and magnesium chelated with any of the various amino acids.
157. 157. The method according to claims 48, 49 or 50, characterized in that the movement disorder is selected from the group consisting of, tics, Tourettes, tardive dyskinesia, late dystonia, and the group of focal dystonias not due to exposure to neuroleptic drugs, including without limitation, blepharospasm and Meige syndrome, spasmodic torticollis, spasmodic dysphonia, writer's cramp, musician's cramp, and other occupational dystonia.
158. 158. The composition according to claim 48, 49 or 50, characterized in that the memantine is replaced by a derivative or congener of the memantine.
159. 159. The composition according to claim 48, 49 or 50, characterized in that the dextromethorphan is replaced by a derivative or congener of the dextromethorphan.