Use of famotidine and related compounds in the treatment of movement disorders

The present invention relates to methods of treating movement disorders which comprise administering famotidine or a related compound to a subject in need of such treatment, wherein the motor disorder is selected from the group consisting of olivo-ponto-cerebellar atrophy, multi-system atrophy, Shy-Drager syndrome, kernicterus, Leigh's disease, cerebellar ataxias, neonatal hypoxemia syndromes, carbon monoxide poisoning, progressive supranuclear palsy, tardive dystonias, oculogyral crises, manganese poisoning, Wilson's Disease, Huntington's Disease, striatonigral degeneration, ingestion by the subject of phenothiazines, butyrophenones or reserpine, Alzheimer's Disease, normal pressure hydrocephalus, obstructive hydrocephalus, physiologic tremor, benign familial tremor, cerebellar tremor, rubral tremor, toxic tremor, metabolic tremor, senile tremor, chorea, ballism, athetosis, dystonia, tics, tardive dyskinesia, paroxysmal choreoathetosis, tonic spasm, akathisia, muscle rigidity, postural instability, bradykinesia, difficulty in initiating movements, muscle cramps, dyskinesias, myoclonus, and Creutzfeldt-Jacob Disease, and wherein the subject does not exhibit bradyphrenia. In preferred embodiments of the invention, the movement disorder is associated with an abnormality in basal ganglia structure or function. In a particularly preferred embodiment of the invention, the movement disorder is a component of Parkinson's Disease. The present invention is based, at least in part, on the discovery that Parkinson's Disease patients treated with famotidine reported improved motor function, diminished tremor, and decreased dyskinesias and "on/off" fluctuations in their response to conventional levodopa therapy.

INTRODUCTION 
The present invention relates to methods of treating movement disorders 
which utilize famotidine or famotidine-related compounds. It is based, at 
least in part, on the discovery that famotidine ameliorates the symptoms 
and signs of Parkinson's Disease. In preferred embodiments of the 
invention, famotidine or a famotidine-related compound may be used to 
treat neurological disorders which are associated with abnormalities in 
basal ganglia structure or function. 
BACKGROUND OF THE INVENTION 
2.1. NEUROLOGICAL MOVEMENT DISORDERS 
Components of the human nervous system which control movement may be 
classified into the following five categories: (1) "upper" motor neurons 
located in the cerebral cortex and their fiber projections to "lower" 
motor neurons in the spinal cord; (2) lower motor neurons in the spinal 
cord and their fiber projections to neuromuscular junctions; (3) brainstem 
nuclei which project to the spinal cord and control posture, automatic and 
repetitive movements; (4) two subcortical systems, namely the basal 
ganglia and the cerebellum, which control muscle tone, posture, and 
coordination of movement; and (5) cortical structures, such as the 
premotor and accessory motor cortex, which are involved in the planning 
and programming of voluntary movement (Adams and Victor, 1985, Principles 
of Neurology, Third Edition, McGraw-Hill Book Company, New York, 
pp.35-36). Conditions which disturb the structure and/or function of these 
components give rise to movement disorders that may be associated with 
paralysis, lack of coordination, or adventitious movements such as tics 
and tremor (Id.) 
2.2. DISORDERS OF THE BASAL GANGLIA 
The term "basal ganglia" refers to a group of subcortical structures which 
includes the caudate, putamen, globus pallidus, subthalamic nucleus, and 
substantia nigra (Adams and Victor, 1985, Principles of Neurology, Third 
Edition, McGraw-Hill Book Company, New York, p.53). The caudate, putamen 
and nucleus accumbens are often considered to be a single structure, 
referred to as the neostriatum or striatum, in which case the more medial 
region, which includes the globus pallidus, is termed the palleostriatum 
or pallidum (Adams and Victor, 1985, Principles of Neurology, Third 
Edition, McGraw-Hill Book Company, New York, p.54). 
The basal ganglia, which are interconnected with numerous central nervous 
system ("CNS") structures, are important for "fine-tuning" movements 
initiated in the cerebral cortex (Plum and Posner, 1985, "Neurology", 
reprinted from Pathophysiology--The Biological Principles Of Disease, 
Smith and Thier, eds., W. B. Saunders, Philadelphia, p.1040). The basal 
ganglia receive a signal from the cerebral cortex before the newly 
initiated movement begins, integrate the signal with input gathered from 
other CNS structures, and then return the synthesized information to the 
cortex, which modulates its instructions regarding the movement (Id.). In 
this manner, posture, the speed of initiation and continuity of movement, 
and the ability to perform several tasks at once are controlled. 
The important role played by the basal ganglia in motor function may be 
appreciated by considering the consequences of basal ganglia dysfunction. 
The manifestations of basal ganglia dysfunction, often referred to as 
"extrapyramidal symptoms" have been placed in five major categories: (1) 
dyskinesias including tremor, writhing movements ("athetosis"), distorted 
posturing ("dystonia"), rapid dance-like movements ("chorea"), and 
flinging of the extremities ("ballism"); (2) abnormal resistance of 
muscles to stretching; (3) disorders involving the initiation of movements 
and in the ability to perform successive motor acts; (4) prominent 
impairment of midline and other bilaterally innervated movements (e.g., 
abnormal speech); and (5) abnormal postural control (Plum and Posner, 
1985, "Neurology" reprinted from Pathophysiology--The Biological 
Principles Of Disease, Smith and Thier, eds., W. B. Saunders, 
Philadelphia, p.1066). Two well-known examples of basal ganglia disorders 
are Parkinson's Disease and Huntington's Chorea. 
2.3. KINSON'S DISEASE 
Parkinson's Disease is a prevalent, serious neurological disorder 
(afflicting approximately one-half million people in the United States; 
Bianchine, 1985, in The Pharmacological Basis of Therapeutics, Seventh 
Edition, Gilman et al., eds., Macmillan Publishing Co., New York, p. 473) 
which is associated with a number of clinical motor symptoms and signs, 
the most prominent of which are tremor, rigidity, and bradykinesia. The 
tremor of Parkinson's Disease is most characteristically observed in the 
patient's hands, which exhibit a distinctive "pill-rolling" movement 
(Patten, 1983, Neurological Differential Diagnosis, Springer-Verlag, New 
York, pp.125-126). The patient typically demonstrates rigidity in all 
muscle groups, resulting in stiffness of movement throughout the entire 
range (Id.). Bradykinesia, a slowing of movements, renders the execution 
of even the most routine daily tasks difficult or impossible (Id.). The 
consequent inability to rapidly adjust posture leaves the patient 
susceptible to tripping and falling (Id.). In addition to the motor 
symptoms, many Parkinson's Disease patients become depressed or demented 
(Sano et al., 1989, Arch. Neurol. 46:1284-1286). 
The physiological basis for Parkinson's Disease appears to lie in the 
degeneration of pigmented dopamine-synthesizing cells in the pars compacta 
of the substantia nigra (Plum and Posner, 1985 "Neurology", reprinted from 
Pathophysiology--The Biological Principles Of Disease, Smith and Thier, 
eds., W. B. Saunders, Philadelphia, p.1067). Although sometimes the result 
of exposure to toxins, in most instances, the cause of this degeneration 
is unknown (Id.) The loss of dopamine-producing cells has a profound 
impact on motor function because many neurons within the basal ganglia 
utilize dopamine as a neurotransmitter (Id.). Most current therapies for 
Parkinson's Disease attempt to compensate for this loss of 
dopamine-producing cells. 
The cornerstone of Parkinson's Disease treatment has been dopamine 
replacement therapy, in which levodopa (L-3, 4-dihydroxyphenylalanine) is 
administered together with an inhibitor of peripheral dopa decarboxylase 
enzyme (for example, carbidopa), which permits dopamine to cross the blood 
brain barrier in sufficient quantities. While levodopa therapy is 
initially beneficial to most Parkinson's Disease patients, its therapeutic 
effectiveness often declines after long-term treatment (Ludin and 
Bass-Verry, 1976, J. Neural Transm. 38:249-258). In particular, 
fluctuations in the response of motor symptoms to therapy ("on-off" 
phenomena; Marsden and Parkes, 1976, Lancet 1:292-296; Lewitt and Chase, 
1983, Trends Neurosci. 6:1) and drug-induced psychosis (Goodwin, 1971, 
JAMA 218:1915-1920) occur with relative frequency. While a number of 
agents, including bromocriptine, lisuride, amantadine, apomorphine, 
selegiline, trihexyphenidyl, benztropine mesylate, procyclidine 
hydrochloride, biperiden hydrochloride, ethopropazine hydrochloride, 
diphenhydramine hydrochloride, orphenadrine hydrochloride and pergolide 
have been used with varying success, none of these medications has proved 
to be completely satisfactory, and a better agent for treating the 
symptoms of Parkinson's Disease, which would provide continuous relief of 
symptoms without substantial adverse side effects has been sought (Akai et 
al., 1993, Ann. Neurol. 33:507-511). 
2.4. HISTAMINE RECEPTORS IN THE BRAIN 
Three species of histamine receptor have been identified in the brain, and 
are referred to as H.sub.1, H.sub.2, and H.sub.3 receptors. H.sub.1 and 
H.sub.2 receptors appear to occur in a number of tissues. H.sub.1 
receptors are coupled to inositol phospholipid hydrolysis, and are 
associated with a variety of functional responses, including smooth muscle 
contraction, increased vascular permeability, hormone release and cerebral 
glycogenolysis (Hill, 1992, Biochem. Soc. Transac. 20:122-125). H.sub.2 
receptors are positively coupled to adenylate cyclase and stimulate the 
formation of intracellular cyclic AMP, and are associated with gastric 
acid secretion, smooth muscle relaxation, cardiac muscle effects, and 
inhibition of lymphocyte function (Id.). H.sub.3 receptors are found in 
both the central and peripheral nervous systems, and regulate the release 
of a range of neurotransmitter substances. Whereas H.sub.1 and H.sub.2 
receptors in the nervous system are postsynaptically distributed, H.sub.3 
receptors are localized presynaptically (Schwartz et al., 1986, J. Exp. 
Biol. 124:203-224). 
The regional distribution of these receptors in the brain has been studied 
using radiolabelled, receptor-specific ligands. In particular, when 
radiolabelled iodobolpyramine, which binds to H.sub.1 receptors; 
radiolabelled iodoaminopotentidine, which binds to H.sub.2 receptors; and 
radiolabelled (R).alpha.-methylhistamine, which binds to H.sub.3 
receptors, were incubated with sections of human or monkey brain, the 
following results were obtained (as described in Martinez-Mir, 1990, Brain 
Res. 526:322-327). High densities of H.sub.1 receptors were observed in 
the most internal layers of the neocortex, claustrum, hippocampal 
formation and thalamus, and, perhaps nonspecifically, in the globus 
pallidus. H.sub.2 receptors were detected predominantly in the basal 
ganglia (in particular the caudate, putamen and accumbens nuclei), and to 
a somewhat lesser extent in the superficial layers of cerebral cortex, 
claustrum, globus pallidus, and hippocampal formation. H.sub.3 receptors 
were found to be particularly concentrated in the globus pallidus, 
caudate, putamen, and hippocampus, and, to a somewhat lesser extent, the 
external layers of the cortex. In human, monkey, and guinea pig brain, 
H.sub.1 receptors appeared to be particularly abundant in the neocortex 
whereas H.sub.2 and H.sub.3 receptors were observed to be enriched in the 
basal ganglia. It was suggested that drugs acting at these sites may 
influence the control of motor functions. 
Studies performed to evaluate the effects of centrally administered H.sub.2 
receptor antagonists on motor activity, performed in mice, indicated that 
two structurally distinct H.sub.2 receptor antagonists, cimetidine and BMY 
25,368, reduced locomotor activity (O'Neill and Gertner, 1987, Pharmacol., 
Biochem. Behavior 26:683-686). Similarly, Sakai et al. (1991, Life Sci. 
48:2397-2404) reported that a H.sub.3 antagonist, thioperamide, increased 
locomotor activity in mice (presumably by promoting histamine release) but 
that this increase could be blocked by pretreatment with either an H.sub.1 
or H.sub.2 -receptor antagonist (pyrilamine or zolantidine, respectively). 
A role of histamine in arousal is suggested (O'Neill and Gertner, 1987, 
Pharmacol., Biochem. Behavior 26:683-686; Sakai et al., 1991, Life Sci. 
48:2397-2404). 
Antihistamine compounds, such as diphenhydramine hydrochloride and 
orphenadrine hydrochloride, antagonists which act at the H.sub.1 histamine 
receptor, have been used to treat Parkinson's disease (Garbarg et al., 
1983, Lancet Jan. 1/8, p.74-75; Yahr and Duvoisin, 1972, N. Engl. J. Med. 
287:20). These drugs have been found to demonstrate limited efficacy 
(Bianchine, 1985, in The Pharmacological Basis of Therapeutics, Seventh 
Edition, Gilman et al., eds., Macmillan Publishing Co., New York, p. 484). 
Because H.sub.1 receptor antagonists have been used in the treatment of 
Parkinson's Disease (Yahr and Duvoisin, 1972, N. Engl. J. Med. 287:20), 
the levels of histidine decarboxylase, the specific synthesizing enzyme of 
histamine, were measured in Parkinson's Disease patients and compared with 
levels in normal controls (Garbarg et al., January 1/8, 1983, Lancet pp. 
74-75). The amount of histidine decarboxylase activity in Parkinson's 
Disease patients was found not to significantly differ from activity 
measured in normal controls, suggesting that histaminergic 
neurotransmission may not be affected and that, therefore, H.sub.1 
antihistaminics might still improve parkinsonian symptoms by reducing 
histamine neurotransmission (Id.). 
2.5. PRIOR USES OF FAMOTIDINE AND RELATED COMPOUNDS 
Famotidine and related compounds such as cimetidine and ranitidine are 
antagonists of the H.sub.2 receptor for histamine, and, as such, suppress 
gastric acid secretion. They are widely used in the treatment and 
prevention of gastric and duodenal ulcers, gastritis, reflux 
gastroesophagitis, gastrointestinal bleeding and pulmonary aspiration of 
acid (Langtry et al., 1989, Drugs 38: 551-590), and are associated with a 
low incidence of adverse reactions which, when they do occur, are 
generally minor (Douglas, 1985, in The Pharmacological Basis of 
Thereapeutics, Seventh Edition, Gilman et al., eds., Macmillan Publishing 
Co., New York, p. 626). More recently, these compounds, particularly 
famotidine, have been found to be useful as psychopharmaceutical agents in 
the treatment of the so-called negative symptoms of schizophrenia (see, 
for example, U.S. Pat. No. 5,177,081 by Kaminski, issued Jan. 5, 1993) and 
apathy-amotivation ("bradyphrenia") of Parkinson's Disease (Kaminski et 
al., 1994, New Trends Clin. Neuropharmacol., 8:306; U.S. patent 
application Ser. No. 07/954,258). No motor effects of these compounds had 
been documented prior to the present invention. 
3. SUMMARY OF THE INVENTION 
The present invention relates to methods of treating movement disorders 
which comprise administering famotidine or a famotidine-related compound 
to a subject in need of such treatment. In preferred embodiments of the 
invention, the movement disorder is associated with an abnormality in 
basal ganglia structure or function. In a particularly preferred 
embodiment of the invention, the movement disorder is a component of 
Parkinson's Disease. The present invention is based, at least in part, on 
the discovery that Parkinson's Disease patients treated with famotidine 
reported improved motor function, diminished tremor, and decreased 
"on/off" fluctuations in their response to conventional levodopa therapy.

4. DETAILED DESCRIPTION OF THE INVENTION 
For purposes of clarity of disclosure, and not by way of limitation, the 
detailed description of the invention is divided into the following 
subsections: 
(i) famotidine and famotidine-related compounds; 
(ii) movement disorders; and 
(iii) treatment regimens. 
4.1. FAMOTIDINE AND FAMOTIDINE-RELATED COMPOUNDS 
The present invention employs famotidine or famotidine-related compounds in 
the treatment of movement disorders, particularly those which are 
associated with abnormalities in basal ganglia structure or function. 
Famotidine, has the following structural formula: 
##STR1## 
and may be obtained under the trade name Pepcid. 
The term "famotidine-related compounds", as used herein, refers to 
compounds which are structurally or functionally related to famotidine. 
Structurally related compounds include enantiomers, isomers, analogs and 
derivatives of famotidine and compounds having structural formulas which 
exhibit substantial similarity to the structural formula of famotidine, as 
set forth above. For example, but not by way of limitation, a famotidine 
related compound may belong to the guanidinothiazole group of compounds. 
Compounds which are functionally related to famotidine include other 
H.sub.2 antagonists, including but not limited to ranitidine, cimetidine, 
nizatidine, omeprazole, tiotidine, zolantidine, aminofurazan compounds and 
ORF 17578. 
In certain non-limiting embodiments, famotidine-related compounds which may 
be used according to the invention may be identified by testing the 
ability of the compound to compete with famotidine for binding to a 
histamine receptor and/or to bind to brain tissue, and preferably basal 
ganglia tissue. For example, the techniques for evaluating the binding of 
histamine agonists and antagonists to brain tissue are well known (Schwarz 
et al., 1986, J. Exp. Biol. 124: 203-224; Bouthenet, 1988, Neuroscience 
26:553-600; Martinez-Mir, 1990, Brain Res. 526:322-327). Such techniques 
could be used to evaluate, for example, the ability of a putative 
famotidine-related compound to compete with radiolabelled famotidine for 
in situ binding to basal ganglia tissue. The ability to compete 
successfully with famotidine for binding sites (with either a stronger or 
weaker binding affinity compared to famotidine) would identify a compound 
as being famotidine-related. 
For example, and not by way of limitation, a famotidine-related compound 
may be identified by demonstrating the ability of the compound to inhibit 
the binding of radiolabelled famotidine or the binding of [.sup.125 I] 
iodoaminopotentidine to brain tissue, particularly to basal ganglia 
tissue. According to the latter embodiment, preparations of brain tissue, 
preferably human brain tissue, may be preincubated in 50 mM Na.sub.2 /K 
phosphate buffer, pH 7.4, at room temperature, followed by a 3 hour 
incubation at room temperature in the same buffer to which either 0.05 nM 
[.sup.125 I] iodoaminopotentidine alone, or in combination with various 
concentrations of putative famotidine-related compound, has been added. 
Non-specific H.sub.2 binding may be determined by incubating consecutive 
tissue sections in the presence of 3 .mu.M tiotidine. If the presence of 
putative famotidine-related compound decreases the amount of radioactivity 
bound, preferably in a dose-dependent manner, the compound may be 
considered to be famotidine related. Alternatively if, in analogous 
experiments which utilize radiolabelled famotidine, the presence of 
putative famotidine-related compound decreases the amount of radioactivity 
bound, preferably in a dose-dependent manner, then the compound may be 
considered to be famotidine-related. See, for example, Martinez-Mir, 1990, 
Brain Res. 526:322-327. 
4.2. MOVEMENT DISORDERS 
The present invention may be used to treat movement disorders, and in 
particular movement disorders associated with abnormalities in basal 
ganglia structure and/or function. Such movement disorders include, but 
are not limited to, the following. 
The present invention may be used in the treatment of (i) tremor, 
including, but not limited to, the tremor associated with Parkinson's 
Disease, physiologic tremor, benign familial tremor, cerebellar tremor, 
rubral tremor, toxic tremor, metabolic tremor, and senile tremor; (ii) 
chorea, including, but not limited to, chorea associated with Huntington's 
Disease, Wilson's Disease, ataxia telangiectasia, infection, drug 
ingestion, or metabolic, vascular or endocrine etiology (e.g., chorea 
gravidarum or thyrotoxicosis); (iii) ballism (defined herein as abruptly 
beginning, repetitive, wide, flinging movements affecting predominantly 
the proximal limb and girdle muscles); (iv) athetosis (defined herein as 
relatively slow, twisting, writhing, snake-like movements and postures 
involving the trunk, neck, face and extremities); (v) dystonia (defined 
herein as a movement disorder consisting of twisting, turning tonic 
skeletal muscle contractions, most, but not all of which are initiated 
distally); (vi) paroxysmal choreoathetosis and tonic spasm; (vii) tics 
(defined herein as sudden, behaviorally related, irregular, stereotyped, 
repetitive movements of variable complexity); (viii) tardive dyskinesia; 
(ix) akathesia, (x) muscle rigidity, defined herein as resistance of a 
muscle to stretch; (xi) postural instability; (xii) bradykinesia; (xiii) 
difficulty in initiating movements; (xiv) muscle cramps; (xv) dyskinesias 
and (xvi) myoclonus. 
The present invention may be used in the treatment of disorders with 
extrapyramidal symptoms and signs, including, but not limited to, 
olivo-ponto-cerebellar atrophy, multi-system atrophy, Shy-Drager syndrome, 
kernicterus, Leigh's disease, cerebellar ataxias, neonatal hypoxemia 
syndromes, carbon monoxide poisoning, progressive supranuclear palsy, 
tardive dystonias, oculogyral crises, manganese poisoning, Wilson's 
Disease, Huntington's Disease, striatonigral degeneration and conditions 
associated with the ingestion of compounds such as phenothiazines, 
butyrophenones, and reserpine. 
In a preferred, non-limiting embodiment, the present invention may be used 
to treat the motor symptoms of Parkinson's Disease, including, but not 
limited to, tremor, bradykinesia, rigidity, difficulty in initiating 
movements and postural instability. The term "Parkinson's Disease, as used 
herein, refers to conditions having the clinical features set forth above 
in Section 2.3, regardless of the pathogenesis. Advantageously, the 
present invention may be used to reduce the "on-off" phenomena and 
dyskinesias associated with conventional levodopa therapy. 
The present invention may also be used in the treatment of the motor 
symptoms of Alzheimer's Disease, normal pressure and obstructive 
hydrocephalus, and Creutzfeldt-Jacob Disease. 
4.3. TREATMENT REGIMENS 
The present invention provides for methods of ameliorating a motor symptom 
in a subject suffering from a movement disorder, as set forth in the 
preceding section, comprising administering, to the subject, a 
therapeutically effective amount of famotidine or a famotidine-related 
compound, as set forth in section 4.1. 
The phrase "ameliorating a motor symptom" refers to either subjective or 
objective improvement of a motor symptom, and does not require that the 
motor symptom be eliminated completely. Rather, the motor symptom may be 
rendered reduced to an extent that is noticeable by the subject or a 
clinician. Preferably, the reduction results in an improvement in the 
quality of life of the subject. 
Further, the present invention provides for a method of reducing the 
occurrence of "on-off" phenomena in a person suffering from Parkinson's 
Disease, comprising administering, to the subject, a therapeutically 
effective amount of famotidine or a famotidine-related compound. The 
phrase "reducing the occurrence", as used herein, refers to reducing 
either the frequency or severity of "on-off" phenomena or of increasing 
the time interval between fluctuations. 
The subject may be a human or non-human subject. 
A therapeutically effective amount is defined herein as an amount which 
ameliorates the motor symptoms and signs associated with a movement 
disorder or which reduces the occurrence of "on-off" phenomena in a 
patient suffering from Parkinson's Disease. Such dosage may vary from 
patient to patient, depending on the movement disorder being treated, the 
physical characteristics of the patient, the route of administration, and, 
where, a famotidine-related compound is being utilized, the potency and 
bioavailability of the compound, but may be ascertained using routine 
techniques, such as those described in Benet and Sheiner, Ross and Gilman, 
and Blaschke et al., 1985, in The Pharmacological Basis of Therapeutics, 
Seventh Edition, Gilman et al., eds., Macmillan Publishing Co., New York 
pp. 3-65. For example, if a subject is suffering from tremor, the subject 
may first be administered a low dosage of famotidine or a 
famotidine-related compound; if the patient's tremor is eliminated, the 
dosage may be maintained or reduced, but if the tremor is unchanged or 
insufficiently lessened, then the dosage may be incrementally increased 
until the tremor is reduced or until a therapeutic ceiling has been 
reached. 
According to the invention, famotidine or famotidine-related compound may 
be administered as a sole agent for the treatment of the motor disorder or 
in conjunction with another agent or agents. Such agents include, but are 
not limited to, levodopa, carbidopa, combinations of carbidopa and 
levodopa (e.g. trade name Sinemet), bromocryptine mesylate (e.g. trade 
name Parlodel), lisuride, pergolide mesylate (e.g. trade name Permax), 
selegiline hydrochloride (e.g. trade name Eldepryl), trihexyphenidyl 
hydrochloride (e.g. trade name Artane), benztropine mesylate (e.g. trade 
name Cogentin), orphenadrine citrate (e.g. trade name Norflex), Parsitan, 
Madopar, Benserazide, apomorphine, biperiden hyrochloride and biperiden 
lactate (e.g. trade name Akineton), diphenhydramine hydrochloride (e.g. 
trade name Benadryl), procyclidine hydrochloride (e.g. trade name 
Kemadrin), hyoscyamine sulfate (e.g. trade name Levsin), Ropinirole, 
Tolcapone, amantidine hydrochloride (e.g. trade name Symmetrel), 
cabergoline, other dopaminergic agonists, MAO-inhibitors, growth factors, 
COMT-inhibitors. 
In particular, non-limiting embodiments of the invention, an initial dose 
of between 20-160 mg famotidine, or an equivalent amount of 
famotidine-related compound, may be administered per day to a patient 
suffering from a movement disorder. In preferred embodiments of the 
invention, the initial dose may be between 40-80 mg famotidine, or an 
equivalent amount of a famotidine-related compound, administered orally 
per day. An equivalent amount of a famotidine-related compound refers to 
an amount of the famotidine-related compound having essentially the same 
functional activity as the specified amount of famotidine. The 
determination of what constitutes an "equivalent amount" of a 
famotidine-related compound may take into consideration how the potency 
and bioavailability of the famotidine-related compound compares to the 
potency and bioavailability of famotidine. For example, if a 
famotidine-related compound has twice the potency and the same 
bioavailability characteristics as famotidine, then if an initial dose of 
between 20-160 mg per day famotidine is recommended, the recommended 
initial dose of the famotidine-related compound would be 10-80 mg per day. 
The term "bioavailability", as used herein, refers to the extent to which 
a drug reaches its site of action or a biological fluid from which the 
drug has access to its site of action, as set forth in Benet and Sheiner, 
1985, in The Pharmacological Basis of Therapeutics, Seventh Edition, 
Gilman et al., eds., Macmillin Publishing Co., New York, p. 5. 
Further, according to this same particular non-limiting embodiment of the 
invention, the subject may then be observed for several weeks to determine 
whether his or her motor symptom or symptoms have improved. If they have 
improved substantially, it is preferred that the initial dose of 
famotidine or famotidine-related compound be maintained. If the motor 
symptom or symptoms have not shown any improvement, then the dose of 
famotidine or famotidine-related compound may be increased by between 
50-100 percent, again, taking into consideration the characteristics of 
the particular subject being treated. If, alternatively, the motor symptom 
or symptoms have improved somewhat, but not to a sufficient extent, then 
the dose of famotidine or famotidine-related compound may be increased by 
between 25-100 percent. The patient may then be reevaluated after several 
weeks, and the dose again adjusted, as set forth above. This process may 
be repeated until the desired therapeutic effect is obtained. The amount 
of famotidine administered may be increased to a maximum dose of about 600 
mg or until serious side effects appear. The maximum dose of 
famotidine-related compound may be equivalent but also may vary depending 
on the specific characteristics of the compound. 
In a preferred, non-limiting embodiment of the invention, an initial daily 
dose of between 40-80 mg oral famotidine, or an equivalent amount of 
famotidine-related compound, is administered to a human subject suffering 
from Parkinson's disease, in conjunction with that subject's previous 
treatment regimen (for example, but not by limitation, in addition to, 
that subject's levodopa treatment regimen). If the subject is not yet 
receiving other anti-Parkinsonism medication, then it may be appropriate 
to administer famotidine as the sole therapeutic agent. After several 
weeks, the motor symptoms and signs of the subject may be reevaluated. If 
the symptoms and signs have not improved, the dose may be increased by 
between 50-100%. If the symptoms and signs have not improved sufficiently, 
the dose may be increased by between 25-100%. The subject may then be 
again evaluated in several weeks, and the process repeated until the 
desired therapeutic effect is achieved. Maximum doses are as described 
above. 
In further embodiments of the invention, famotidine or famotidine-related 
compound may be administered subcutaneously, intramuscularly, 
intranasally, by inhalation, intravenously, intraperitoneally, 
intrathecally, or rectally. Famotidine or famotidine-related compound may 
also be administered via sustained release microparticles or implants. In 
addition, the dosing intervals may be adjusted to meet the needs of a 
particular subject and multiple doses per day may be administered. 
5. EXAMPLE: FAMOTIDINE DECREASED MOTOR SYMPTOMS OF KINSON'S DISEASE 
Four patients suffering from Parkinson's Disease were treated according to 
the invention with 80 mg/day of famotidine, administered orally. 
Prior to and during famotidine treatment, the patients were treated with 
the following medications: 
Patient No. 1 was treated with Symmetrel, 100 mg twice daily; Eldepryl, 5 
mg twice daily, and Sinemet 25/100, 1/2 tablet five times daily. 
Patient No. 2 was treated with Cogentin, 1 mg twice daily; Eldepryl, 5 mg 
twice daily; and Sinemet 25/100, one tablet three times daily. 
Patient No. 3 was treated with Cogentin, 1 mg twice daily; Nortryptyline 25 
mg before sleep; Eldepryl 5 mg twice daily; CR-Sinemet (50/200), 1/2 
tablet daily; and Sinemet 25/100, one tablet five times daily. 
Patient No. 4 was treated with Betoptic eye drops 0.25% to both eyes four 
times daily; Eldepryl 5 mg twice daily; and Sinemet 25/100, one tablet 
four times daily. 
About 2-3 weeks after famotidine treatment had been initiated, the 
following improvements in the motor symptoms of the patients were noted. 
Evaluation of motor symptoms was by standard neurological clinical 
examination. 
In Patent No. 1, tremor had nearly disappeared, on/off fluctuations had 
virtually disappeared, rigidity had improved, and dyskinesias had 
significantly improved. These clinical improvements have persisted for 
fifteen months to date. 
In Patient No. 2, tremor had significantly improved. This improvement 
continued for three months of famotidine therapy, at which point treatment 
was stopped for reasons unrelated to the patient's Parkinson's Disease. 
In Patient No. 3, tremor and on/off fluctuations had virtually disappeared, 
rigidity had improved and dyskinesias had significantly improved. These 
improvements have persisted for one year of famotidine therapy, except 
that a slight amount of tremor has reappeared. 
In Patient No. 4, tremor improved. This patient has been lost to follow-up. 
In neither patient who continues in the famotidine study has the stage of 
Parkinson's Disease advanced, an observation atypical of the standard 
course of the disease. 
Various publications are cited herein, each of which is hereby incorporated 
by reference in its entirety.