JP2003524573A - Nicotine antagonist for neuropsychiatric disorders - Google Patents

Abstract

  (57) [Summary] Nicotine responsive neuropsychiatric disorders can be treated by administering nicotine antagonists, especially mecamylamine. Combination therapy of mecamylamine and a neuroleptic is also disclosed. Neuropsychiatric disorders include Tourette's syndrome, schizophrenia, depression, manic depression, tremor, attention deficit hyperactivity disorder, obsessive-compulsive disorder, dysarthria, furious violence and tardive dyskinesia. No.

Description

Detailed Description of the Invention

[0001] Technical Field The present invention relates to drug treatment of nicotine responsive neuropsychiatric disorders, for the treatment by administering a combination of nicotine antagonist (especially mecamylamine) alone or neuroleptics. Examples of such disorders include schizophrenia, manic depression (bipolar disorder), obsessive-compulsive disorder, attention deficit hyperactivity disorder, Tourette's syndrome and other movement disorders.

BACKGROUND OF THE INVENTION Tourette syndrome (Tourett's Syndrome: TS) is a dominant neuropsychiatric disorder on autosomal characterized by symptoms including multiple motor and vocal tics.
It is a hyperkinetic disorder that most often presents with sudden, rapid, brief, recurrent, aperiodic, stereotypic movements (motor tics) or speech (voice tics). , An inevitable urge, but it can be suppressed for a certain period of time (Tourette Syndrome Classification Study Group
up), Arch Neurol 50: 1013-16). In general, motor tics include blinking, involuntary head movements, shrugging, and distorted faces, while vocal tics include throat clearing, sniffing, screaming, and tongue ringing. , And apologetics. These symptoms generally begin in early childhood and can range from relatively mild to very severe throughout life (Robertson).
), MM, Br J Psychiatry, 154: 147-169, 1989). Also. Many TS patients have obsessive-compulsive syndrome (Pauls, DL et al., Psychopharm Bull, 22: 730-733, 1986.
), Hyperactivity and attention deficit (Comings, DE, Himes,
Other neuropsychiatric abnormalities, including JA, Comings, BG, J Clin Psychiatry, 51: 463-469, 1990). Problems with intense temperament or aggressive behavior are also often seen (Riddle, MA et al., "Wiley Series in Child and Adolescent Mental Heal Healing".
th) ”Cohen, DJ, Bruun, RD, Leckman,
JF, John Wiley & Sons, NY, pp
.151-162, 1988; Stelf, ME, Bornstein, RA,
Hammond, L, "A Survey of Patients with Tourette's Syndrome and Their Families: The 1987 Survey of Tourettes in Ohio.
Syndrome Association) ", Cincinnati, Ohio Tourette Syndrome Association (1988), School refusal and learning disability (Harris, D, Silver AA, Learning Disabilit)
ies, 6 (1): 1-7, 1995; Silver, AA, Hagin, RA, "
Disorders of Learning Childhood, Nospitz
hpitz), New York, Wiley, pp.469-508, 1990).

Although the pathogen of TS has not yet been elucidated, therapeutic effects have been obtained by antagonists of dopamine receptors, suggesting hypersensitization of striatal dopamine and / or dopamine receptors. (Singer, HS, Ann Neurol, 12: 361-366, 1982). Treatment of TS is often done with the dopamine antagonist haloperidol (Haldol, McNeil Pharmaceuticals, Inc. (Raritan, NJ)) in about 70% of cases. Valid (Erenberg, G, Cruse, RP, Rothner
ner), AD, Ann Neurol, 22: 383-385, 1987; Shapiro, AK, Shapiro, E, "Willet Series: Mental Health in Childhood and Adolescence (Wi
ley Series in Child and Adolescent Mental Health) "Cohen, D
J, Bruun, RD, Leckman, JF, John Wiley & Sons, NY, pp.267-280, 1988). Other neuroleptics include pimozide (Shapiro, ES et al., Arch Gen Psy.
chiatry, 46: 722-730, 1989), fluphenazine (Singer, HS, Gammon, K, Quaskey, S, Pediat Neuroscience, 12: 71
-74, 1985-1986) and risperidone (Stamenkovic et al., Lancet 344: 1577-78, 1994). Another commonly used drug is the alpha-adrenergic antagonist clonidine, which is effective in attention deficit hyperactivity disorder (ADHA) but only 40% effective in motor and vocal tics (Bruun, RD, J Am Acad Child Psychiatry, 2
3: 126-133, 1984; Cohen, DJ et al., Arch Gen Psychiatry, 37: 1350.
-1357, 1980). Other drugs used to varying degrees of efficacy include clonazepam (
Gonce, M, Berbeau, A, Can J Neurol Sci, 4: 279-2
83, 1977), Naloxone (Davidson, PW et al., Appl Res Men
t Petardation 4: 1-4, 1983) and fluoxetine (Riddle, MA et al., J Am Acad Cild Adol Psychiatry 29: 45-48, 1990). One of the most commonly used drugs is haloperidol (Erenberg
berg), G, Cruse, RP, Rothner, AD, Ann Neurol, 2
2: 383-385, 1987). However, the therapeutic dose of haloperidol is often accompanied by side effects that prevent continued administration, such as lack of concentration, nap, depression, weight gain, and Parkinson's-like symptoms. Spontaneous movement disorders appear (Shapiro, AK, Shapiro, E, “Tourette's syndrome and tic: clinical understanding and treatment.
Tic Disorders: Clinical Understanding and Treatment; Wiley Series in Child and Adolescent M
Ental Health ”Cohen, DJ, Bruun, RD, Wreckman (
Leckman), edited by JF, John Wiley & Sos, NY
ns), pp.267-298, 1988). The side effect of dyskinesia is particularly difficult to address, as it involves additional abnormal involuntary movements of the tongue, jaw, torso and / or limbs.

Due to these side effects, Erenberg et al.
Use of haloperidol or other neuroleptic drugs should be discontinued in patients with TS (Erenberg, G, Cruse, RP, Rothner, AD, Ann Neurol, 22: 383- 385, 1987). After TS patients have stopped taking the drug due to side effects, it is difficult to control their speech and exercise, depriving them of many full-time, responsible occupations. Among the general public, including law enforcement officers, this syndrome is often considered an addiction symptom. Unexpected movements and abusive language cause great social disability.

[0005] Systemic or intracaudal administration of nicotine has been shown to significantly enhance reserpine-induced catalepsy in rats (Montgome.
ry), SP, Moss, DE, Manderscheid, PZ, "Mariluana 84", Harvey, DJ, Paton, WDM
Edited by IRL Press (Oxford, England), pp. 295-302,
1985; Moss, DE et al., Life Sci 44: 1421-1525, 1989). Follow-up experiments have shown that low doses of nicotine also enhance haloperidol-induced catalepsy (Sanberg, PR et al., Biomedicine and Pharmacothera).
py 43: 19-23, 1989; Emerich, DF, Norman, AB,
Sanberg, PR, Psychopharmacol Bull 27 (3): 385-390, 1990; Emerich, DF et al., Pharmacol Biochem Behav 38: 875-880, 1991).
These preclinical findings suggest that nicotine may also enhance the therapeutic effect of neuroleptic drugs used to treat hyperkinetic behaviors such as TS.

In a preliminary clinical trial, 10 TS patients were subsequently prescribed haloperidol and the nicotine chewing gum under the tradename Nicorette (2 mg). Patients showed rapid, marked and clear improvement from tics and other TS syndromes, which were not well controlled by haloperidol alone (Sanberg, PR et al., Biomedicine and Pharmacotherapy 43: 19). -23, 1989
). In two subsequent experiments, nicotine gum alleviated tics in patients who were already on haloperidol, but no placebo gum was effective (McConville, BJ et al., Am J. Psychiatry 148: 793-794,
1991; McConville, BJ et al., Biological Psychiatry, 31: 832.
-840, 1992). However, the effect of gum is short-lasting (1 to 4 hours), and it is difficult to adhere to it due to bitterness and side effects on the gastrointestinal tract (McConville (Mc
Conville), BJ et al., Biological Psychiatry, 31: 832-840, 1992).

For 11 TS patients who did not respond adequately to neuroleptic treatment,
I tried using a 7 mg, 24-hour transdermal nicotine patch (Trademark: Nicoderm TNP) (Silver, AA et al., “Effect of nicotine on biological systems (
The Effects of Nicotine on Biological Systems II ”, PBS Clark (Clark
e), edited by M. Quik and K. Thurau, "Advances in Pharmacological Sciences," Birkhauser Publisher (Birk).
hauser Publishers), pp. 293-299, 1995). The patient's tics were videotaped before and 3 hours after the start of treatment. At 3 hours, the frequency and severity of tics decreased by 47% and 34%, respectively. Patients who had little control over treatment with neuroleptics showed a more dramatic improvement than those who responded to neuroleptics alone. The effect of TNP lasted longer than the expected 24 hours. TNP
The effect persisted for 3 to 4 months without further nicotine administration in 2 patients who had suppressed TS syndrome prior to administration of.

[0008] To further investigate the effective therapeutic response to TS patients, 20 infants and 17 adolescents with TS and 17 adolescents and 3 adults (of which 18 were neuroleptics well controlled for tic disorders) No, they were given 2 doses of TNP after 2 years of no drug administration and were followed for various periods (Silver, AA et al., J Amer Acad Ch).
ild & Adolescent Psychiatry 35 (12): 1631-1636, 1996; Shytle
), RD et al., Drug Development Research, 38 (3/4): 290-298, 1996). Although there was considerable individual variation in response, a single dose of TNP resulted in a significant decrease in the mean Yale Global Tic Severity Scale for approximately 1 to 2 weeks. I understood. Therefore, transdermal nicotine was an effective adjunct to the neuroleptic treatment of TS, and was effective alone in two patients.

Attention deficit hyperactivity disorder (ADHD) is also present in 50% of children with TS.
ADHD is a neurobiological disorder characterized by lack of attention, increased impulsive behavior, and hyperactivity.ADHD is currently the most commonly diagnosed childhood neuropsychiatric condition affecting approximately 3.5 million people. is doing. In addition, 60% of adolescents with ADHD present with symptoms in adults, with an additional 2.5 million patients.

The present patent application relates to the administration of nicotine antagonists, especially mecamylamine (3-methylamino-2,2,3-trimethylnorcamphane). Mecamylamine is well known as an antagonist of nicotine and blocks the ganglia stimulated by nicotine. Mecamylamine was first introduced as an antihypertensive drug, blocking sympathetic ganglion transmission, thereby causing vasodilation and lowering blood pressure (Taylor, P, "Pharmacological Basis of Treatment. Ther
apeutics) ”, Goodman, LS, Gilman, A, edited by McMillan Publishing Company, New York). In general, ganglion block also results in relaxation of the bladder and gastrointestinal tract, sexual dysfunction, ciliary muscle paralysis, xerostomia, decreased sweating and orthostatic hypotension. Although clinical use of mecamylamine as a ganglion agonist has been replaced by more effective antihypertensive drugs, mecamylamine's ability to block the nicotine binding site in the brain has continued to interest scientists in mecamylamine. (Eg Martin, BR, Onaivi, ES, Martin, TJ, Biochemical Pharmacology
38: 3391-3397, 1989; Banerjee, S. et al., Biochemical Pharmacol.
ogy 40 (9): 2105-2110, 1990, etc.). Known as the nicotinic acetylcholine receptor (nAChr), these nicotine binding sites are normally activated in the brain by the prominent neurotransmitter acetylcholine.

Nicotine obtained from tobacco is one of the most widely used drugs for many years in various forms (Wilbwet, J, J Ethnopharmacol 32 (1-
3): 179-186, 1991). Nicotine functions as a regulator of nAChr (Changeux, JP, Sci Amer (November), pp. 58-62, 1993). Via these receptors, nicotine activates presynaptic release of several neurotransmitters including acetylcholine, norepinephrine, cetronine and dopamine (Balfour, DJK, Pharmacological therapeutics 16: 269-282, 1982).
). Compounds that act on nAChr and can modulate monoaminergic central neurotransmission could be effective therapeutic agents for the treatment of neuropsychiatric disorders (Jarvick, ME, Br J Addict 86: 571-575. , 1991; Newhouse
, PA, Hughes, JR, Br J Addict 86: 521-526, 1991; and Hughes, J, Clarke, PBS, “The effects of nicotine on biological systems) II / Summary S40 ", 1994
Decker, MW et al., Life Sci 56: 545-570, 1995).

[0012] Unlike some ganglion inhibitors, drugs that do not easily reach the central nervous system (CNS), mecamylamine has been reported to exert central nervous effects in humans, such as , Inhibits the CNS action of nicotine (Martin (Martin
), BR, Onaivi, ES, Martin, TJ, Biochemical
Pharmacology 38: 3391-3397, 1989) and alter cognitive effects (Newhouse, PA et al., Neuropsychopharmacology 10: 93-107, 1994) and alter electrical EEG (Pickhouse, WB). , Herning
), RI, Henningfield, JE, Pharmacology Biochemistr
y & Behavior 30: 149-153, 1988), changes cortical blood flow (Gitalman (Gita
lman), DR, Prohovnik, I, Neurobiology of Aging 13: 313-
318, 1992) and so on.

In most animal studies, 0.5 mg / kg or more of mecamylamine is used, but Driscoll is a small dose (<0.3 mg / kg) for rats with high avoidance behavior.
, But not 0.5 mg / kg), showed a similar increase in the number of successful avoidance behaviors (but 0.2 mg / kg) that was similar to 0.1 mg / kg nicotine. The increase was lower than that of nicotine). Based on this experiment
Driscoll concludes that "mecamylamine may exert unpredictable effects on rats at doses as low as those used to inhibit nicotine in behavioral testing" (Driscoll ), P, Psyciopha
rmacologia (Berl) 46: 119-21, 1976).

In a recent study of the nicotine receptor (nicotine binding site) and its ion channel (mecamylamine binding site), Banerjee et al. Reported that mecamylamine and several nicotine analogs have a strong affinity for the mecamylamine binding site. (Affinity) is disclosed (Ban-y (Ba
nerjee), S et al., Biochem Pharmacol 40 (9): 2105-10, 1990). Studies have also been conducted on alkaloids acting on nicotine receptor channels (Daly, JW, “Alkaloids as Agonists, Antagonists, Antagonists and Antagonists of Nicotine Receptor Channels.
ists and Noncompetitive Blockers of Nicotinic Receptor Channels) "("
Nicotinic acetylcholine receptor as a drug target
"Oline Receptors as Pharmaceutical Targets)", 24-2 July 1997
5th, Washington DC).

Many neuropsychiatric disorders are associated with abnormal or involuntary movements, including obsessive-compulsive disorder (OCD), TS, ADHD, hemitonia and Huntington's chorea, and such movements are associated with these. It is not limited. It is believed that these diseases are due to an imbalance of neurochemicals within the basal ganglia of the brain. In humans, acetylcholine regulates motor behavior by activating nAChr in the basal ganglia. The action of nAChr in the basal ganglia is well understood (Clerk, PBS, Part, A, Brain Res 348: 355-35.
8, 1985). Nicotinic stimulation stimulates the activity of dopamine (DA) -producing cells in the basal ganglia (Clerk, PBS, J Pharmacol Exper Therapeutics
246: 701-708, 198847; Grenhoff, J, Aston-Jones (
Aston-Johns), G, Svennson, TH, Acta Physiol Acand 128:
351-358, 1986; Imperato, A, Mulas, A, Di Chiara, G, Eur J Pharmacol 132: 337-338, 1986), mecamylamine
Inhibits nAChr and prevents DA release from the basal ganglion structure (Ahtee (Ahtee
), L, Kaakkola, S, Br J Pharmacol 62: 213-218, 1978).

US Pat. No. 5,774,052 to Rose and Levin discloses reducing the use of nicotine and other drugs by agonist-antagonist combinations. In combination with nicotine, the nicotinic antagonist mecamylamine is used to treat tobacco dependence. Rose and Levin propose to include both nicotine and mecamylamine in the patch. Rose and Levin showed that such agonist-antagonist combinations are associated with other psychopathological and neurological dysfunctions (eg, mania, schizophrenia, hypertension, etc. due to sympathetic autonomic disorders). It is also suggested that it can be used when including.

The excellent controllability of symptoms and the small number of side effects are beneficial to patients. In particular, it is preferable to take a single agent, such as patients in at least some of the reports disclosed herein. Our clinical experience in human patients using mecamylamine for a variety of diagnoses suggests various uses. The present invention is
Disclosed are improved methods of symptom control by using a nicotine antagonist (mecamylamine) alone or in combination with neuroleptic agents for the treatment of various nicotine responsive neuropsychiatric disorders.

The disclosed object of the present invention the invention is to provide a new treatment for patients with nicotine-responsive neuropsychiatric disorders.

A further object of the present invention is to provide a therapeutic method with less side effects, improve patient compliance, and improve quality of life and social function.

Disclosed herein is a method of treating a patient having a nicotine-responsive neuropsychiatric disorder, comprising administering an effective amount of a nicotine antagonist.
Preferably, the nicotine antagonist is mecamylamine, a stereoisomer, or mecamylamine analog. An effective amount of mecamylamine is an amount that ameliorates the signs and symptoms of the patient. In tics, the frequency of tics in each patient and / or
Or the amount that reduces the severity. In addition, there may be an additional step of administering to the patient an effective amount of a neuroleptic drug. Examples of neuroleptics include haloperidol, pimozide, fluphenazine and risperidone.

Examples of nicotine-responsive diseases include movement disorders including Tourette's syndrome, essential tremor, dysthymia of the half-body muscles, late movement disorder, and Huntington's chorea (HD). Other nicotine-responsive mental disorders include schizophrenia, depression,
Attention deficit hyperactivity disorder, manic depression, outbreaks of anger and obsessive-compulsive disorder.

[0022] DETAILED DESCRIPTION inventors of carrying out the invention so far, by administering nicotine or additionally following the neuroleptic treatment with haloperidol, neuroleptics alone tics and other that could not be controlled It has been shown to provide rapid and significant relief for TS syndrome. Utilizing neuroleptic-induced catalepsy as a model to understand the therapeutic effects of neuroleptics and nicotine in patients with TS, uninhibited striatal cholinergic interneurons (which are striatal mandibular GABA It was thought that nicotine potentiates the activity of D2 antagonists in catalepsy by activating the neuronal innervation of process neurons. In this way, inhibition of the pallidum also occurs (Emerich, DF et al., Pharmacol Biochem Behav 38: 875.
-880, 1991). However, because of the complex neuropharmacological effects of nicotine, it is difficult to explain the exact mechanism by which nicotine interacts with neuroleptic drugs to reduce the symptoms of TS. One hypothesis is that nicotine that permeates the skin exerts its therapeutic effect by continuously inactivating the nicotine receptor (Shytle, RD et al., Drud Dev
elopment Research 38 (3/4): 290-298, 1996). Neuropharmacological effects consistent with this hypothesis have been observed in vitro (Luka (Luka
s), RJ, Drug Dev Res 38: 136-48, 1996).

In some TS patients who do not respond to conventional treatment, the inventors have found that the nicotine receptor antagonist mecamylamine is suitable for the treatment of hypertension and the alleviation of the TS sign group. It was unexpected that the TS syndrome improved after treatment with mecamylamine alone or in combination with neuroleptics, which, in general,
It is believed that the effects of mecamylamine are counter to that of nicotine: that is, if nicotine alleviates tic, mecamylamine may be more aggressive. Thus, it is a surprising finding that mecamylamine treatment has observed significant relief in patients. The inventors
In addition to mecamylamine, it was envisioned that other nicotine receptor antagonists, described in detail below, could also be used. Furthermore, considering the effects on concomitant medical conditions, nicotine receptor antagonists are not limited to TS, but other neuropsychiatric disorders (eg, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive disorder (OCD), essential tremor). It was also considered to be effective for anesthesia (ET), late movement disorder (TD), depression (D) and Huntington's chorea (HD). Nicotine antagonists are expected to be effective against other nicotine responsive diseases such as schizophrenia, depression, manic depression, outbreaks of panic and panic.

Hemimuscular tone abnormalities are also nicotine responsive and are focal movement disorders involving one arm and leg of the body. In general, it progresses in adulthood and the symptoms rarely spread to the normal side of the body. This is one of the symptoms that also include spasmodic torticollis (intermittent spasms that cause the head to rotate and move up and down). In general and partial muscle tone, which involves a wider part of the body, the anticholinergic drugs benzodiazepines, baclofen, carbamazepine, reserpine and erdopa have been used to ameliorate symptoms. In severe focal myotonia, diluted botulinum toxin may be injected intramuscularly in the problem or surgically denervated.
Unilateral muscle tone abnormalities can be expected to respond to mecamylamine.

Definitions The term “nicotine antagonist” is a broad and ever-expanding category, mecamylamine being just one example. A comprehensive list of all such compounds cannot be placed due to space considerations. The following description is not intended to be exhaustive of the compounds that fall within the scope of this term, but teaches how to identify. Recently, a study on interesting nicotine antagonists and related compounds was reported by Daly, JW (ibid.), Which is incorporated by reference. Clark and Reuben disclose dihydro-β-erythroidine, methyllycaconitine, chlorisondamine and trimetaphane (Br. J. Pharmacol.
. 117: 595-601, 1996). Normecamylamine, N- (1,2,2) trimethyl-
1-bicyclo [2,2,1] -heptibenzenamine, dimethylaminoisocamphan, exo-aminonorbornane, 2,2,6,6-tetramethylpiperidine, 2,2,6,6-tetramethyl- 4-aminopiperidine and pempidine are identified as active nicotine antagonists (Banerjee
), Biochemical Pharmacology 40: 2105-2110, 1990). This document and the test methods described therein are incorporated herein by reference. Further examples of nicotine antagonists include erythodine (Decker, Euro
pean Journal of Pharmacology 280: 79-89, 1995), phenyl tropanecarboxylic acid methyl esters (Lerner-Marmarosh et al., Life.
Sciences 56 (3): PL67-70, 1995), allyl pempidine analogs (Wang
) Et al., Life Sciences 60 (15): 1271-1277, 1997), Ibogaine (Daly
), Biochemical Pharmacology 40 (9): 2105-2110, 1990).

In addition, various stereoisomers of mecamylamine and substituted analogs have been tested for activity (Stone et al., J Med Pharm Chem 5 (4): 665-.
90, 1962: incorporated herein by reference). When rats were tested for nicotinic convulsions and mydriasis, the activity disappeared when the methyl group substitution increased. Both the methyl or dimethyl groups on the amino group were more active than the other substituents. The d form was active; however, the dl racemate was slightly more active. Therefore, in this use of mecamylamine, the 1-form is considered to have a remarkable activity. Stone et al. Found that the exo form (the methylamino group is on the same plane as the methylene bridge) is in the endo form (the methylamino group is below the methylene bridge and is inside the cage formed by the bridge). It has always been more powerful than existing). Furthermore, the partial structure 2,2
-Dimethyl-3-methylaminobutane was also active. A slight difference in activity was observed between the various d-body models and other analogs, suggesting that the activities and effects in neuropsychiatric disorders may be different.

Other compounds that are theoretically expected to be active in such applications are described in US Pat. No. 4,837,218 (Alkylated Bicycloalkaneamines for Neurotoxic Injury) for use in the treatment of neurotoxic injury.
), U.S. Pat. No. 2,894,987 (N-allyl-2-aminoisocamphan), U.S. Pat. No. 3,148,118 (Analeptically Active Agents), U.S. Pat. No. 3,164,601 (has excitatory activity). N-Substituted Aminonorcamphane Derivatives (Analeptically Active N-Sucstituted Aminonorcamphane Derivatives))
Is disclosed in. These patents are incorporated as a reference.

“Beneficial effect” refers to a clear improvement in clinically observed signs and symptoms beyond the norm. For example, beneficial effects in movement disorders include a reduction in the frequency and severity of tick disease, but not only that often anxiety, aggressive rage and anxiety that precede or overlap the severity of abnormal behavior. It also includes improvements that are not directly visible, such as the reduction of signs of urgency. The therapeutic effect can be quantified by clinical observation and videotape evaluation. Beneficial effects in obsessive-compulsive disorder include a reduction in obsessive-compulsive behavior, which can be confirmed by patient reports. Suemaru et al. (Id.) Propose that nicotine-induced rat tail tremor can be used to screen for compounds that treat tremor. Repeated administration of nicotine could induce locomotor hyperactivity and tail tremor in rats, which resulted in mecamylamine (0.1-1 mg / day,
It can be blocked by intraperitoneal administration), but hexamethonium cannot be blocked because it cannot easily reach the brain. Centrally active clonidine (adrenergic agonist) and prazosin (adrenergic antagonist) significantly reduced tail tremor rather than hyperactivity. However, centrally active haloperidol and chlorpromazine, a dopaminergic antagonist, significantly reduced hyperlocomotion rather than tail tremor (Suemaru, K., Oishi, R.,
Gomita, Y, Arch Pharm 350: 153-57, 1994).

[0029] Yale Global Tic Severity Sca
le, YGTTS) is the most widely used clinical assessment rating and is used to assess tic disorders. It provides an objective measure of tic frequency and severity based on clinical observations. The scale includes a tic questionnaire that is filled out based on the patient's own memory of tics that occurred the previous week. Using this questionnaire as a guide, physicians rank severity for both motor and vocal tics with respect to five independent numbers (number, frequency, intensity, complexity and interference). Furthermore, apart from this, there is also a previous week's assessment of a wide range of injuries that describe the impact of the disease on the patient's social role, self-esteem, etc.

An objective method for assessing tic disorder is to video-record the patient. Watch videotape for a minimum of 5 minutes and record frequency and severity for both motor and vocal tics. Video recordings of drug trials (Leckman, JF et al., Arch Gen Psychiatry, 48: 324-328, 1991; Shapiro (Sha
piro), ES et al., Arch Gen Psychiatry, 46: 722-730, 1989; McConville (Mc
Conville), BJ, Fogelson, HM, Norman, AB,
Klykylo, WM, Manderscheid, MA, Parker, KW, Sanberg, PR, Am J Psychiatry, 148: 793-794
, 1991; Silver, AA, Shytle, RD, Philip
ilipp), KK, Sanberg, PR, "The Effects of Nicotine on Biological Systems II", PBS Clark (Cla
rke), M. Quik and K. Thurau, "Advances in Pharmacological Sciences," Birkhauser Publishers (Bi).
rkhauser Publishers), pp. 293-299, 1995); Reveley, MA et al., Journal of Psychopharmacology Suppliment, A30, 117, 1994) and challenge tests (Chappel, PB et al., Adv Neurol 58: 253-). 262, 1992) and has proven to be an important adjunct to a clinical evaluation system. In a recent report, Chappel and coworkers identified videotapes for motor and vocal tics, and such data correlated well with established clinical rating scales. (Chappel, PB et al., J Am Acad Child Adolesc Psychiatry, 33: 386-393,
1994).

As used herein, “neuroleptic agent” refers to an agent that affects thought, emotion and neurological status, particularly movement and posture (as seen in TS). Almost all neuroleptics have a strong effect on the extrapyramidal path that causes late movement deficits (see above). Examples of neuroleptics include haloperidol (Haldol, trade name McNeil Pharmaceuticals, Inc. (Raritan, NJ)), pimozide (
Trade names Orap, Teva Pharmaceuticals
ticals, Inc., Calpsville, PA), fluphenazine and risperidone (trade name Risperdal), Janssen Pharmaceutical (Titusville, NJ).
) And the like.

“Effective dose” refers to the amount of nicotine antagonist required to achieve an effect. The required dosage depends on the compound selected, the age and weight of the patient, the severity of the disease,
Although it depends on the route of administration and the like, it can be easily determined by an ordinary experiment as described in the following clinical examples. Generally, however, an effective dose will be from about 0.001 mg / kg to about 6 mg / kg per day, preferably from about 0.002 mg / kg to about 3 mg / kg per day, more preferably about 0.005 mg per day. / kg to about 2 mg / kg
, And most preferably about 0.01 mg / kg to about 1.5 mg / kg per day. The starting dose for adults with drug-resistant TS is about 2.5 mg / day, and the dose is adjusted according to recurrent symptoms (see case below). For younger children with moderate ADHD it is preferable to start at 1 mg / day or less. The effective dose of neuroleptics is
The minimum amount that alleviates symptoms when combined with a nicotine antagonist. Our clinical experience suggests that in some patients it may be possible to obtain maximal therapeutic effect without the use of neuroleptic drugs.

“Pharmaceutically acceptable” refers to the absence of unacceptable toxicity to compounds such as salts or excipients. The pharmaceutically acceptable salts include chlorine, bromine, iodine, sulfite, sulfate, nitrite, nitrate, inorganic anions such as phosphate, and acetate, malonate, pyruvate, Organic anions such as propionate, cinnamate, tosylate and citrate may be mentioned. For information on pharmaceutically acceptable excipients, see “Remington 7s Pharma
ceutical Sciences ”(Mac Pub.), Martin (Mar
tin), EW describes in detail.

The pharmaceutical composition containing the nicotine antagonist may include one or more pharmaceutical carriers. The term "pharmaceutically acceptable carrier" refers to any relatively acceptable, non-toxic and non-irritating generally accepted excipient. When the carrier is a diluent, solid, semi-solid, or liquid materials which act as vehicles, excipients or medium for the active ingredient can be used.
Pharmaceutical dosage unit forms are prepared for any of several routes of administration, including oral and parenteral (particularly by intramuscular and intravenous injection, or subcutaneous implantation or transdermal administration). can do. Representative of such forms include tablets, soft and hard gelatin capsules, powders, troches, chewing gums, emulsions, suspensions, syrups, solutions, sterile injectable solutions and sterile filled powders. . Compositions containing a nicotine antagonist can be formulated by methods known in the art to release any, or all, compounds rapidly, sustained, or delayed after administration.

The nicotine antagonist formulations of the present invention are suitable for oral administration and can be formulated in the form of tablets or capsules with a preferred carrier. Solid pharmaceutical excipients (magnesium stearate, calcium carbonate, silica, starch,
Sucrose, dextrose, polyethylene glycol (PEG), talc, and other conventional pharmaceutical adjuvants (fillers, lubricants, humectants, preservatives,
Anti-degradation agents, fragrances etc.) and binders (gelatin, gum arabic, cellulose,
Methylcellulose, etc.) to provide a mixture for use as described above or for tableting, encapsulation, or other suitable forms described above. For a general description of formulation, see “Remington 7s Pharmaceutical Sciences” (Mac Publishing
ub.)).

Mode of administration Although oral administration is preferred, transdermal application, nasal spray, bronchial inhalation, suppository,
Parenteral injection (such as intramuscular or intravenous injection) may be used. Examples of the carrier for parenteral administration include dextrose, mannitol, mannose, an aqueous solution of sorbitol, physiological saline, pure water, ethanol, glycerol, propylene glycol, peanut oil, sesame oil, polyoxyethylene-polyoxypropylene block polymer and the like. However, it is not limited to these. Appropriate preservatives, stabilisers, antioxidants, antimicrobials and buffers (eg BHA, BHT, citric acid, ascorbic acid, tetracycline, etc.) may additionally be included. Alternatively, the nicotine antagonist formulation can be incorporated or encapsulated within a suitable polymer matrix or membrane to provide a sustained release system suitable for implantation or application on the skin. Other systems include devices such as indwelling catheters and the brand name Alzet minipump.

As described above, the present invention has been described directly, but the following is an example regarding the effects of the method that was useful. The following examples are merely illustrative and do not limit the scope of the method.

Clinical Example Patient 1 is a tall, 15-year-old boy weighing 78.6 kg who was diagnosed with TS. This patient is a patient of our clinic, and for the purpose of effectively controlling severe TS symptoms,
Haloperidol 2 mg / day and twice weekly transdermal nicotine patch (for about 1 year)
14 mg / 24 hours) was prescribed. However, about 2 months before the scheduled follow-up diagnosis, tic disease (previously well controlled) recurred. At that time, the dose of haloperidol was increased to 3 mg / day, and the frequency of nicotine patch application was 1
It increased every day and some improvement was seen. However, the side effects of the nicotine patch, especially nausea, caused the patient to refuse and refused the patch. In addition, the increased risk of nicotine addiction from daily use was hesitant to let patients continue to use the patch.

The patient discontinued the nicotine patch two weeks before coming to the clinic. Blinks, raised eyebrows, distorted face, head reflexes, abdominal tics, and leg / foot movements were observed. The patient's YGTSS score was 17/30, total 245 tic episodes in 5 minutes were 245, 7
Overall severity was rated 3 (moderate) on a scale of grades.

Mecamylamine (5 mg) was orally administered at about 11:30 am. After about 2 hours, the patient reported having a reduced tic impulse. The YGTSS score was 6/20. The frequency of tics decreased by 25%, although tics still remained. Overall tic severity was reduced by 50%. By 6 pm, the patient's mother reported that she felt better, had no visible tics, and had no side effects. However, the next morning,
The tic disorder began to recur. One month later, ticosis was controlled by taking mecamylamine 5 mg / day at breakfast, and the patient reported relieving tension and becoming alert. The boy, who was shy and quiet up to 30 days ago, became more extroverted and more talkative.

Clinical experience in the treatment of this first patient suggested that the combination of haloperidol and mecamylamine could suppress motor tics.
The effect of a single oral administration of mecamylamine appeared after 2-3 hours and lasted for about 8-12 hours. The daily dose of mecamylamine was 21 without any side effects.
It continued for one day.

Patient 2 was a 16-year-old boy in the third grade of junior high school, and although the overall cognitive function was excellent, he had a serious defect in the visual motor function. This patient was at age 10 years of age due to attention deficit disorder and learning difficulties of Within 6 months after starting the administration, motor and vocal tics developed. 0.1 m
The patient's parents reported that the patient's tics were suppressed by using g of clonidine three times daily. However, they have not been prescribed medication for motor and vocal tics for the last two years. At the end of the second year of junior high school, he failed in mathematics and was rated C and D in other subjects, and the difficulty of visual motor function was noticeable. Writing was slow and I had a hard time. I refused to write, felt frustrated at writing, and felt that I was destined to fail. Tics were evident when patients visited our clinic: blinks, mouth distortions, large body tics, rapid shoulder and reflex movements, head tics, and sniffing.
The patient complained that he was "active in his head" (confused). During the summer, the patient attempted to study mathematics so she could retake the exam and in high school he entered high school. However, patients were unable to write down the steps necessary to answer a mathematical problem (as required by the test), despite being "in the head knowing the process." The patient could not stand it, was irritated, and was about to throw it.

Mecamylamine was prescribed and instructed to take it after dinner. The patient's mother (nurse) reported that the patient had begun studying mathematics two hours after taking 5 mg of mecamylamine. At this point, the patient was patient, feeling "clear", relieved of tension, and distracted for three hours to tackle math problems. The patient's tic disorder is
Both intensity and frequency decreased. The next morning, the patient felt restless and his tics recurred, albeit less severely than before. There was blinking and large and reflexive body movements. The patient was prescribed mecamylamine at 5 mg at breakfast and 2.5 mg after dinner. 12
A day later, patients reported that they were able to focus more on their studies, rather than on their “higher” status than they were before. Tic symptoms occasionally appeared but diminished. Blood pressure did not change 114/80. In this patient, no neuroleptic was administered in combination with mecamylamine, suggesting that mecamylamine alone could also suppress TS. After 8 weeks of treatment, the patient's mother reported that she was in good shape, wanted to continue treatment, and entered high school. The patient continued to use mecamylamine for 208 days with no side effects.

Patient 3 is a 35 year old female with severe motor and vocal tics since the age of 6 years,
He presented with TS with obsessive-compulsive disorder. The patient was a mother of three, and an older 12-year-old girl also had TS. Over the years, various medications have been used to control depression and mood swings, including Zoloft (Sertraline Hydrochloride, Pfizer Roerig Division (New York)). When a transdermal nicotine patch (7 mg) was tried in our clinic in July 1996, tic disorder was attenuated within 3 hours. However, within the next 24 hours, the knee, ankle, and wrist joints became sore and swollen that he discontinued use of the patch. A trial dose of haloperidol (0.5 mg) was administered. Within 12 hours, there was a sudden rise in body temperature that required discontinuation of haloperidol. At one year's follow-up diagnosis in our clinic, the patient was in a state of tension and did not seem to be happy and had multiple severe tic disorders (almost continuous blinking, distortion, nasal spasms, sniffing). ) As well as the obsession that everything in the house had to "fit".

He took 5 mg of mecamylamine at 2 pm. At 5 pm, tics were still alleviated, albeit still, with a marked (50%) decrease in intensity. 5 patients
He continued to take mg of mecamylamine for 4 days and reported that he had weakened his tic disorder. The patient reported feeling less anxious and feeling relaxed. In addition, he reported that while taking mecamylamine, he felt less urgency for the furious outbursts found in stressful situations. Mecamylamine was administered once daily for 30 days, but no significant changes in blood pressure and heart rate were observed. The patient complained of constipation during the menstrual period, but did not report any other side effects. At the end of the mecamylamine regimen, the patient requested continued mecamylamine. In the case of this patient,
As in Patient 2, no neuroleptic was needed. Patient received mecamylamine 195
She took it for a day and was happy that she had less tingling at the time of diagnosis, but she said she had stopped taking mecamylamine because it was hard to give up her "uplifted" mood.

Patient 4 is a 43 year old male salesman with a history of TS from the age of 14. This patient was using haloperidol (0.5 mg twice daily) and a 14 mg transdermal nicotine patch twice weekly, but was unable to fully control motor and vocal tics. Rather than increasing the dose of haloperidol or increasing the frequency of nicotine patches, nicotine patches were discontinued and mecamylamine (5 mg / day) was prescribed. Initially,
YGTSS was 27/30 and from a 5 minute videotape, the total number of ticks was 207 and the overall severity on a 7-point scale was 4 (very pronounced). About 90 minutes after the first dose of mecamylamine, the patient reported feeling relaxed. 20/2 for YGTSS
The severity was 0 and the severity was 2.5 (somewhat remarkable). After 6 hours, the patient reported continuing to feel relaxed, with no facial distortion and no head cramps. I was blinking, but it was reducing. However, by the next morning, tic disease began to recur. Taking 5 mg of mecamylamine at breakfast again provided tic alleviation within 1-2 hours. About 8 hours later, tic disease began to recur. An additional dose of 2.5 mg mecamylamine was prescribed before dinner. This dose reduced evening motility and vocal tics. As a maintenance dose, mecamylamine was prescribed at 5 mg at breakfast and 2.5 mg before dinner. Haloperidol (0.5 mg twice daily) was continued. Nicotine was discontinued. Locomotor and vocal tic disorders were controlled by the combined use of small doses of mecamylamine and haloperidol.

Patient 4 recently reported that his physician was unable to determine the cause of chronic fatigue that had begun prior to the start of mecamylamine therapy. There was no change in blood pressure. However, the patient discontinued mecamylamine and resumed the nicotine patch.

Patient 5 was a 18 year old male with the first visit at the age of 15. From the age of 10, Pimozide (Orap), Teva Pharmaceuticals (Teva Pharmaceuti
Cals) (Calpsville, PA) has been used to treat TS syndrome with 16 mg / day. The patient had a strong family history of tics. The patient's mother,
The maternal grandmother, maternal uncle and cousin all showed Tourette's syndrome. At the first visit, the patient was branded Prozac (fluoxetine hydrochloride, Eli.
12 mg pimozide was taken with Eli Lilly (Indianapolis, IN). He had a slight motor tic disorder, but he had a severe Parkinson-like expression and was depressed. Due to the tension, his fine tremor was exacerbated. When pimozide was reduced to 4 mg / day and Prozac was discontinued, depression and Parkinson-like symptoms except persistent hand tremor were alleviated. During the treatment period under the inventors, an aberrant EEG with moderate background division and a sharp movement for the left temporal region was observed. Patients were treated with carmavazepine, haloperidol and the brand name Cogentin (benztropine mesylate, Merck, West Point, PA) resulting in a marked reduction in motor and vocal tics . However, tremor persisted and obsessive-compulsive disorder became dominant. The patient said she couldn't concentrate on her work because she "wandered about somewhere else." Attempts at a nicotine patch resulted in nausea, headaches, and non-submission. Two months after visiting the clinic, they took a test dose of 2.5 mg mecamylamine. Within two hours, the patient said, "I'm feeling calm," and that I'm likely to be able to return to studying at a community college. Furthermore, the tremor of the hand, which had been complaining before mecamylamine administration, almost disappeared.

Patient 6 was a 23-year-old man who had had severe Tourette's syndrome since the second grade. Over the years, this patient has been treated with many neuroleptic agents, as well as clonidine and clonazepam (brand name Klonopin, Roche Laboratories, Inc., Nutley, NJ). At first visit, patients had been taking pimozide 12 mg / day for at least 2 years and were working as counselors in a camp for children with emotional disorders. The patient twice failed the exam of becoming a paramedic. The patient's Tourette's syndrome was the most severe of what we saw in our clinic. The patient was constantly on the move, reluctantly speaking, with tic-like distortion of the face, shrugging shoulders, and copropraxis (the patient's fingertips were pointing towards the groin),
The most common symptom was apologism. All words were emphasized, oppressed, delimited, and large, with interjections that originally had a sexual meaning. The patient was trying to hide with a smile and cheerfulness. However, the patient was afraid and depressed, and his fingers were clearly trembling. A neuropsychological test revealed severe visual movement disorders. A test dose of a 7 mg transdermal nicotine patch slightly weakened the intensity of tics and apocalypse. However, within 4 hours the patient complained of nausea and dizziness. The nicotine patch was applied once a day for one week while increasing the application time. However, side effects persisted and nicotine was discontinued.

Two weeks after nicotine was excreted from the body, 2.5 mg of mecamylamine was prescribed once a day. After 7 days, the patient reported that about 70% of the apology had disappeared. In the follow-up diagnosis at this time, not only was there a marked decrease in apocalypse, but the remaining whisper was. The restless movement stopped until the distortion of the face disappeared. Only slight shaking of the hands remained.

Patient 7 was a female high school student of 16 years old, and the first visit was in July 1997. He has a long history of Tourette's syndrome and is responsible for obsessive-compulsive disorder and depression.
Opin) 1 mg was taken 3 times a day, and a slight improvement in tic disorder was observed. twenty five
The addition of mg sertraline twice daily and the addition of a transdermal nicotine patch resulted in a marked improvement in tics and emotions. However, nicotine patch was discontinued immediately because of side effects of nicotine patch including headache and nausea. 8 of 1997
In the middle of the month, 2.5 mg of mecamylamine was prescribed, sertraline was gradually discontinued, and chronopin (Klonopin) was reduced to 1 mg / day. Within a few days, the patient reported that his tic disorder had "significantly reduced" and his irritability had subsided and he felt better. However, in early December 1997, the patient's mother reported that "aggression and loss of self-confidence" had begun to reappear and the sniffing vocal tic had rebounded. Mecamylamine was increased to 3.75 mg / day to reduce depression, dysphoria and irritability, some improvement in tics (+4 to +5 on a 10-point scale), and improved attitudes towards school and friends. There were no complaints about the side effects of mecamylamine.

Patient 8 was a small, lean, 9-year-old boy who was diagnosed with ADHD at the age of 5 and had methylphenidate (20 mg twice daily) about 6 months before visiting our clinic. Was taking. Methylphenidate increased alertness and a weak feeling of behavior, but he developed motor tic within 4 months after use. Therefore, he discontinued the use of methylphenidate and found that a 7 mg transdermal nicotine patch was not acceptable due to nausea. Mecamylamine had a minimal effect at 2.5 mg, but 3.75 mg / day suppressed hyperactivity and continued attention. The patient feels good,
Satan's voice "is no longer heard. On the overall improvement scale, the patient's mother rated it as +3 on a scale of 10. No side effects were reported during 210 days of use.

Patient 9 was a boy who visited our clinic at 11 months. Because of the patient's opposition, the patient's mother entrusted her to her paternal uncle in another state. When he returned to our clinic at the age of 14, his motor and vocal tics were still severe, but the patient was about to be treated. Symptoms were relieved with risperidone (2 mg / day) and a transdermal nicotine patch (7 mg / day, about twice a week). However, the patient was still moody, frustrated and complaining. Mecamylamine 2.5 mg
/ Day was added. Since her mother's addition of mecamylamine within three weeks, she has been "improving like never before", calming, blinking disappeared, and rage outbreaks diminished. During the 6-month telephone follow-up diagnosis period after starting mecamylamine, the patient's grandmother, the patient discontinued risperidone at will, and about 5 months after the start of treatment, also mecamylamine at will. Have been suspended. Patients continue to use nicotine patches "usually once a week or more". The patient's grandmother reported that the patient's tics were largely suppressed, but complained and occasionally angry.

Patient 10 is a 37-year-old smoking man with alcoholism. Is depressed,
He presented with severe and unacceptable apologetics and anxiety attacks, treated with antidepressants, benzodiazepines and haloperidol, with only minor improvement in symptoms. He was observing his medication, but was not effective. Mechamiramine 2.5 mg / day was started on July 1, 1997. The patient reported that he was "relaxed, spoke well (less apologetic) and became fluent". However, the patient complained of "headache and heartburn". On December 8, 1997, mecamylamine was re-administered. The initial dose of 2.5 mg suppressed verbs for about 1 hour, and the patient subsequently complained, "I was irritated and nervous." I stopped Mecamylamine.

Patient 11 is a 14 year old boy with Tourette's syndrome, ADHD, OCD, severe visual and motor impairment, anxiety, and loss of self-confidence. This patient's thumb peeling was associated with the patient feeling "imperfect" and physically different from his classmates. Symptoms were controlled to some extent with haloperidol. The transdermal nicotine patch enhanced the therapeutic effect of haloperidol, but the patient eventually refused the patch because of the discomfort and nausea of the patch. Mechamiramine 2.5 mg / day was started on July 17, 1997. Within 3 hours of the first dose, the patient's movements diminished and subsided. The severity of the patient's tics was significantly reduced. There were no side effects and blood pressure was maintained at 110-114 / 70-76. Within a week of starting mecamylamine, the patient's mother reported marked improvements in mood and behavior, reduced irritability, and pleasant involvement with her parents. "The patient has beaten his brother." He continued to reduce his haloperidone and clonidine doses. Mecamylamine lasted 215 days. During this period, the patient had "much improved" mood, behavior and attitude towards school. However, the persistent cough did not recover. Mecamylamine was discontinued and sertraline was started to relieve the cough. A nasty cough started only at meals. Considering returning to mecamylamine therapy.

Patient 12 was a boy who started methylphenidate at age 9 as a treatment for distraction and hyperactivity. He developed tic disorder in the month when he started methylphenidate. The symptoms of Tourette's syndrome, OCD and ADHD worsened. The patient was taking pimozide, haloperidol, Prozac and Paxil in combination, which gave him some control over his tics but increased his depression.
Also, due to the increase in dozing at school, he was away from school (second grader) for home study for two months before visiting the clinic of the inventors at the age of 14.5. The patient was gradually reduced from the many medications prescribed to only haloperidol 2 mg and clonidine was added, but the symptoms changed little. Symptoms were alleviated by using a transdermal nicotine patch (7 mg) twice a week. However, when nicotine was discontinued and mecamylamine 3.75 mg / day was added, there was a clear improvement in motor and vocal tics. Although the tic disorder remained slightly, it was remarkably reduced and the intensity was weakened. The patient's mood was relaxed. The patient is doing well at school and participating in a high school exercise program. The immaturity in the Bender-Gestalt test is no longer present. The patient's blood pressure was 114/80 in December 1997 and 100/70 on June 12, 1998. There were no complaints of side effects.

Patient 13 is a 12-year-old boy who has been examined at the inventor's office since the age of 9. From the age of four, motor and vocal tics and obsessive-compulsive behavior worsened,
It became worse after 7 years old. Repeated EEG showed abnormal "Grade 3 arrhythmia, simultaneous left-right independent centrality, and temporal spike waves in the crown". Tegretol exacerbated all symptoms. It has been difficult to control patient motility and vocal tics with standard prescriptions. Although nicotine helped alleviate tic disorder, the patient was associated with nicotine-sensitive and unacceptable side effects. 1997
Mecamylamine 2.5 mg / day was started on August 13, 2014. The patient said, "I'm calm,
I don't complain so much. " However, the improvement lasted only 3-5 days, the tic recurred and the headache worsened. Increasing the dose to 5 mg / day did not reduce tics but worsened the headache. Blood pressure was usually between 110/76 but decreased to 90/68. My heart rate was 68, instead of 70 to 76. I stopped Mecamylamine.

Patient 14 was a 9 year old boy. He was dysplastic in appearance, had a small build, had a triangular head, and was constantly moving, talking about his guns and weapons. Patients may have severe motor and vocal tics, abusive language, contact obsessive compulsive disorder,
He had obvious anxiety. The patient was prescribed multiple medications, including carmavazepine, methylphenidate, but only increased exercise. Haloperidol reduced patient activity, but the effect lasted only 3 weeks. The transdermal nicotine patch (7 mg) only caused nausea. Even with the use of mecamylamine 1.25 mg / day, he became more restless, crying and irritated. Mecamylamine was discontinued after 10 days.

Summary of Findings: As reported above, 12 of 14 patients had improved tics and mood after taking mecamylamine. All but one reported feeling relaxed. The medications eased the upset of two female patients. There was significant change in blood pressure in one patient at the dose taken. High doses of mecamylamine are used to treat hypertension, so the dose should be low,
It was acceptable enough. These patients had multiple symptoms. Patient 2 besides TS
Had ADHD and compulsion, both improved with the new treatment. Patients 3 and 7 also showed obsessive-compulsive behavior, which was reduced by mecamylamine treatment. Furthermore, patient 5 presented with tremor of the hand, which decreased after mecamylamine administration.
In this group of patients treated with mecamylamine, distraction, hyperactivity, tremor, obsessive-compulsive behavior, depression and mood agitation, and Tourette (To
urette) with motor and vocal tics.

The doses for these TS patients whose symptoms could not be controlled by conventional treatment are summarized in Table 1 below. The dose range was about 0.03-0.10 mg / kg. The calculation of Table 2 was performed using this range.

[0061]

[Table 1]

[Table 2] Other Uses In a recent report, nicotine was reported to cause schizophrenia (Adler, LE et al., Am
J Psychiatry 150: 1856-1861, 1993), attention deficit hypermobility disease (ADHD) (Levin, ED et al., Psychopharmacology 123: 55-62, 1995) and depression (Salin-Pascual). , RJ et al., Psychopharmacology 121 (4): 47.
6-479, 1995) has been suggested. It is generally believed that the therapeutic effect of nicotine in these "nicotine responsive" diseases is due to activation of nAChr (Decker, MW et al., Life Sci 56: 545-570, 1995.
However, like many other drugs, it is clear that nicotine has complex neuropharmacological effects. Therefore, many patients with such nicotine-responsive diseases can be treated with nAChr blockers, such as mecamylamine, which are disclosed herein by way of example, and nAChr blockers are nicotine-responsive diseases. There is T
Alleviated the symptoms of S and ADHD.

Schizophrenia is a mental disorder that is assumed to exhibit a dopamine excess state and is often treated with a neuroleptic drug, but there is an idea that it is a nicotine-responsive disease. For example, a survey of schizophrenic patients showed that smoking rates were 74% to 92%.
%, While 35% to 54% of all patients with psychosis and the general population
It was 30-35%. Smoking is thought to increase focus and reduce anxiety due to overstimulation and ameliorate potential psychosis (Gopalaswam
y), AK, Morgan, R, Br J Psychiatry 149: 523, 1986). In addition, nicotine may play some role in ameliorating the cognitive deficits associated with schizophrenia and neuroleptic treatment. Smoking normalizes sensory anomalies in schizophrenia patients (Adler, LE et al., Am J Psychiatry 150).
: 1856-1861, 1993), and a recent study found that transdermal administration of nicotine restored some of the cognitive side effects of standard antipsychotic treatment and It was discovered that cognitive performance was improved in patients with schizophrenia (Levin, ED et al., Psychopharmacology 123: 55-62, 1995).
Assuming that nicotine administration really has a similar effect to nAChr blocker administration, nAChr blockers such as mecamylamine and related compounds also restore some of the cognitive side effects of antipsychotic treatment, and It should be possible to improve cognitive ability in schizophrenic patients. In addition, nicotine enhances the therapeutic effect of neuroleptics on TS (McConville, BJ et al., Bi
Therefore, the dose of the neuroleptic drug can be increased by using mecamylamine as an adjunct to “neuroleptic responsiveness” diseases such as schizophrenia and Huntington's chorea. The side effects of neuroleptic drugs can be reduced without diminishing the therapeutic effect.

The above description and examples are merely illustrative and do not limit the scope of the invention.

[Brief description of drawings]

[Figure 1]   Chemical structural formulas of mecamylamine and several other nicotinic antagonists.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) A61K 31/445 A61K 31/445 31/505 31/505 31/54 31/54 A61P 25/00 A61P 25 / 00 25/18 25/18 25/24 25/24 C07D 471/06 C07D 471/06 491/16 491/16 // C07D 209/44 209/44 (31) Priority claim number US9720689 (32) Priority date Heisei November 7, 1997 (November 1, 1997) (33) Priority claiming countries United States (US) (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB , GR, IE, IT, LU, MC, NL, PT, SE), OA (BF, BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG ), AP (GH, GM, K E, LS, MW SD, SZ, UG, ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), AL, AU, BA, BB, BG, BR, CA, CN, CU, CZ, EE, GE, HR, HU, ID, IL, IS, JP, KP, KR, LC, LK, LR, LS, LT, LV, MG, MK, MN, MX, NO, NZ, PL, RO, SG , SI, SK, SL, TR, TT, UA, US, UZ, VN, YU (72) Inventor Shaitor, Roland Douglas, Florida 33549 Rats Sterling Silver Circle 18416 (72) Inventor Silver, Archie Aaron, Florida 33624 Tampa Hayward Place 13906 F Term (Reference) 4C065 AA03 AA07 BB04 BB11 CC01 CC09 DD02 EE02 HH01 JJ01 KK05 PP13 PP16 4C084 AA17 AA19 AA20 ZA121 ZA181 ZC422 4C086 AA01 AA02 BC10 BC21 BC39 BC89 CB05 CB09 CB22 GA07 GA10 GA12 MA02 MA04 MA10 ZA12 ZA18 4C204 BB01 CB04 DB01 EB01 FB03 FB16 GB24 4C206 AA01 AA02 FA29 KA04 KA06 MA02 MA04 ZA12 ZA18

Claims (12)

[Claims] 1. A method of treating a patient with a nicotine-responsive psychotic disorder requiring treatment, the method comprising administering to the patient an effective dose of a nicotine antagonist. 2. The nicotine-responsive mental illness is Tourette's syndrome, schizophrenia, depression, manic depression, attention deficit hyperactivity disorder, furious outbursts, obsessive compulsive disorder, or a combination thereof. The method of claim 1. 3. A method of treating a patient with a nicotine-responsive motor disorder requiring treatment, the method comprising administering to the patient an effective dose of a nicotine antagonist. 4. The method of claim 3, wherein the nicotine-responsive motor disorder is selected from the group comprising Tourette's syndrome, essential tremor, hemitonia dystonia and late movement disorder. . 5. A method of treating a patient with Tourette Syndrome in need of treatment comprising administering to the patient an effective dose of a nicotine antagonist. 6. A method of treating a patient with attention deficit dyskinesia that requires treatment, the method comprising administering to the patient an effective dose of a nicotine antagonist. 7. Treating patients with signs and symptoms including distraction, hyperactivity, tremor, obsessive-compulsive behavior, depression and mood swings, motor and vocal tics with Tourette syndrome, or a combination thereof. A method comprising administering to a patient an effective dose of a nicotine antagonist. 8. The nicotine antagonist is mecamylamine, a stereoisomer of mecamylamine, or an analog of mecamylamine.
~ The method according to 7. 9. The method of claims 1-7, wherein the nicotine antagonist is mecamylamine. 10. The method of claims 1-9, comprising the additional step of administering to the patient an effective dose of a neuroleptic drug. 11. The neuroleptic agent is selected from the group consisting of haloperidol, pimozide, fluphenazine and risperidone.
The method described. 12. The method of claims 1-5 and 7, wherein the effective dose is an amount that reduces the frequency and severity of tics in a patient.