U.S. patent application number 15/413898 was filed with the patent office on 2017-07-13 for methods of treating patients suffering from movement disorders.
The applicant listed for this patent is KYOWA HAKKO KIRIN CO., LTD.. Invention is credited to Akira Karasawa, Hiroshi Kase, Yoshihisa Kuwana, Akihisa Mori, Yutaka Ohsawa, Yutaka Waki.
Application Number | 20170196872 15/413898 |
Document ID | / |
Family ID | 27663091 |
Filed Date | 2017-07-13 |
United States Patent
Application |
20170196872 |
Kind Code |
A1 |
Kase; Hiroshi ; et
al. |
July 13, 2017 |
METHODS OF TREATING PATIENTS SUFFERING FROM MOVEMENT DISORDERS
Abstract
The present invention is directed to methods of treating
movement disorders by administering an effective amount of one or
more adenosine A.sub.2A receptor antagonists to a patient in need
thereof. The present invention also provides methods of decreasing
the adverse effects of L-DOPA in patients receiving L-DOPA therapy
in the treatment of Parkinson's disease. The present invention
further provides methods and compositions for treating Parkinson's
disease patients with sub-clinically effective doses of L-DOPA by
combining L-DOPA treatment with an effective amount of one or more
adenosine A.sub.2A receptor antagonists (i.e., L-DOPA sparing
effect). The present invention further provides methods of
effective treatment of Parkinson's disease by co-administering at
least one adenosine A.sub.2A receptor antagonist, L-DOPA and a
dopamine agonist and/or a COMT inhibitor and/or a MAO inhibitor.
The present invention further provides methods of prolonging
effective treatment of Parkinson's disease by administering an
adenosine A.sub.2A receptor antagonist singly or together with a
dopamine agonist, and/or a COMT inhibitor, and/or a MAO inhibitor
without prior or subsequent administration of L-DOPA, delaying or
removing on-set of L-DOPA motor complication.
Inventors: |
Kase; Hiroshi; (Koganei-shi,
JP) ; Mori; Akihisa; (Narashino-shi, JP) ;
Waki; Yutaka; (Princeton, NJ) ; Ohsawa; Yutaka;
(Beckford Close, GB) ; Karasawa; Akira;
(Sunto-gun, JP) ; Kuwana; Yoshihisa; (Sunto-gun,
JP) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
KYOWA HAKKO KIRIN CO., LTD. |
Tokyo |
|
JP |
|
|
Family ID: |
27663091 |
Appl. No.: |
15/413898 |
Filed: |
January 24, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14227421 |
Mar 27, 2014 |
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15413898 |
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13297341 |
Nov 16, 2011 |
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14227421 |
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10353240 |
Jan 28, 2003 |
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13297341 |
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60352413 |
Jan 28, 2002 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0019 20130101;
A61K 31/198 20130101; A61K 9/48 20130101; A61K 9/20 20130101; A61K
31/522 20130101; A61K 45/06 20130101; A61P 25/00 20180101; A61P
25/16 20180101; A61P 25/14 20180101; A61P 25/02 20180101 |
International
Class: |
A61K 31/522 20060101
A61K031/522; A61K 9/00 20060101 A61K009/00; A61K 9/48 20060101
A61K009/48; A61K 45/06 20060101 A61K045/06; A61K 9/20 20060101
A61K009/20 |
Claims
1-50. (canceled)
51. A method of reducing or suppressing the adverse effectiveness
of L-DOPA and/or dopamine agonist therapy, comprising administering
an effective amount of
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically salt thereof to a Parkinson's disease patient.
52. The method according to claim 51, wherein the patient suffers
from L-DOPA- or other dopaminergic agent-induced motor
complications.
53. The method according to claim 52, wherein OFF time in motor
fluctuations is reduced.
54. The method according to claim 52, wherein dyskinesias in motor
complications are improved.
55. A method for L-DOPA sparing treatment comprising administering
to a patient in need thereof a combination of a subclinically
effective amount of L-DOPA and
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically acceptable salt thereof in an amount effective to
render the L-DOPA efficacious.
56. A composition for L-DOPA sparing treatment comprising a
subclinically effective amount of L-DOPA and
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically acceptable salt thereof in an amount of effective
to render the L-DOPA efficacious.
57. A method of treating Parkinson's disease and L-DOPA motor
complications, comprising administering an effective amount of
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically acceptable salt thereof in combination with at
least one of a COMT, DA or MAO inhibitor to a patient in need
thereof.
58. A composition for the treatment of Parkinson's disease
comprising an effective amount of
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically acceptable salt thereof, and a at least one of
COMT, DA or MAO inhibitor.
59. A method of prolonging effective treatment of Parkinson's
disease comprising administering either (i)
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically acceptable salt thereof, or (ii)
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically acceptable salt thereof and a dopamine agonist to
a patient in need thereof in an amount effective to delay or remove
the patient's need for add-on L-DOPA therapy.
60. A method of treating movement disorders comprising
administering an effective amount of
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine or a
pharmaceutically acceptable salt thereof to a patient in need
thereof.
61. The method according to claim 60, wherein the patient suffers
from tremors, bradykinesias, shuffling gait, dystonias,
dyskinesias, tardive dyskinesias or other extrapyramidal syndromes.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] The present application is a continuation of application
Ser. No. 14/227,421 filed Mar. 27, 2014, which in turn is a
continuation of application Ser. No. 13/297,341 filed Nov. 16,
2011, which in turn is a continuation of U.S. patent application
Ser. No. 10/353,240 filed Jan. 28, 2003, which in turn claims
benefit of U.S. Provisional Application No. 60/352,413 filed Jan.
28, 2002.
FIELD OF THE INVENTION
[0002] The present invention is directed to methods of treating
patients suffering from movement disorders comprising administering
at least one adenosine A.sub.2A receptor antagonist.
BACKGROUND OF THE INVENTION
[0003] Movement Disorders are neurological conditions characterized
by either a paucity or lack of movement (such as Parkinson disease)
or excessive movement (such as dystonia, dyskinesia, tremor,
chorea, ballism, akathisia, athetosis, bradykinesia, freezing,
rigidity, postural instability, myoclonus, and tics or Tourette
syndrome). See, Watts and William eds. (1997); and Shulman and
Weiner (1997).
[0004] Parkinson's Disease and Motor Complication
[0005] Parkinson's disease (paralysis agitans) is a disorder of the
brain characterized by shaking and difficulty with walking,
movement, and coordination. The disease is associated with damage
to a part of the brain that controls muscle movement.
[0006] Parkinson's disease was first described in England in 1817
by James Parkinson. The disease affects approximately 2 out of
1,000 people, and most often develops after age 50. The symptoms
first appear, on average, at about age 60, and the severity of
Parkinson's symptoms tends to worsen over time. It affects both men
and women and is one of the most common neurologic disorders of the
elderly. The term "parkinsonism" refers to any condition that
involves a combination of the types of changes in movement seen in
Parkinson's disease. Parkinsonism may be genetic, or caused by
other disorders or by external factors (secondary
parkinsonism).
[0007] In the United States, about a million people are believed to
suffer from Parkinson's disease, and about 50,000 new cases are
reported every year. Because the symptoms typically appear later in
life, these figures are expected to grow as the average age of the
population increases over the next several decades. The disorder is
most frequent among people in their 70s and 80s, and appears to be
slightly more common in men than in women.
[0008] The dopaminergic neurons of the substantia nigra pars
compacta and ventral tegmental area play a crucial role in
regulating movement and cognition, respectively.
[0009] Several lines of evidence suggest that the degeneration of
dopaminergic cells (i.e. dopamine-producing cells) in the
substantia nigra produces the symptoms of Parkinson's disease.
Dopaminergic cells, concentrated in the region of the substantia
nigra, are the fastest aging cells in the body. As dopaminergic
cells decay, control over movement is diminished and Parkinson's
disease develops.
[0010] Usually the first symptom of Parkinson's disease is tremor
(trembling or shaking) of a limb, especially when the body is at
rest. The tremor often begins on one side of the body, frequently
in one hand. Other common symptoms include other movement disorders
such as slow movement (bradykinesia), an inability to move
(akinesia), rigid limbs, a shuffling gait, and a stooped posture.
Parkinson's disease patients often show reduced facial expression
and speak in a soft voice. The disease can cause secondary symptoms
of depression, anxiety, personality changes, cognitive impairment,
dementia, sleep disturbances, speech impairments or sexual
difficulties. There is no known cure for Parkinson's disease.
Treatment is aimed at controlling the symptoms. Medications control
symptoms primarily by controlling the imbalance between the
neurotransmitters. Most early Parkinson's disease patients respond
well to symptomatic treatment with dopamine replacement therapy,
but disability increases with progression of the disease.
[0011] The medications used, the dose and the amount of time
between doses vary, depending on the case. The combination of
medications used may need to be adjusted as symptoms change. Many
of the medications can cause severe side effects, so monitoring and
follow-up by the health care provider is important.
[0012] Although currently available medications for Parkinson's
disease generally provide adequate symptomatic control for a number
of years, many patients develop motor fluctuations and dyskinesias
that compromise clinical response. Rascol et al. (2000); and
Parkinson Study Group (2000). Once this occurs, increasing
dopaminergic therapy is likely to worsen dyskinesias and decreasing
dopaminergic therapy is likely to worsen motor function and
increase OFF time. In light of this problem, attention has turned
to potential therapeutic manipulation of non-dopaminergic
neurotransmitter systems.
[0013] Most Parkinson's disease symptoms arise from a deficiency of
dopamine and most anti-Parkinson drugs restore dopamine or mimic
dopamine's actions. However, the drugs do not permanently restore
dopamine or exactly mimic dopamine's actions. While a loss of
dopamine cells in the substantia nigra is the main feature of
Parkinson's disease, non-dopamine nerve cells are also lost.
Moreover, dopamine-responsive cells are present not only in the
substantia nigra but in other brain regions. Thus drugs that are
effective in Parkinson's disease can, by stimulating these cells,
cause side effects such as nausea, hallucinations, and
confusion.
[0014] In 1967, L-DOPA was introduced and remains the most
effective anti-Parkinson drug. Symptoms most likely to benefit from
L-DOPA include bradykinesia, rigidity, resting tremor, difficulty
walking, and micrographia. Symptoms least likely to benefit from
L-DOPA include postural instability, action tremor, and difficulty
swallowing. L-DOPA may worsen dementia. Although L-DOPA provides
robust and rapid therapeutic benefits in Parkinson's disease,
eventually, severe adverse reactions to dopamine emerge, including
motor complications such as wearing off phenomenon, ON-OFF
fluctuations, and dyskinesia. Marsden et al. (1982). Once
established, motor complications are not typically controllable
with manipulation of L-DOPA or other dopaminergic drugs.
[0015] Early in Parkinson's disease L-DOPA is taken 3 times per
day. Peak concentrations in the brain occur 1 to 2 hours after
administrations. Although the drug has a short half-life (0.5 to 1
hour) there are sufficient remaining dopamine cells in the brain to
store dopamine and maintain its activity over several hours. As
Parkinson's disease progresses, more dopamine cells die and the
remaining cells cannot store sufficient dopamine to maintain its
benefits: the duration of action of each dose decreases and
patients need higher or more frequent doses. After 2-5 years as
many as 50-75% of patients experience fluctuations in their
response to L-DOPA: ON/OFF periods. Associated with the
fluctuations, patients develop dyskinesias. The dyskinesias usually
occur at the peak effect of L-DOPA but can also occur as the drug
wears off, or at stressful times. The fluctuations and dyskinesias
can seriously impact the patient's life. If L-DOPA is given
continuously (through an intravenous pump) ON/OFF effects disappear
and dyskinesias decrease. However, it is impractical to give L-DOPA
intravenously.
[0016] When L-DOPA is taken alone part of it is changed outside the
brain to dopamine by dopa-decarboxylase. The dopamine so produced
cannot enter the brain and causes side effects such as nausea,
vomiting, and appetite loss. Therefore L-DOPA is often combined
with carbidopa or benserazide. Carbidopa blocks dopa-decarboxylase
outside the brain allowing more L-DOPA to enter the brain without
causing nausea, vomiting, and appetite loss. Atamet or Sinemet are
tablets containing both carbidopa and L-DOPA. In combination with
carbidopa, the half-life of L-DOPA is 1.2 to 2.3 hours.
[0017] Thirty years after its discovery, L-DOPA is still the best
treatment for Parkinson's disease. In the early stages of the
disease, patients usually enjoy a good response to L-DOPA, but as
the disease progresses L-DOPA tends to become less helpful. This is
not due to loss of L-DOPA efficacy, but rather to development of
motor complications such as adverse fluctuations in motor response
including end-of-dose deterioration or "wearing-off", and the
"ON/OFF fluctuations" and dyskinesias. ON/OFF fluctuations are a
sudden, unacceptable loss of therapeutic benefit of a medication
("ON" state, during which the patient is relatively free from the
symptoms of Parkinson's disease) and onset of the parkinsonian
state ("OFF" state). Wearing off phenomenon is a decrease in the
duration of L-DOPA action, and characterized by the gradual
reappearance of the "off" state, and shortening the `on` state.
Dyskinesia can be broadly classified as chorea (hyperkinetic,
purposeless dance-like movements) and dystonia (sustained, abnormal
muscle contractions). In 1974, Duvoisin first focused on these
abnormal involuntary movements, and found that over half of
patients with Parkinson's disease developed dyskinesia within six
months of treatment. With increasing duration of treatment, there
is an increase in both the frequency and severity of dyskinesia. In
a seminal study of the potential benefits of possible
neuroprotectants in Parkinson's disease- the DATATOP trial- L-DOPA
induced dyskinesia was observed in 20-30% of patients who received
L-DOPA treatment for a mean of 20.5 months. Ultimately, most L-DOPA
treated patients experienced dyskinesia; up to 80% of patients
developed dyskinesia within five years of treatment. Parkinson
Study Group (1996); and Rascol et al. (2000). Treatment-related
dyskinesias are not solely a problem of L-DOPA, as dopamine
receptor agonists are also capable of eliciting dyskinesia. Thus,
the common term "L-DOPA-induced dyskinesia" could be used to
describe dopamine-treatment-related dyskinesia in general terms.
Most dyskinesias occur when levodopa or other dopamine receptor
agonists have a concentration in the brain that is sufficient to
overactive dopamine receptors in the putamen
(peak-dose-dyskinesia). However, dyskinesia also occurs when
dopamine concentration is low (OFF dystonia) or in stages when the
concentration of dopamine rises or falls (biphasic dyskinesia).
Other movement disorders, such as myoclonus and akathisia, might
also be components of the L-DOPA induced dyskinesia spectrum.
[0018] The biological basis of L-DOPA motor complications in
Parkinson's disease is still far from clear. It has been suggested
that they may involve not only advancing disease and continued loss
of nigral neurons, but also changes of dopamine receptor
sensitivity and their downstream expression of proteins, and genes,
the sequence of events of which relate, at least in part, to the
dose and method of administration of L-DOPA or dopamine agonists.
Changes in non dopamine systems such as glutamate-mediated
neurotransmission, GABA-mediated neurotransmission, and opioid
peptide mediated transmission, might also be involved in the
neuronal mechanisms that underlie L-DOPA motor complications in
Parkinson's disease. Bezard et al. (2001). Notably, it seems that
the short plasma half-life and consequent short duration of action
of dopaminergic agents and the pulsatile stimulation of dopamine
receptors by dopaminergic agents are associated with motor
fluctuations and peak-dose-dyskinesias. All these events combine to
produce alterations in the firing patterns that signal between the
basal ganglia and the cortex.
[0019] Originally introduced as adjunctive therapy to L-DOPA in
patients with fluctuations, dopamine agonists are now increasingly
proposed as monotherapy in early patients. The antiparkinsonian
effects of dopamine agonists, however, are usually less than those
of L-DOPA, and after two to four years their efficacy wanes. When
more potent treatment is required, low doses of L-DOPA can be
"added on" to the agonist. An alternative strategy is to combine an
agonist with low doses of L-DOPA from the beginning. Both
strategies are purported to be as effective as L-DOPA and to have
the advantage of significantly reducing the risk of motor
fluctuations and dyskinesias. These claims, however, are based upon
a small number of pilot studies, all of which suffer from
methodological shortcomings.
[0020] Additionally, dopamine receptor agonists are also capable of
eliciting dyskinesia. Dopamine agonists also provoke dyskinesia in
parkinsonian animals previously exposed by L-DOPA. Neuropsychiatric
side effects, especially hallucination and psychosis, often limit
the use of dopamine agonists. Despite the potential benefits
provided by the adjunctive use of dopamine agonists, L-DOPA motor
complications can thus be extremely difficult or even impossible to
control. See, Olanow, Watts and Koller eds. (2001). Finally,
dopamine agonists are sometimes used in monotherapy as substitutes
for L-DOPA in patients with advanced Parkinson's disease and severe
motor fluctuations and dyskinesias.
[0021] More recently, catecholamine-O-methyltransferase (COMT)
inhibitors such as tolcapone and entacapone have been proposed as
adjunctive therapy to L-DOPA. These compounds extend the plasma
half-life of L-DOPA, without significantly increasing C.sub.max.
Thus, they decrease the duration of wearing-off but tend to
increase the intensity of peak-dose side effects including
peak-dose-dyskinesias. Tolcapone appears to induce significant
liver toxicity in a small percentage of patients.
[0022] Anti-cholinergics such as tri-hexiphenidyl (Artane) and
biperidine (Cogentin) block the actions of acetylcholine in the
brain. This may result in a mild to moderate degree of improvement
in symptoms such as drooling and tremor.
[0023] Patients above age 65 are likely to experience side effects
such as dry mouth, blurred vision, constipation, confusion and
hallucinations when treated with anti-cholinergics.
[0024] Dystonias
[0025] The term dystonia refers to a movement disorder
characterized by sustained muscle contractions resulting in a
persistently abnormal posture. Based on this definition, there are
a number of dystonic syndromes, which can be subdivided according
to their clinical features as: generalized (affecting all body
parts); segmental (affecting adjacent body parts); or focal
(restricted to a single body part). Focal dystonias include
spasmodic torticollis, blepharospasm, hemifacial spasm,
oromandibular dystonia, spasmodic dysphonia, and dystonic writer's
cramp.
[0026] There are several degrees of dystonia. Some people can
maintain a relatively normal life-style, while others are
permanently hindered, often needing full time assistance.
[0027] Symptoms may be focal or limited to one region of the body,
such as the neck or an arm or a leg. There are many different types
of focal dystonia. Blepharospasm is marked by involuntary
contraction of the muscles that control the movement of the
eyelids. Symptoms may range from intermittent, painless, increased
blinking to constant, painful, eye closure leading to functional
blindness. In patients with cervical dystonia (CD), also known as
spasmodic torticollis, muscle spasms of the head and neck may be
painful and cause the neck to twist. These sometimes painful spasms
may be intermittent or constant. Oromandibular and lingual dystonia
is characterized by forceful contractions of the lower face causing
the mouth to open or close. Chewing and unusual tongue movements
may also occur. In spasmodic dysphonia (SD), also known as
laryngeal dystonia, the muscles in the voice box (larynx) are
affected. SD is marked by difficulties either opening or closing
the vocal cords, causing the voice to have either a strained,
hoarse, strangled, or whispering quality. In limb dystonia, there
are involuntary contractions of one or more muscles in the arm,
hand, leg, or foot. These types of focal dystonias include writer's
cramp and other occupational dystonias.
[0028] Some patients have symptoms that are segmental or involve
two adjacent areas of the body, such as the head and neck or arm
and trunk. In other patients, symptoms may be multifocal or appear
in two areas of the body that are not next to each other, such as
the two arms, or an arm and a leg. In generalized dystonia,
symptoms begin in an arm or a leg and advance, becoming more
widespread. Eventually, the trunk and the rest of the body are
involved.
[0029] Most cases of primary or idiopathic dystonia are believed to
be hereditary and occur as the result of a faulty gene(s). In these
patients, dystonia occurs as a solitary symptom and is not
associated with an underlying disorder. For example, most cases of
early-onset primary dystonia are due to a mutation in the DYT-1
gene. Early-onset dystonia that occurs as a result of this disease
gene is the most common and severe type of hereditary dystonia.
Other genetic causes of primary dystonia are rare.
[0030] Diseases involving dystonias include hereditary spastic
paraplegia (HSP), a group of genetic, degenerative disorders of the
spinal cord characterized by progressive weakness and stiffness of
the legs; Huntington's disease (HD) a hereditary progressive
neurodegenerative disorder characterized by the development of
emotional, behavioral, and psychiatric abnormalities and movement
abnormalities; multiple system atrophy (MSA) a neurodegenerative
disease marked by a combination of symptoms affecting movement,
blood pressure, and other body functions; pathologic myoclonus;
progressive supranuclear palsy; restless legs syndrome; Rett
syndrome; spasticity; Sydenham's chorea; Tourette syndrome; and
Wilson disease.
[0031] Dystonia may occur because of another underlying disease
process such as Wilson disease, multiple sclerosis, stroke, etc.;
trauma to the brain, such as injury during a vehicular accident or
anoxia during birth; or as a side effect of a medication. This type
of dystonia is termed secondary or symptomatic dystonia. In adults,
the most common type of secondary dystonia is tardive dystonia,
which occurs as a result of the use of certain neuroleptic or
antipsychotic drugs (used to treat psychiatric disorders). These
drugs include haloperidol (Haldol.RTM.) or chlorpromazine
(Thorazine.RTM.). Other drugs that block central dopamine receptors
may also cause tardive dystonia. In most patients, symptoms occur
some time after ongoing exposure to the drug. Table 1 provides a
list of drugs that can cause dystonia.
TABLE-US-00001 TABLE 1 Generic (Trade Names) Acetophenazine (Tindal
.RTM.) Amoxapine (Asendin .RTM.) Chlorpromazine (Thorazine .RTM.)
Fluphenazine (Permitil .RTM., Prolixin .RTM.) Haloperidol (Haldol
.RTM.) Loxapine (Loxitane .RTM., Daxolin .RTM.) Mesoridazine
(Serentil .RTM.) Metaclopramide (Reglan .RTM.) Molindone (Lindone
.RTM., Moban .RTM.) Perphenazine (Trilafon .RTM. or Triavil .RTM.)
Piperacetazine (Quide .RTM.) Prochlorperazine (Compazine .RTM.,
Combid .RTM.) Promazine (Sparine .RTM.) Promethazine (Phenergan
.RTM.) Thiethylperazine (Torecan .RTM.) Thioridazine (Mellaril
.RTM.) Thiothixene (Navane .RTM.) Trifluoperazine (Stelazine .RTM.)
Triflupromazine (Vesprin .RTM.) Trimeprazine (Temaril .RTM.)
[0032] There are a number of options available to treat dystonia.
Drugs may be used alone or in combination. In addition, they may be
combined with other forms of treatment. Drugs currently in use
include botulinum toxin (BTX), benzodiazepines, Baclofen,
anticholinergics and dopamine-blocking agents/dopamine-depleting
agents. Surgical treatment is also available and includes
thalamotomy, pallidotomy, deep brain stimulation, myectomy
(myotomy), ramisectomy, rhizotomy and peripheral denervation.
[0033] Tardive Dyskinesia and Other Extrapyramidal Syndromes
[0034] The extrapyramidal system of the nervous system is centered
on the basal ganglia and influences motor control through pyramidal
pathways, generally by means of input to the thalamus. When the
extrapyramidal system is disturbed, motor control is affected and
patients suffer extrapyramidal syndromes. These are a combination
of neurological effects that include tremors, chorea, athetosis,
and dystonia. This is a common side effect of neuroleptic agents.
Other medications known to cause these reactions include
haloperidol, molindone, perphenazine and aminotriptyline, loxapine,
pimozide, and rarely, benzodiazepines.
[0035] Tardive dyskinesia is an involuntary neurological movement
disorder. Depending upon the type of onset, a differential
diagnosis might include Sydenham's chorea, Huntington's chorea,
congenital torsion dystonia, hysteria, and the stereotyped behavior
or mannerism of schizophrenia. American College of
Neuropsychopharmacology-FDA Task Force (1973). Tardive dyskinesia
results from the use of neuroleptic drugs that are prescribed to
treat certain psychiatric or gastrointestinal conditions. Long-term
use of these drugs may produce biochemical abnormalities in the
striatum. Tardive dystonia is believed to be the more severe form
of tardive dyskinesia.
[0036] Other closely related, untreatable neurological disorders
have now been recognized as variants of tardive dyskinesia. Tardive
akathisia involves painful feelings of inner tension and anxiety
and a compulsive drive to move the body. In the extreme, the
individual undergoes internal torture and can no longer sit still.
Tardive dystonia involves muscle spasms, frequently of the face,
neck and shoulders, and it too can be disfiguring, disabling and
agonizing.
[0037] Treatment of tardive dyskinesia has been unsatisfactory.
Removal of the antipsychotic agent is often advocated (Baldessarini
(1990)) but often results in more severe forms of the movement
disorder. Various pharmaceutical agents have been tried with some
reported success; early investigators in this area turned their
attention to reserpine (Serpasil.RTM., tradename of Ciba-Geigy) a
compound known to deplete dopamine levels. Reserpine and
.alpha.-methyldopa (Aldomet.RTM.) in the treatment of long-standing
tardive dyskinesia showed that both compounds were statistically
more effective than placebo in reducing symptomatology. Huang et
al. (1981). However, another study showed that, catecholamine
synthesis blockers such as .alpha.-methyldopa have not demonstrated
a beneficial effect on tardive dyskinesia. AMPT, an experimental
agent that inhibits tyrosine hydroxylase, the rate-limiting step in
the synthesis of dopamine and norepinephrine, has shown partial
reduction of dyskinesia.
[0038] Formerly, tardive dyskinesia was often treated by increasing
the dose of the neuroleptic. This initially treats the
pathophysiology of tardive dyskinesia but can aggravate the
pathogenesis by further denervation and subsequent
hypersensitivity. Thus, the movements may decrease or disappear
initially but then reappear later. The use of the atypical
neuroleptic, clozapine may be useful in certain situations in which
patients with disfiguring tardive dyskinesia need neuroleptic
treatment alternative.
[0039] Lithium interferes with the presynaptic release of
monoamines as well as having other actions on the CNS. Two studies
report mild improvement in tardive dyskinesia with lithium while
two others report no improvement or exacerbation. Tepper and Haas
(1979).
[0040] Oral pimozide caused improvement in degree of movement.
Claveria et al. (1975). Buspirone (BuSpar.RTM.), a partial
serotonin receptor agonist, may also be useful in treating the
condition. Moss et al. (1993). In rats, buspirone reverses the DA
receptor subsensitivity induced by chronic neuroleptic
administration, and it is this effect that may also occur in humans
due to partial agonist effects at D2 receptors. Reports have
associated tardive dyskinesia with reserpine, tetrabenazine,
metoclopramide, tricyclic antidepressants, benztropine, phenytoin
and amphetamines.
[0041] Other than neuroleptics, the drug that regularly produces
dyskinesia is L-DOPA and other dopaminergic agents, in patients
receiving these drugs for Parkinson's diseases. L-DOPA actually can
improve neuroleptic-induced tardive dyskinesia.
[0042] There is no accepted treatment for tardive dyskinesia. Casey
(1999). Either discontinuing the offending antipsychotic or
switching a patient to an atypical antipsychotic (with the possible
exception of risperidone) may alleviate the movement disorder. The
treatment of tardive dyskinesia has been recently reviewed. Egan et
al. (1997). Most pharmacologic treatment strategies are directed
toward reducing dopamine activity or enhancing CNS cholinergic
effect. If the etiology of tardive dyskinesia relates to chronic
dopaminergic receptor site blockade and the pathophysiology relates
to the denervation hypersensitivity, agents that interrupt this
sequence would, theoretically, be of potential benefit.
[0043] Many drugs have been tried in treating neuroleptic-induced
tardive dyskinesia. Because of differences in patient populations,
study design, and doses of agents used, the results for individual
agents are conflicting. Baldessarini and Tarsy (1978); and Klawans
et al. (1980).
[0044] Amine depleting agents e.g., reserpine and tetrabenazine,
act by blocking the reuptake of dopamine, norepinephrine, and
serotonin into the presynaptic neuronal storage vesicles, thereby
depleting the brain of these substances. Studies with these agents
have indicated improvement in tardive dyskinesia but side effects
have limited their use and the studies are of short duration.
Short-term suppression may occur as reported with neuroleptics.
[0045] Several cholinergic agonists have been administered to
patients with tardive dyskinesia. Choline chloride and
phosphatidylcholine (lecithin), which are orally bioavailable
precursors of acetylcholine, have been reported to be useful in
short-term studies. Deanol acetaminobenzoate was originally
reported to be efficacious in the treatment of tardive dyskinesia,
but other studies have not confirmed these findings. Gelenberg et
al. (1990).
[0046] There have been several attempts to treat tardive dyskinesia
with drugs believed to potentiate central GABA mechanisms. Thaker
et al. (1990). In a study involving 10 patients with tardive
dyskinesia of greater than a 6 month duration, benztropine 2 mg IV
increased dyskinetic movements in 7 patients and reduced them in
the remaining three. Moore and Bowers (1980). In a preliminary
report the 3-adrenergic blocking agent propranolol (Inderal.RTM.)
in a dose of 30-60 mg/day produced marked resolution of tardive
dyskinesia within 1 to 10 days of treatment in four patients.
Wilbur and Kulik (1980).
[0047] Several studies have examined the effectiveness of treating
tardive dyskinesia with vitamin E. Adler et al. (1999); Lohr and
Caligiuri (1996); Lohr et al. (1988); Elkashef et al. (1990);
Shriqui et al. (1992); Egan et al. (1992); Adler et al. (1993a);
Adler et al. (1993b); Goldberg (1996); McCreadie et al. (1994);
Dabiri et al. (1993); Bischot et al. (1993); Akhtar et al. (1993);
and Dabiri et al. (1994).
[0048] It was previously thought that in the majority of patients,
tardive dyskinesia is permanent or irreversible. However, this is
not necessarily the case. The earlier tardive dyskinesia is
diagnosed and the neuroleptic discontinued, the better the
prognosis for disorder reversal. In young adults, tardive
dyskinesia disappears within several weeks after early drug
withdrawal. Uhrbrand and Faurbye (1960); Itoh et al. (1981);
Driesens (1988); and Gardos et al. (1994).
[0049] Table 2 summarizes various agents that have been used to
treat tardive dyskinesia.
TABLE-US-00002 TABLE 2 Classes of Agents Specific agents Dopamine
antagonists Butyrophenones, clozapine, metoclopramide (Karp et al.
(1981)), papaverine (mechanism uncertain), phenothiazines,
bromocriptine, pimozide Dopamine D2 Agonists Buspirone
Amine-depleting agents Reserpine, tetrabenzine Blocker of
catecholamine .alpha.-methyldopa, .alpha.-methyltyrosine (AMPT)
synthesis Catecholamine release Lithium salts blocker Cholinergic
agents Deanol, physostigmine, choline and lecithin GABA agonists
Progabide (Bartholini (1983)), valproic acid, baclofen, iazepam,
clonazepam Anticholinergic agents. Benztropine, trihexyphenidyl
Moore et al. (1980) Agents with variable, .alpha.-methyldopa,
amantadine, anticholinergics negligible, or antihistamines,
apomorphine, barbiturates, uncertain effects benzodiazepines,
methylphenidate, penicillamine, physostigmine, pyridoxine (B6),
tryptophan, .alpha.-tocopherol (Vitamin E) Agents that worsen
Anticholinergic agents, antiparkinson agents tardive dyskinesia
(e.g., benztropine), dopamine agonists, amphetamines, L-DOPA Newer
investigational endopioids, Substance P, Cholecystokinin, agents
(peptides). Ceruletide, Neurotensin, Cyclo-Leucine- Blurn et al.
(1983) Glycine
[0050] Other motor syndromes caused by the effects of neuroleptic
drugs on the extrapyramidal system include drug induced
parkinsonism, akathisia, dystonia, oculogyric crisis, and
opisthotonus. Akathisia is a condition that is characterized by
motor restlessness, which may range from anxiety to an inability to
lie or sit quietly, or to sleep, and possible causes include a
toxic reaction to neuroleptics such as phenothiazine. An oculogyric
crisis is the paroxysmal, involuntary upward deviation of the eyes.
The eyelids are often retracted. Attacks last from a few minutes to
a few hours. It may occur in patients sensitive to phenothiazines,
haloperidol, and metoclopramide. Opisthotonus is a form of spasm in
which head, neck and spine are arched backwards
[0051] Adenosine A.sub.2A Receptors
[0052] Adenosine is known to act via four major receptor subtypes,
A.sub.1, A.sub.2A, A.sub.2B, A.sub.3, which have been characterized
according to their primary sequences. Fredholm et al. (1994).
Adenosine A.sub.2 receptors are further divided into A.sub.2A
(high-affinity) and A.sub.2B (low-affinity) subtypes. Daly et al.
(1983); and Burns et al. (1986). In contrast to the widespread
distribution of A.sub.1, A.sub.2B, and A.sub.3 receptors in the
brain, A.sub.2A receptors are highly localized to the basal
ganglia, especially to the caudate-putamen (striatum), nucleus
accumbens and globus pallidal, and the olfactory tubercles. Jarvis
et al. (1989); and Schiffmann (1991b). The basal ganglia are
located in the telencephalon and consist of several interconnected
nuclei: the striatum, globus pallidus external segment (GPe),
globus pallidus internal segment (GPi), substantia nigra pars
compacta (SNc), substantia nigra pars reticulata (SNr), and
subthalamic nucleus (STN). The basal ganglia are a critical
component of subcortical circuits involved in the integration of
sensorimotor, associative, and limbic information to produce motor
behavior. A major component of basal ganglia is the striatum, where
GABAergic medium spiny neurons, which represent more than 90% of
striatal neuronal population, are the only projection neurons.
[0053] The medium spiny neurons receive massive glutamatergic
inputs from the cortex and thalamus, and project their GABAergic
output onto the major output nuclei of basal ganglia, i.e. GPi and
SNr, via the striatopallidal medium spiny neurons in an "indirect
pathway" and the striatonigral medium spiny neurons in a "direct
pathway." Alexander et al. (1990); Gerfen (1992); and Graybiel
(1990). The medium spiny neurons also receive intrastriatal
GABAergic, cholinergic, and nigrostriatal dopaminergic modulatory
inputs. Neurons of the striatonigral direct pathway contain GABA
plus substance P/dynorphin and directly project from the striatum
to GPi/SNr. These neurons provide a direct inhibitory effect on
GPi/SNr neurons. Striatal neurons in the striatopallidal indirect
pathway contain GABA plus enkephalin and connect the striatum with
the GPi/SNr via synaptic connections in the GPe and STN. In these
neurons, A.sub.2A receptors are located almost exclusively on
striatopallidal medium spiny neurons in the striatum and globus
pallidus of the indirect pathway [Schiffmann et al. (1991a)], and
acetylcholine-containing large aspiny interneurons in the striatum
[Dixon et al. (1996)], and have been shown to modulate the
neurotransmission of GABA, acetylcholine and glutamate. Kurokawa et
al. (1996); Mori et al. (1996); Shindou et al. (2001); Ochi et al.
(2000); Richardson et al. (1997); and Kase (2001).
[0054] Recent advances in neuroscience together with development of
selective agents for the A.sub.2A receptors have contributed to
increased knowledge about adenosine and the adenosine A.sub.2A
receptor. Behavioral studies show that adenosine A.sub.2A receptor
antagonists improve motor dysfunction of several parkinsonian
animal models (e.g., MPTP-treated monkeys), but also reveal
features of A.sub.2A receptor antagonists distinctive from
dopaminergic agents. Richardson et al. (1997); and Kase (2001).
[0055] The antiparkinsonian effects of the selective adenosine
A.sub.2A receptor antagonist KW-6002 have been studied in
MPTP-treated marmosets and cynomologus monkeys. Kanda et al.
(1998a); Grondin et al. (1999); and Kanda et al. (2000). In
MPTP-treated marmosets, oral administration of KW-6002 induced an
increase in locomotor activity lasting up to 11 hours in a
dose-related manner. Kanda et al. (1998a). Locomotor activity was
increased to the level observed in normal animals whereas L-DOPA
induced locomotor hyperactivity. Furthermore, in L-DOPA-primed
MPTP-treated marmosets, treatment with KW-6002 for 21 days induced
little or no dyskinesias whereas under the same conditions,
treatment with L-DOPA induced marked dyskinesias. When KW-6002 (20
mg/kg) was administered once a day for 5 days with a threshold dose
of L-DOPA to
[0056] MPTP-treated marmosets primed to exhibit dyskinesias,
antiparkinson activity was potentiated without an increase in
dyskinesia. Kanda et al. (2000). KW-6002 also additively increased
the antiparkinsonian effect of quinpirole, a dopamine D2 receptor
agonist but not SKF80723, a dopamine D1 receptor agonist. Taken
together, these findings suggest that adenosine A.sub.2A
antagonists might provide antiparkinsonian benefit as monotherapy
in patients with early Parkinson's disease and might be able to
improve antiparkinsonian response without increasing dyskinesia in
L-DOPA-treated patients with motor complications.
[0057] Although the mechanisms by which adenosine A.sub.2A
antagonists exert an antiparkinsonian effect remain to be fully
elucidated, the following mechanism is now proposed.
[0058] In either Parkinson' s disease or MPTP treatment of
primates, following destruction of the nigro-striatal dopaminergic
pathway, the most relevant alteration is hyperactivity in the
striatopallidal pathway, and such hyperactivity is attributed to an
imbalance between the direct striatonigral pathway and the indirect
striatopallidal pathway to give rise to parkinsonian state. DeLong
(1990); and Obeso et al. (2000). It is noted that A.sub.2A
receptors are specifically expressed on a subpopulation of medium
spiny neurons, the striatopallidal medium spiny neurons but not the
striatonigral medium spiny neurons.
[0059] The GABAergic striatopallidal medium spiny projection neuron
was found as one of major target neurons of A.sub.2A
receptor-mediated modulation. Kase (2001). Thus, in the striatum,
A.sub.2A receptors control excitability of the projection neurons
through the intrastriatal GABAergic feedback/feedforward inhibition
network [Mori et al (1996)], and in the globus pallidus (GPe),
A.sub.2A receptor activation enhances GABA release from the nerve
terminals and might suppress excitability of GPe projection
neurons, which project to subthalamus nucleus (STN) [Shindou et al.
(2001)]. A.sub.2A receptor antagonists selectively block this "dual
modulation mechanism in the striatopallidal system", leading to
suppression of the excessive activation in the striatopallidal
medium spiny neurons. This might shift the
striatopallidal/striatonigral neuronal imbalance towards the normal
state, resulting in recovery of the motor function in parkinsonean
state. Ochi et al (2000); Kase (2001), Aoyama et al (2002).
[0060] The action mechanism via A.sub.2A receptors could work
independently of dopamine D.sub.2 receptors (Aoyama et al. (2000)),
which are co-localized with A.sub.2A receptors in the
striatopallidal medium spiny neurons. Gerfen et al. (1990). D.sub.2
receptor knockout mice (D.sub.2R-/-) presented a locomotor
phenotype with analogies to
[0061] Parkinson's disease and significantly altered in the levels
of neuropeptide genes expressed in the striatal medium spiny
neurons. No difference in the distribution and level of expression
of A.sub.2A receptor mRNA and the binding properties of the
receptor were found between D.sub.2R-/- and wild type mice,
indicating that D.sub.2 receptor absence had no influence on
A.sub.2A receptor properties. Blockade of A.sub.2A receptors by
KW-6002 reestablished their locomotor activity and coordination of
movement and lowered the levels of striatal enkephalin expression
to those in normal mice. Aoyama et al. (2000). The results indicate
that A.sub.2A and D.sub.2 receptors have antagonistic but
independent activities in controlling neuronal and motor function
in the basal ganglia. Independent functioning of A.sub.2A receptors
from the dopaminergic system was confirmed by studies using
A.sub.2A and D.sub.2 receptor knockout mice. Chen et al.
(2001b).
[0062] Physiological and pathophysiological functions of A.sub.2A
receptors in L-DOPA motor complications in Parkinson's disease are
far from clear. Neuronal mechanisms of L-DOPA induced dyskinesia
are generally thought to involve the indirect rather than the
direct pathway. Crossman (1990). L-DOPA-induced dyskinesias arise
when the activity in the STN or GPi falls below a given level as a
consequence of excessive inhibition from the GPe. Obeso et al.
(1997). Another hypothesis that abnormalities primarily in the
direct pathway might contribute significantly to the genesis of
L-DOPA-induced dyskinesia isproposed.
[0063] The neuroprotective effect of A.sub.2A receptor antagonists
has been demonstrated in neurotoxin (MPTP or
6-hydroxydopamine)-induced dopaminergic neurodegeneration in rats
and mice and A.sub.2A receptor knock-out mice. Ikeda et al. (2002);
and Chen et al. (2001a). To date, no treatment has been successful
in interfering with the basic pathogenic mechanism, which results
in the death of dopaminergic neurons.
[0064] Therefore, non-dopaminergic drug therapies, which effect an
adenosine A.sub.2A receptor blockade, offer a means to treat
Parkinson's disease. Moreover, adenosine A.sub.2A receptor
antagonists, which provide antiparkinsonian effects with little or
no risk of typical dopaminergic drug adverse effects, i.e.,
increasing or developing motor complications, are desirable.
[0065] Some xanthine compounds are known to show adenosine A.sub.2A
receptor antagonistic activity, anti-Parkinson's disease activity,
antidepressant activity, inhibitory activity on neurodegeneration,
or the like (U.S. Pat. Nos. 5,484,920; 5,587,378; and 5,543,415; EP
1016407A1; etc.)
SUMMARY OF THE INVENTION
[0066] The present invention provides methods of reducing or
suppressing the adverse effectiveness of L-DOPA therapy comprising
administration or co-administration of one or more A.sub.2A
receptor antagonists to Parkinson's disease patients. Such
treatment can be therapeutic such as to treat patients suffering
from L-DOPA- or other dopaminergic-agent-induced motor
complications to reduce OFF time and/or to improve dyskinesias.
[0067] The present invention further provides methods and
compositions for L-DOPA-sparing treatment. The method comprises
administering to a patient in need thereof a combination of a
sub-clinically effective amount of L-DOPA and one or more adenosine
A.sub.2A receptor antagonists in an amount effective to render the
L-DOPA efficacious.
[0068] The present invention further provides methods of treating
Parkinson's disease and/or L-DOPA motor complications, comprising
administering an effective amount of at least one adenosine
A.sub.2A receptor antagonist in combination with a COMT inhibitor
and/or DA and/or MAO inhibitor.
[0069] The present invention also provides methods of prolonging
effective treatment of Parkinson's disease comprising administering
to a patient in need thereof either an adenosine A.sub.2A receptor
antagonist or a combination of an adenosine A.sub.2A receptor
antagonist and a dopamine agonist without prior or subsequent
administration of L-DOPA or dopaminergic agents, such that the
patient's need for L-DOPA therapy or add-on L-DOPA therapy is
delayed or removed entirely, delaying the onset of or preventing
the development of L-DOPA motor complications.
[0070] The invention also includes methods of treating movement
disorders comprising administering an effective amount of at least
one adenosine A.sub.2A receptor antagonist to a patient in need
thereof. Such treatment can be therapeutic such as to treat
tremors, bradykinesias, gait, dystonias, dyskinesias, tardive
dyskinesias, or other extrapyramidal syndromes, or preventative
such as to prevent or lessen the effects of drugs that cause
movement disorders.
BRIEF DESCRIPTION OF THE DRAWINGS
[0071] FIG. 1 is a graph depicting the change in hours OFF as
recorded on home patient diaries for placebo and combined KW-6002
groups. At 12 weeks, subjects treated with KW-6002 had a
significantly greater reduction in hours OFF (*p=0.004).
[0072] FIGS. 2A and 2B are graphs depicting the effect of KW-6002
on nigral GABA (FIG. 2A) and glutamate (FIG. 2B) levels in
6-hydroxydopamine lesion rats. GABA and glutamate levels are
expressed as percentage changes from the pre-values before
administration of the compound. KW-6002 at 1 mg/kg p.o.
significantly increased nigral GABA and glutamate levels.
[0073] FIGS. 3A and 3B are graphs depicting the effect of L-DOPA on
nigral GABA (FIG. 3A) and glutamate (FIG. 3B) levels in
6-hydroxydopamine lesion rats. L-DOPA induced significant increases
of nigral GABA and glutamate to levels similar to those by
KW-6002.
[0074] FIG. 4 is a graph depicting the time courses of the effect
of KW-6002 and L-DOPA on total abnormal involuntary movements
(AIMs) score in chronically L-DOPA-treated 6-hydroxdopmanine lesion
rats. L-DOPA elicited marked AIMs, whereas KW-6002 induced little
or no AIMs.
[0075] FIGS. 5A and 5B depict the time courses of the effect of
KW-6002 and L-DOPA on nigral GABA (FIG. 5A) and glutamate (FIG. 5B)
levels in chronically L-DOPA-treated 6-hydroxydopamine lesion rats.
L-DOPA increased glutamate levels without effect on nigral GABA
levels. KW-6002 gave no or little effects on nigral GABA and
glutamate levels.
[0076] FIG. 6 is a graph depicting the effect of KW-6002 on
antiparkinsonian response to L-DOPA during the treatment L-DOPA
alone (L-DOPA/benserazide; 100/25 mg (total dose) once daily) and
L-DOPA plus KW-6002 (90 mg/kg once daily) in cynomologus monkeys.
The antiparkinsonian response to L-DOPA in terms of improvement of
the parkinsonian score over four weeks in was stable and comparable
in the two groups.
[0077] FIG. 7 is a graph depicting the effect of KW-6002 on
Locomotor response to L-DOPA during the treatment L-DOPA alone
(L-DOPA/benserazide; 100/25 mg (total dose) once daily) and L-DOPA
plus KW-6002 (90 mg/kg once daily) in cynomologus monkeys. The
locomotor activity counts increased to a higher level in the
combination treatment group and its level was maintained over four
weeks.
[0078] FIG. 8 is a graph depicted the effect of KW-6002 on
dyskinetic response to L-DOPA during the treatment L-DOPA alone
(L-DOPA/benserazide; 100/25 mg (total dose) once daily) and L-DOPA
plus KW-6002 (90 mg/kg once daily) in cynomologus monkeys.
Dyskinesias increased more rapidly and reached a higher level in
the L-DOPA group than in the combination treatment group. The onset
of dyskinesia was delayed in the presence of KW-6002.
[0079] FIG. 9 is a graph depicted the effect of KW-6002 on L-DOPA
induced dyskinesias. KW-6002 was administered simultaneously when
L-DOPA (2.5 mg/kg p.o. plus benserazide 0.625 mg/kg p.o.) was
administered daily for 21 days to induce dyskinesia in MPTP-treated
common marmosets primed with L-DOPA to exhibit dyskinesia. The
animals previously received 28 days of L-DOPA at 10 mg/kg p.o. plus
benserazide at 2.5 mg/kg p.o. twice daily (L-DOPA). Each column
represents the mean (.+-.SEM) of the maximal dyskinesia score (Max
dyskinesia score) for 8 animals. #P<0.05 compared with vehicle
control *P<0.05 compared with L-DOPA pre (10 mg/kg). +P<0.05
compared with L-DOPA control (2.5 mg/kg). The amplitude of
involuntary movements produced by the combined treatment was not
increased, but instead reduced significantly on day 21 as compared
with 2.5 mg/kg of L-DOPA alone. KW-6002 showed significant
reduction of L-DOPA induced dyskinesias by chronic treatment for 21
days.
DETAILED DESCRIPTION OF THE INVENTION
[0080] The present invention relates to the following (1) to
(50).
[0081] (1) A method of reducing or suppressing the adverse
effectiveness of L-DOPA and/or dopamine agonist therapy, comprising
administering an effective amount of at least one adenosine
A.sub.2A receptor antagonist to a Parkinson's disease patient.
[0082] (2) The method according to the above (1) wherein the
patient suffers from L-DOPA- or other dopaminergic-agent-induced
motor complications.
[0083] (3) The method according to the above (2) wherein OFF time
in motor fluctuations is reduced.
[0084] (4) The method according to the above (2) wherein
dyskinesias in motor complications are improved.
[0085] (5) The method according to the above (1) wherein the
adenosine A.sub.2A receptor antagonist is a xanthine derivative or
a pharmaceutically acceptable salt thereof.
[0086] (6) The method according to the above (1) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I):
##STR00001##
[0087] wherein
[0088] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00002##
[0089] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00003##
[0090] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S.
[0091] (7) The method according to the above (1) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-A):
##STR00004##
[0092] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00005##
[0093] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00006##
[0094] (in which R.sup.6 and m have the same meanings as defined
above, respectively).
[0095] (8) The method according to the above (1) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-B):
##STR00007##
[0096] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00008##
[0097] (in which R.sup.6 and m have the same meanings as defined
above); and Y.sup.1 and Y.sup.2 have the same meanings as defined
above, respectively.
[0098] (9) The method according to the above (1) wherein the
adenosine A.sub.2A receptor antagonist is
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
[0099] (10) A method for L-DOPA sparing treatment comprising
administering to a patient in need thereof a combination of a
sub-clinically effective amount of L-DOPA and one or more adenosine
A.sub.2A receptor antagonists in an amount effective to render the
L-DOPA efficacious.
[0100] (11) The method according to the above (10) wherein the
adenosine A.sub.2A receptor antagonist is a xanthine derivative or
a pharmaceutically acceptable salt thereof.
[0101] (12) The method according to the above (10) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I):
##STR00009##
[0102] wherein
[0103] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00010##
[0104] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00011##
[0105] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S.
[0106] (13) The method according to the above (10) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-A):
##STR00012##
[0107] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00013##
[0108] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00014##
[0109] (in which R.sup.6 and m have the same meanings as defined
above, respectively).
[0110] (14) The method according to the above (10) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-B):
##STR00015##
[0111] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00016##
[0112] (in which R.sup.6 and m have the same meanings as defined
above, respectively); and Y.sup.1 and Y.sup.2 have the same
meanings as defined above, respectively.
[0113] (15) The method according to the above (10) wherein the
adenosine A.sub.2A receptor antagonist is
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
[0114] (16) A composition for L-DOPA sparing treatment comprising a
sub-clinically effective amount of L-DOPA and one or more adenosine
A.sub.2A receptor antagonists in an amount of effective to render
the L-DOPA efficacious.
[0115] (17) The composition according to the above (16) wherein the
adenosine A.sub.2A receptor antagonist is a xanthine derivative or
a pharmaceutically acceptable salt thereof.
[0116] (18) The composition according to the above (16) wherein the
adenosine
[0117] A.sub.2A receptor antagonist is represented by formula
(I):
##STR00017##
[0118] wherein
[0119] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00018##
[0120] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00019##
[0121] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S.
[0122] (19) The composition according to the above (16) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-A):
##STR00020##
[0123] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00021##
[0124] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00022##
[0125] (in which R.sup.6 and m have the same meanings as defined
above, respectively).
[0126] (20) The composition according to the above (16) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-B):
##STR00023##
[0127] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00024##
[0128] (in which R.sup.6 and m have the same meanings as defined
above, respectively);
[0129] and Y.sup.1 and Y.sup.2 have the same meanings as defined
above, respectively.
[0130] (21) The composition according to the above (16) wherein the
adenosine A.sub.2A receptor antagonist is
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
[0131] (22) A method of treating Parkinson's disease and/or L-DOPA
motor complications, comprising administering an effective amount
of at least one adenosine A.sub.2A receptor antagonist in
combination with a COMT inhibitor and/or DA and/or MAO inhibitor to
a patient in need thereof.
[0132] (23) The method according to the above (22) wherein the
adenosine A.sub.2A receptor antagonist is a xanthine derivative or
a pharmaceutically acceptable salt thereof.
[0133] (24) The method according to the above (22) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I):
##STR00025##
[0134] wherein
[0135] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00026##
[0136] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00027##
[0137] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S.
[0138] (25) The method according to the above (22) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-A):
##STR00028##
[0139] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00029##
[0140] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00030##
[0141] (in which R.sup.6 and m have the same meanings as defined
above, respectively).
[0142] (26) The method according to the above (22) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-B):
##STR00031##
[0143] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00032##
[0144] (in which R.sup.6 and m have the same meanings as defined
above, respectively); and Y.sup.1 and Y.sup.2 have the same
meanings as defined above, respectively.
[0145] (27) The method according to the above (22) wherein the
adenosine A.sub.2A receptor antagonist is
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
[0146] (28) A composition for the treatment of Parkinson's disease
comprising an effective amount of at least one adenosine A.sub.2A
receptor antagonist, and a COMT inhibitor and/or DA and/or MAO
inhibitor.
[0147] (29) The composition according to the above (28) wherein the
adenosine A.sub.2A receptor antagonist is a xanthine derivative or
a pharmaceutically acceptable salt thereof.
[0148] (30) The composition according to the above (28) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I):
##STR00033##
[0149] wherein
[0150] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00034##
[0151] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00035##
[0152] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S.
[0153] (31) The composition according to the above (28) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-A):
##STR00036##
[0154] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00037##
[0155] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00038##
[0156] (in which R.sup.6 and m have the same meanings as defined
above, respectively).
[0157] (32) The composition according to the above (28) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-B):
##STR00039##
[0158] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00040##
[0159] (in which R.sup.6 and m have the same meanings as defined
above, respectively); and Y.sup.1 and Y.sup.2 have the same
meanings as defined above, respectively.
[0160] (33) The composition according to the above (28) wherein the
adenosine A.sub.2A receptor antagonist is
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
[0161] (34) A method of prolonging effective treatment of
Parkinson's disease comprising administering to a patient in need
thereof either an adenosine A.sub.2A receptor antagonist or a
combination of an adenosine A.sub.2A receptor antagonist and a
dopamine agonist in an amount effective to delay or remove the
patient's need for add-on L-DOPA therapy.
[0162] (35) The method according to the above (34) wherein the
development of motor complications is delayed.
[0163] (36) The method according to the above (34) wherein the
patient has not had prior administration of L-DOPA or a
dopaminergic agent.
[0164] (37) The method according to the above (34) wherein the
patient does not have subsequent administration of L-DOPA or a
dopaminergic agent. (38) The method according to the above (34)
wherein the adenosine A.sub.2A receptor antagonist is a xanthine
derivative or a pharmaceutically acceptable salt thereof.
[0165] (39) The method according to the above (34) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I):
##STR00041##
[0166] wherein
[0167] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00042##
[0168] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00043##
[0169] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S.
[0170] (40) The method according to the above (34) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-A):
##STR00044##
[0171] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00045##
[0172] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00046##
[0173] (in which R.sup.6 and m have the same meanings as defined
above, respectively).
[0174] (41) The method according to the above (34) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-B):
##STR00047##
[0175] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00048##
[0176] (in which R.sup.6 and m have the same meanings as defined
above, respectively); and Y.sup.1 and Y.sup.2 have the same
meanings as defined above, respectively.
[0177] (42) The method according to the above (34) wherein the
adenosine A.sub.2A receptor antagonist is
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
[0178] (43) A method of treating movement disorders comprising
administrating an effective amount of at least one adenosine
A.sub.2A receptor antagonist to a patient in need thereof.
[0179] (44) The method according to the above (43) wherein the
patient suffers from tremors, bradykinesias, gait, dystonias,
dyskinesias, tardive dyskinesias or other extrapyramidal
syndromes.
[0180] (45) The method according to the above (43) wherein the
adenosine A.sub.2A receptor antagonist lessens the effects of drugs
that cause movement disorders.
[0181] (46) The method according to the above (43) wherein the
adenosine A.sub.2A receptor antagonist is a xanthine derivative or
a pharmaceutically acceptable salt thereof.
[0182] (47) The method according to the above (43) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I):
##STR00049##
[0183] wherein
[0184] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00050##
[0185] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00051##
[0186] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S.
[0187] (48) The method according to the above (43) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-A):
##STR00052##
[0188] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00053##
[0189] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00054##
[0190] (in which R.sup.6 and m have the same meanings as defined
above, respectively).
[0191] (49) The method according to the above (43) wherein the
adenosine A.sub.2A receptor antagonist is represented by formula
(I-B):
##STR00055##
[0192] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00056##
[0193] (in which R.sup.6 and m have the same meanings as defined
above, respectively); and Y.sup.1 and Y.sup.2 have the same
meanings as defined above, respectively.
[0194] (50) The method according to the above (43) wherein the
adenosine A.sub.2A receptor antagonist is
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine.
[0195] The present invention is directed to methods of treating
patients suffering from movement disorders comprising administering
one or more adenosine A.sub.2A receptor antagonists. By "adenosine
A.sub.2A receptor antagonist" is meant a compound that inhibits,
suppresses or causes the cessation of at least one
adenosine-mediated biological activity by, e.g., binding to
adenosine A.sub.2A receptors, interfering with, or preventing the
binding of adenosine to the receptor.
[0196] The present invention contemplates that adenosine A.sub.2A
receptor antagonists can be used to treat movement disorders, since
the adenosine A.sub.2A receptor functions, for example, in
controlling the indirect pathway or basal ganglia output nuclei
activity. The adenosine A.sub.2A receptors are also considered to
be involved in controlling motor behavior or motor
dysfunctions.
[0197] An adenosine A.sub.2A receptor antagonist functions in
several ways. The antagonist may bind to or sequester adenosine
with sufficient affinity and specificity to substantially interfere
with, block or otherwise prevent binding of adenosine to an
adenosine A.sub.2A receptor, thereby inhibiting, suppressing or
causing the cessation of one or more adenosine A.sub.2A receptor
-mediated biological functions, such as modulation of striatal
GABAergic output of the indirect pathway, and activities of the
basal ganglia output nuclei, SNr, for example, thereby controlling
motor behaviors in basal ganglia. The present invention
contemplates that antiparkinsonian activity of the adenosine
A.sub.2A receptor antagonist results from this activity. The
present invention further contemplates that the capability of the
adenosine A.sub.2A receptor antagonist to reduce or suppress the
adverse effectiveness of L-DOPA and/or dopamine agonist therapy in
Parkinson's disease patients results from this activity. The
present invention further contemplate that involvement of the
adenosine receptor antagonists in development of L-DOPA and/or
dopamine agonist induced motor complications results from this
activity. Alternatively, an adenosine A.sub.2A receptor antagonist
may inhibit neuron degeneration cascades induced by dopaminergic
neurotoxins such as 6-OHDA (6-hydroxydopamine) and
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and
dopaminergic neurotoxin production via glial cells. These features
of adenosine A.sub.2A receptor antagonists prevent the development
of L-DOPA motor complications and/or progress of Parkinson's
disease. Thus, the use of adenosine A.sub.2A receptor antagonists
provide therapy such that the patient's need for L-DOPA therapy or
add-on L-DOPA therapy is delayed or removed entirely, or delaying
the onset of or preventing the development of L-DOPA motor
complications.
[0198] The adenosine A.sub.2A receptor antagonists of the present
invention are thus directed to methods of treating Parkinson's
disease patients and other patients suffering from movement
disorders by administering an effective amount of one or more
adenosine A.sub.2A receptor antagonists. The adenosine A.sub.2A
receptor antagonists of the present invention are also useful in
methods of reducing or suppressing the adverse effectiveness of
L-DOPA therapy including L-DOPA motor complications in the
treatment of Parkinson's disease. Furthermore, treatment of
Parkinson's disease with adenosine A.sub.2A receptor antagonists
can avoid the need for treatment with L-DOPA and reduce the amounts
of L-DOPA required to effectively treat
[0199] Parkinson's disease in the absence or reduction of side
effects such as, nausea, hyperactivity, motor fluctuations such as
wearing off and ON-OFF fluctuations, and dyskinesia. The present
invention further provides methods for treating Parkinson's disease
patients by administering adenosine A.sub.2A receptor antagonists
such that the patient's need for L-DOPA therapy is delayed or
removed entirely, delaying the onset of or preventing the
development of L-DOPA motor complications. The present invention
further provides methods for treating tremors, bradykinesias, gait,
dystonias, and tardive dyskinesias and other extrapyramidal
syndromes in patients suffering from other movement disorders.
[0200] The adenosine A.sub.2A receptor antagonist used in the
present invention is not limited as long as it has A.sub.2A
receptor antagonistic activity. Examples thereof include compounds
disclosed in U.S. Pat. No. 5,484,920, U.S. Pat. No. 5,703,085, WO
92/06976, WO 94/01114, US 5,565,460, WO 98/42711, WO 00/17201, WO
99/43678, WO 01/92264, WO 99/35147, WO 00/13682, WO 00/13681, WO
00/69464, WO 01/40230, WO 01/02409, WO 01/02400, EP 1054012, WO
01/62233, WO 01/17999, WO 01/80893, WO 02/14282, WO 01/97786, and
the like. More specifically, examples include:
[0201] (1) compounds represented by the following formula (I):
##STR00057##
[0202] wherein
[0203] R.sup.1, R.sup.2 and R.sup.3 represent independently
hydrogen, lower alkyl, lower alkenyl or lower alkynyl; R.sup.4
represents cycloalkyl, --(CH.sub.2).sub.n--R.sup.5 (in which
R.sup.5 represents substituted or unsubstituted aryl, or a
substituted or unsubstituted heterocyclic group; and n is an
integer of 0 to 4), or
##STR00058##
[0204] {in which Y.sup.1 and Y.sup.2 represent independently
hydrogen, halogen, or lower alkyl; and Z represents substituted or
unsubstituted aryl, or
##STR00059##
[0205] (in which R.sup.6 represents hydrogen, hydroxy, lower alkyl,
lower alkoxy, halogen, nitro, or amino; and m represents an integer
of 1 to 3)}; and X.sup.1 and X.sup.2 represent independently O or
S,
[0206] (2) compounds represented by the following formula
(I-A):
##STR00060##
[0207] wherein R.sup.1a and R.sup.2a represent independently methyl
or ethyl; R.sup.3a represents hydrogen or lower alkyl; and Z.sup.a
represents
##STR00061##
[0208] (in which at least one of R.sup.7, R.sup.8 and R.sup.9
represents lower alkyl or lower alkoxy and the others represent
hydrogen; R.sup.10 represents hydrogen or lower alkyl) or
##STR00062##
[0209] (in which R.sup.6 and m have the same meanings as defined
above, respectively), and
[0210] (3) compounds represented by the following formula
(I-B):
##STR00063##
[0211] wherein R.sup.1b and R.sup.2b represent independently
hydrogen, propyl, butyl, lower alkenyl or lower alkynyl; R.sup.3b
represents hydrogen or lower alkyl; Z.sup.b represents substituted
or unsubstituted naphthyl, or
##STR00064##
[0212] (in which R.sup.6 and m have the same meanings as defined
above, respectively); and Y.sup.1 and Y.sup.2 have the same
meanings as defined above, respectively,
[0213] and pharmaceutically acceptable salts thereof.
[0214] In the definitions of the groups of formula (I), formula
(I-A), and formula (I-B), the lower alkyl and the lower alkyl
moiety of the lower alkoxy mean a straight-chain or branched alkyl
group having 1 to 6 carbon atoms, such as methyl, ethyl, propyl,
isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,
neopentyl, and hexyl. The lower alkenyl means a straight-chain or
branched alkenyl group having 2 to 6 carbon atoms, such as vinyl,
allyl, methacryl, crotyl, 3-butenyl, 2-pentenyl, 4-pentenyl,
2-hexenyl, and 5-hexenyl. The lower alkynyl means a straight-chain
or branched alkynyl group having 2 to 6 carbon atoms, such as
ethynyl, propargyl, 2-butynyl, 3-butynyl, 2-pentynyl, 4-pentynyl,
2-hexynyl, 5-hexynyl, and 4-methyl-2-pentynyl. The aryl means
phenyl or naphthyl. The cycloalkyl means a cycloalkyl group having
3 to 8 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl,
cyclohexyl, cycloheptyl, and cyclooctyl. Examples of the
heterocyclic group are furyl, thienyl, pyrrolyl, pyranyl,
thiopyranyl, pyridyl, thiazolyl, imidazolyl, pyrimidyl, triazinyl,
indolyl, quinolyl, purinyl, and benzothiazolyl. The halogen
includes fluorine, chlorine, bromine, and iodine.
[0215] The substituted aryl, the substituted heterocyclic group,
and the substituted naphthyl each have 1 to 4 independently
selected substituents. Examples of the substituents are lower
alkyl, hydroxy, substituted or unsubstituted lower alkoxy, halogen,
nitro, amino, lower alkylamino, di(lower alkyl)amino,
trifluoromethyl, trifluoromethoxy, benzyloxy, phenyl, and phenoxy.
The lower alkyl and the lower alkyl moiety of the lower alkoxy,
lower alkylamino, and di(lower alkyl)amino have the same meaning as
the lower alkyl defined above. The halogen has the same meaning as
the halogen defined above. Examples of the substituent of the
substituted lower alkoxy are hydroxy, lower alkoxy, halogen, amino,
azide, carboxy, and lower alkoxycarbonyl. The lower alkyl moiety of
the lower alkoxy and lower alkoxycarbonyl has the same meaning as
the lower alkyl defined above, and the halogen has the same meaning
as the halogen defined above.
[0216] The above-mentioned pharmaceutically acceptable salts of
Compounds (I), Compounds (I-A), and Compounds (I-B) include
pharmaceutically acceptable acid addition salts, metal salts,
ammonium salts, organic amine addition salts, and amino acid
addition salts.
[0217] Examples of the pharmaceutically acceptable acid addition
salts are inorganic acid addition salts such as hydrochloride,
sulfate and phosphate, and organic acid addition salts such as
acetate, maleate, fumarate, tartrate, and citrate.
[0218] Examples of the pharmaceutically acceptable metal salts are
alkali metal salts such as sodium salt and potassium salt, alkaline
earth metal salts such as magnesium salt and calcium salt, aluminum
salt and zinc salt. Examples of the pharmaceutically acceptable
ammonium salts are ammonium and tetramethylammonium. Examples of
the pharmaceutically acceptable organic amine addition salts are
salts with morpholine and piperidine. Examples of the
pharmaceutically acceptable amino acid addition salts are salts
with lysine, glycine and phenylalanine.
[0219] Compounds represented by formula (I), formula (I-A), and
formula (I-B) are described and synthesized in accordance with the
methodology described in U.S. Pat. Nos. 5,543,415; 5,587,378; and
5,484,920.
[0220] A preferred adenosine A.sub.2A receptor antagonist useful in
accordance with the methods of the present invention comprises
(E)-8-(3,4-dimethoxystyryl)-1,3-diethyl-7-methylxanthine (the
following formula (II)).
##STR00065##
[0221] Formula II is also identified in accordance with the present
invention as KW-6002.
[0222] By "reducing or suppressing the adverse effectiveness of
L-DOPA" is understood in accordance with the present invention to
mean that the compounds of the present invention reduce the
patients' amount of awake time in an "OFF" state. An OFF state is
understood in accordance with the invention to mean the period of
time where the therapeutic benefit of a dose of a parkinsonian
medication have worn off, such that the patient experiences
symptoms of Parkinson's disease such as are classified by the
Unified Parkinson's Disease Rating Scale (UPDRS) and the Hoehn and
Yahr (HY) scale, for example.
[0223] The present invention is also directed to reducing the
adverse effectiveness of L-DOPA by increasing the proportion of the
patients' awake time in an "ON" state. By ON state is meant, the
period of time following a dose of a parkinsonian medication during
which the patient is relatively free of the symptoms of Parkinson's
Disease as classified by the UPDRS and the HY scale. The present
invention is also directed to suppressing adverse effectiveness of
L-DOPA by suppressing L-DOPA induced dyskinesia. Dyskinesias can be
separately measured by the UPDRS, modified Goetz Dyskinesia Rating
Scale (MGDRS), and/or Abnormal Involuntary Movement Scale
(AIMS).
[0224] Patients treatable by the methods of the present invention
include patients at early, intermediate and advanced stages of
Parkinson's disease with or without motor complications as
determined by the Parkinson Dyskinesia Scale (PDS).
[0225] In accordance with the present invention the adenosine
A.sub.2A receptor antagonists of the present invention can be
co-administered with L-DOPA or a dopamine agonist, i.e.
administered at substantially the same time. It is also
contemplated that the adenosine A.sub.2A receptor antagonists can
be administered alone; either before or after the patient receives
a dose of L-DOPA or a dopamine agonist. A substantial reduction in
the requirement for L-DOPA and/or a reduction or a suppression in
the typical adverse effects of L-DOPA therapy are observed with the
administration of KW-6002, especially in the symptoms of motor
fluctuations and dyskinesia. Thus, the present invention
contemplates an improved method of treating the patients suffering
from L-DOPA- or other dopaminergic agents-induced motor
complications in Parkinson's disease in humans by administering an
adenosine A.sub.2A receptor antagonist with L-DOPA or other
dopaminergic agents that cause motor fluctuations, dyskinesia,
nausea, and other common side effects of dopaminergic therapy.
[0226] The present invention further provides a method of
prolonging effective treatment of Parkinson's disease comprising
the administration of either an adenosine A.sub.2A receptor
antagonist or a combination of an adenosine A.sub.2A receptor
antagonist and a dopamine agonist without prior or subsequent
administration of L-DOPA. The requirement for L-DOPA is eliminated
or at least substantially reduced together with the avoidance of
the concomitant adverse side effects of L-DOPA therapy. A
"combination" of an adenosine A.sub.2A receptor antagonist and a
dopamine agonist is provided to a patient concurrently or at least
in a manner such as to permit an overlap of biological activity.
Since the adenosine A.sub.2A receptor antagonists of the invention
interfere with the development of L-DOPA motor complications and
also prevent dopaminergic neurodegeneration, an adenosine A.sub.2A
receptor antagonist administered singly or together with a dopamine
agonist can delay the onset of or prevent the progress of L-DOPA
motor complications
[0227] In accordance with the present invention, the adenosine
A.sub.2A receptor antagonists can be administered singly or
together with a dopamine agonist such as, for example,
bromocriptine, cabergoline, pramipexol, ropinerole, or pergolide,
and thereby avoid or at least provide an extension of time before
which the need for L-DOPA manifests.
[0228] The present invention further provides methods of
L-DOPA-sparing treatment of Parkinson's patients. That is,
treatment with sub-clinically effective amounts of L-DOPA while
maintaining the efficacy of sub-clinically effective amounts of
L-DOPA. The method comprises treating the patient with
sub-clinically effective amounts of L-DOPA and effective amounts of
an adenosine A.sub.2A receptor antagonist. By sub-clinically
effective amounts of L-DOPA is meant an amount of L-DOPA that is
not effective in treatment of a particular patient. Typically,
L-DOPA is administered at 100 mg to 1 g per day in divided doses
(usually 250 mg 4 times a day). The dose is increased gradually in
increments of 100 to 750 mg a day at 3- to 7-day intervals until
intolerable side effects occur, usually movement disorders. When
co-administered with carbidopa, effective amounts of L-DOPA are
reduced. It is well within the skill of one in the art to determine
the sub-clinically effective dose of L-DOPA for a particular
patient and to adjust it accordingly in the presence of an
adenosine A.sub.2A receptor antagonist.
[0229] Compositions comprising sub-clinically effective amounts of
L-DOPA and optionally an adenosine A.sub.2A receptor antagonist and
optionally a dopamine antagonist are made by methods known in the
art and described herein. Additional amounts of carbidopa and other
active ingredients can also be determined by one of skill in the
art.
[0230] The present invention further provides methods of treating
Parkinson's disease with at least one adenosine A.sub.2A receptor
antagonist and at least one of a COMT or MAO-B inhibitor. The
compositions can be administered together or sequentially, by any
method known in the art. Methods of making and administering such
compositions are known in the art. Suitable COMT and MAO inhibitors
are described herein and are well known in the art. These include,
but are not limited to, entacapone and tolcapone, and deprenyl. As
shown below, concomitant treatment of adenosine A.sub.2A receptor
antagonist and COMT or MAO-B inhibitors does not increase side
effects.
[0231] By "prolonging effective treatment" is meant that the
patient's Parkinson's symptoms and motor complications are reduced
or inhibited either subjectively or objectively according to the
UPDRS, AIMS, PDS, HY and/or MGDRS such that the patient's need for
L-DOPA therapy is delayed or removed entirely.
[0232] The invention also includes methods of treating movement
disorders comprising administering an effective amount of at least
one adenosine A.sub.2A receptor antagonist to a patient in need
thereof. Such treatment can be therapeutic such as to treat
tremors, bradykinesias, gait, dystonias, or tardive dyskinesias or
other extrapyramidal syndromes, or preventative such as to prevent
or lessen the effects of drugs that cause movement disorders. Such
drugs are known in the art and include, but are not limited to,
those listed in Table 1.
[0233] By "treating movement disorders" is meant the cessation or
diminishment of symptoms including, but not limited to, tremor,
dystonia, dyskinesia, spasticity. Changes in symptoms can be
measured by any method known in the art including, but not limited
to, UPDRS, AIMS, PDS, HY and/or MGDRS.
[0234] The term "treatment" or "treat" refers to effective
inhibition, suppression or cessation of the adenosine activity so
as to improve motor dysfunction or delay the onset, retard the
progression or ameliorate the symptoms of the disease or
disorder.
[0235] The present invention thus provides methods of interfering
with, blocking or otherwise preventing the interaction or binding
of adenosine with an adenosine A.sub.2A receptor by employing the
adenosine A.sub.2A receptor antagonists of the present
invention.
[0236] Pharmaceutical compositions for administration according to
the present invention comprise at least one adenosine A.sub.2A
receptor antagonist optionally combined with a pharmaceutically
acceptable carrier. These compositions can be administered by any
means that achieve their intended purposes. Amounts and regimens
for the administration of a composition according to the present
invention can be readily determined by those with ordinary skill in
the art in treating Parkinson's disease patients.
[0237] The compositions described herein can be administered by any
suitable method including, without limitation, orally;
intranasally; intrapulmonarally; parenterally, such as
subcutaneously, intravenously, intramuscularly, intraperitoneally;
intraduodenally; transdermally; or buccally.
[0238] The dosage administered is an effective amount and depends
upon the age, health and weight of the patient, type of previous or
concurrent treatment, if any, frequency of treatment, and the
nature of the effect desired. Several factors are typically taken
into account when determining an appropriate dosage. These factors
include age, sex and weight of the patient, the condition being
treated, the severity of the condition and the form of the drug
being administered.
[0239] An "effective amount" is an amount sufficient to effect a
beneficial or desired clinical result. An effective amount can be
administered in one or more doses. In terms of treatment, an
effective amount is amount that is sufficient to palliate,
ameliorate, stabilize, reverse or slow the progression of the
disease or disorder, or otherwise reduce the pathological
consequences of the disease or disorder. The effective amount is
generally determined by the physician on a case-by-case basis and
is within the skill of one in the art.
[0240] In addition to pharmaceutically active compounds,
compositions according to the present invention can also contain
suitable pharmaceutically acceptable carriers comprising excipients
that facilitate processing of the active compounds into
pharmaceutically acceptable preparations. Preferably, the
preparations, particularly those preparations which can be
administered orally and which can be used for the preferred type of
administration, such as tablets, troches and capsules, and also
preparations which can be administered rectally, such as
suppositories, as well as suitable solutions for administration by
injection, contain from about 0.1 to 99 percent, preferably from
about 20 to 85 percent of active compound(s), together with the
excipient. Liquid pharmaceutically acceptable compositions can, for
example, be prepared by dissolving or dispersing a compound
embodied herein in a liquid excipient, such as water, saline,
aqueous dextrose, glycerol, or ethanol. The composition can also
contain other medicinal agents, pharmaceutical agents, carriers,
and auxiliary substances such as wetting or emulsifying agents and
pH buffering agents.
[0241] Pharmaceutical compositions of the present invention are
administered by a mode appropriate for the form of composition.
Typical routes include subcutaneous, intramuscular,
intraperitoneal, intradermal, oral, intranasal, and intrapulmonary
(i.e., by aerosol). Pharmaceutical compositions of this invention
for human use are typically administered orally.
[0242] Pharmaceutical compositions for oral, intranasal, or topical
administration can be supplied in solid, semi-solid or liquid
forms, including tablets, capsules, powders, liquids, and
suspensions. Compositions for injection can be supplied as liquid
solutions or suspensions, as emulsions, or as solid forms suitable
for dissolution or suspension in liquid prior to injection. For
administration via the respiratory tract, a preferred composition
is one that provides a solid, powder, or liquid aerosol when used
with an appropriate aerosolizer device. Although not required,
pharmaceutical compositions are preferably supplied in unit dosage
form suitable for administration of a precise amount. Also
contemplated by this invention are slow release or sustained
release forms, whereby relatively consistent levels of the active
compounds are provided over an extended period.
[0243] The adenosine A.sub.2A receptor antagonists may preferably
be administered in an amount of from about 0.001 to about 20.0 mg
per kilogram of body weight. A dosage range of from about 0.01 to
about 10 mg per kilogram of body weight is more preferable. Since
the adenosine A.sub.2A receptor antagonist compositions of this
invention will eventually be cleared from the blood stream,
regarding administration of the compositions is indicated and
preferred.
[0244] The adenosine A.sub.2A receptor antagonists can be
administered in a manner compatible with the dosage formulation and
in such amount as will be therapeutically effective. Systemic
dosages depend on the age, weight and conditions of the patient and
on the administration route.
[0245] Pharmaceutical preparations useful in the methods according
to the present invention are manufactured in a known manner. The
preparation of pharmaceutical compositions is conducted in
accordance with generally accepted procedures for the preparation
of pharmaceutical preparations. See, for example, Remington's
Pharmaceutical Sciences 18th Edition (1990), Martin ed., Mack
Publishing Co., PA. Depending on the intended use and mode of
administration, it may be desirable to process the active
ingredient further in the preparation of pharmaceutical
compositions. Appropriate processing may include sterilizing,
mixing with appropriate non-toxic and non-interfering components,
dividing into dose units and enclosing in a delivery device.
[0246] The pharmaceutical preparations for oral use can be obtained
by combining the active compounds with solid excipients, optionally
grinding the resulting mixture, and processing the mixture of
granules, after adding suitable auxiliaries, if desired or
necessary, to obtain tablets.
[0247] Suitable excipients include, but are not limited to fillers
such as saccharides, for example, lactose or sucrose, mannitol or
sorbitol; cellulose derivatives; zinc compounds; calcium phosphates
such as tricalcium phosphate or calcium hydrogen phosphate; as well
as binders such as starch paste, using, for example, maize starch,
wheat starch, rice starch, potato starch; gelatin; tragacanth;
and/or polyvinylpyrrolidone.
[0248] Auxiliaries include flow-regulating agents and lubricants,
such as silica, talc, stearic acid or salts thereof, and/or
polyethylene glycol. Tablet, caplet or capsule cores are provided
with suitable coatings, which, if desired, are resistant to gastric
juices. For this purpose, concentrated saccharide solutions can be
used, which can optionally contain gum Arabic, talc, polyvinyl
pyrrolidone, polyethylene glycol and/or titanium dioxide, lacquer
solutions and suitable organic solvents or solvent mixtures. In
order to produce coatings resistant to gastric juices, i.e.,
enteric coatings, solutions of suitable cellulose preparations such
as acetylcellulose phthalate or hydroxypropylmethyl cellulose
phthalate are used. Dyes or pigments can be added to the tablets or
coatings, for example, for identification or in order to
characterize combinations of active compound doses.
[0249] Other pharmaceutical preparations, which can be used orally,
include push-fit capsules made of gelatin, as well as soft, sealed
capsules made of gelatin and a plasticizer such as glycerol or
sorbitol. The push-fit capsules can contain the active compounds in
the form of granules, which can be mixed with fillers such as
lactose, binders such as starches, and/or lubricants such as talc
or magnesium stearate and, optionally, stabilizers. In soft
capsules, the active compounds are preferably dissolved or
suspended in suitable liquids, such as fatty oils or liquid
paraffin. In addition, stabilizers may be added.
[0250] Adenosine A.sub.2A receptor antagonists of the present
invention can also be administered in the form of an implant when
compounded with a biodegradable slow-release carrier.
Alternatively, the active ingredients can be formulated as a
transdermal patch for continuous release of the active ingredient.
Methods of making implants and patches are well known in the art.
Remington's Pharmaceutical Sciences 18th Edition (1990); and
Kydonieus ed. (1992) Treatise on controlled drug delivery, Marcel
Dekker, NY.
[0251] The following non-limiting Examples, further illustrate the
present invention. All references cited herein are hereby
incorporated by reference.
EXAMPLE 1
[0252] The safety and efficacy of the adenosine A.sub.2A receptor
antagonist KW-6002 as a treatment for Parkinson's disease
complicated by L-DOPA-related motor complications was examined in a
12-week, multicenter, exploratory study. PD subjects with motor
complications were randomly and blindly assigned to 1 of 3 parallel
treatment arms: placebo (n=29); KW-6002 up to 20 mg/d (n=26);
KW-6002 up to 40 mg/d (n=28). There were 2 primary efficacy
measures: 1) change in "off" time as determined by the study
investigator during 8-hour clinic visits and 2) change in "off"
time as determined by subjects' home motor diaries.
[0253] Sixty-five of the 83 enrolled subjects completed the study;
withdrawal rates were equally distributed across treatment arms.
KW-6002 treatment was significantly more effective than placebo
treatment in reducing the proportion of awake time that patients
spent in an "off" state. As assessed by home diaries, subjects
assigned to KW-6002 experienced a reduction in the proportion of
awake time spent in the OFF state of 7.1% compared to an increase
of 2.2% in the placebo group (p=0.008). There was a 1.7 hour
greater reduction in OFF time in the KW-6002 group than the placebo
group (p=0.004). Results for the investigators' on/off 8 hour
evaluation approached statistical significance (p=0.054). Patients
treated with KW-6002 spent 0.51 fewer hours in the "off" state than
did patients in the placebo group (p=0.061).
[0254] The study also showed a reduction in early morning dystonia
in patients treated with KW-6002 from baseline to Week 12 compared
to the placebo group.
Methods
[0255] This was a 12-week, double-blind, placebo-controlled,
randomized, parallel group, multicenter, exploratory study of the
safety and efficacy of KW-6002 as adjunctive therapy in
L-DOPA-treated PD patients with motor complications. Eligible
patients were those who met United Kingdom PD Society (UKPDS) brain
bank diagnostic criteria (Daniel et al. (1993)), had been on
L-DOPA/carbidopa for at least one year, were taking at least four
doses of L-DOPA/carbidopa per day, and were experiencing motor
complications including end-of-dose wearing off.
[0256] After providing informed consent, subjects underwent a
screening period of four to eight weeks. Medications were
stabilized prior to the week-4 visit. At this visit, the subjects
received training regarding completion of home diaries.
[0257] At baseline, subjects underwent an 8-hour in-office
evaluation. Subjects withheld PD medications and fasted from
midnight prior to this evaluation. The first doses of PD
medications for the day were administered after the initial
assessments, and subsequent doses were administered at subjects'
usual interdose intervals. Evaluations were performed by blinded
raters who had undergone specific training and who were blinded to
adverse events and results of laboratory tests. Subjects were
required to exhibit at least 90 minutes of OFF time following PD
medication administration during the 8-hour evaluation to be
eligible for randomization.
[0258] Subjects who successfully completed screening and baseline
evaluations were randomized to one of two dose regimens of KW-6002
or matching placebo in a 1:1:1 ratio. Patients randomized to
KW-6002 received either 5 mg/day during weeks 1-4,10 mg/day during
weeks 5-8, and 20 mg/day during weeks 9-12 (5/10/20 group) or 10
mg/day during weeks 1-4, 20 mg/day during weeks 5-8, and 40 mg/day
during weeks 5-9 (10/20/40 group). (FIG. 1). Study medication was
taken daily as a single dose with the subjects' normal
breakfast.
[0259] Subsequent evaluations were undertaken at 2, 4, 6, 8, 10,
and 12 weeks. Subjects completed three daily home diaries during
the week before each visit. At each visit, adverse events were
assessed. Eight-hour in-office evaluations were completed at weeks
4, 8, and 12. Laboratory blood tests and ECGs were obtained at
baseline and weeks 4, 8, and 12.
[0260] During the course of the study, investigators could decrease
the total daily dose of L-DOPA to ameliorate L-DOPA-related adverse
events. Changes in the interval between L-DOPA doses were not
permitted.
[0261] Results
[0262] Eighty-three subjects underwent randomization.
[0263] No notable differences of demographic and baseline
characteristics were found among the study groups.
[0264] Subjects in all three treatment groups were 99% compliant
with their study medication based on pill counts. During the study,
there were no significant changes in mean daily L-DOPA doses in any
treatment group or comparing combined KW-6002 and placebo
groups.
[0265] Subjects randomized to KW-6002 experienced a significant
decrease in OFF time compared to subjects randomized to placebo as
assessed by home diaries (FIG. 1). Subjects assigned to KW-6002
experienced a reduction in the proportion of awake time spent in
the OFF state of 7.1% compared to an increase of 2.2% in the
placebo group (p=0.008). Both KW-6002 dose groups exhibited a
significant decrease in percent OFF time compared to the placebo
group. Similarly, the combined KW-6002 group, as well as each
KW-6002 group, experienced a significant reduction in total hours
OFF. Subjects assigned to KW-6002 experienced a reduction in OFF
time of 1.2 hours compared to an increase of 0.5 hours in the
placebo group (p=0.004) (FIG. 1).
[0266] Assessment of OFF time by investigators during 8-hour
in-office evaluations identified a trend for greater reduction in
OFF time in the combined KW-6002 group compared to the placebo
group. Subjects assigned to KW-6002 exhibited a 10.0% decrease in
OFF time compared to a decrease of 3.3% in the placebo group
(p=0.05). Similarly, subjects assigned to KW-6002 exhibited a
decrease in OFF time of 0.8 hours compared to a decrease of 0.3
hours in the placebo group (p=0.06). Off time reduction at the
higher dose KW-6002 group was significant (P=0.02).
[0267] Early morning dystonia in patients treated with KW-6002 was
reduced from baseline to Week 12 compared to the placebo group.
[0268] The overall adverse event profile was of no difference in
subjects treated with KW-6002 versus placebo. The overall
occurrence of serious adverse events was similarly distributed
across the study groups. The number of total withdrawals and
withdrawals due to adverse events were similar in the KW-6002 and
placebo groups. No notable changes or differences between KW-6002
and placebo groups were observed in systolic or diastolic blood
pressure, heart rate, respiratory rate, body weight, ECG, and mean
values urinalysis or blood chemistry analyses remained within
laboratory reference range.
[0269] In this study, under a variety of concomitant medication
with dopamine agonists (e.g., Pramipexol, Pergolide, Ropinirol,
Bromocriptine), COMT inhibitors (e.g., Entacapone, Tolcapone) and a
MAO inhibitor selegiline, KW-6002 showed significant OFF time
reduction, and safety and good tolerability.
[0270] Based on the findings of this study, the adenosine A.sub.2A
receptor antagonist KW-6002 can safely and effectively reduce off
time in Parkinson's disease patients with L-DOPA motor
complications.
[0271] The present study also shows that the adenosine A.sub.2A
receptor antagonist KW-6002 showed significant OFF time reduction
in Parkinson's disease patients treated with the concomitant
medication of L-DOPA and a dopamine agonist and/or a COMT inhibitor
and/or a MAO inhibitor.
[0272] The present study also shows that KW-6002 reduces early
morning dystonia in Parkinson's disease patients.
[0273] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
and understanding, it will be apparent to those skilled in the art
that certain changes and modifications may be practiced. Therefore,
the description and examples should not be construed as limiting
the scope of the invention.
EXAMPLE 2
[0274] Sixteen individuals with moderate to advanced Parkinson's
disease consented to participate in this double-blind,
placebo-controlled study. All were randomized to either KW-6002, or
matching placebo capsules. The study employed a rising dose design
(40 and 80 mg/day) lasting 6 weeks. Parkinsonism was rated on the
UPDRS part III Motor Examination. All evaluations were videotaped
for subsequent off-line scoring by a second, blinded rater.
[0275] KW-6002 alone or in combination with a steady-state
intravenous infusion of each patient's optimal L-DOPA dose had no
effect on Parkinsonian severity. At a threshold dose of infused
L-DOPA, KW-6002 potentiated the antiparkinsonian response by 38% (p
<.05). No medically significant drug toxicity was observed.
[0276] KW-6002 in combination with a threshold dose of L-DOPA
improved motor condition (rated using the UPDRS III Motor
Examination scale) items as much as the optimal L-DOPA dose
alone.
[0277] Thus, the present invention provides methods and
compositions for treating Parkinson's disease patients with a
sub-clinically effecteve dose of L-DOPA by combining L-DOPA
treatment with an effective amount of one or more adenosine
A.sub.2A receptor antagonists (i.e., L-DOPA sparing effect).
[0278] The study showed that mean scores for tremor at rest and
rise from chair demonstrated substantial improvement at Weeks 4 and
6 with respect to baseline and the placebo group. Mean scores for
gait and body bradykinesia were observed to appreciably improve in
KW-6002-treated patients at Week 6, relative to baseline and the
placebo treated group. This means that KW-6002 also effectively
treats tremor and gait of both Parkinson's disease patients and
patients having other movement disorders.
[0279] Thus, the present invention provides methods for the
effective treatment of movement disorders with tremor,
bradykinesias, gait and bradykinesia.
[0280] The findings derived from Examples 1 and 2 confirm that
adenosine A.sub.2A receptor mechanisms play a role in symptom
production in Parkinson's disease and motor complications, and that
drugs able to block the receptors selectively confer therapeutic
benefit to L-DOPA treated patients with this disorder.
[0281] That is, the present invention provides methods of treating
movement disorders by administering an effective amount of one or
more adenosine A.sub.2A receptor antagonists to a patient in need
thereof, as well as methods of reducing or suppressing the adverse
effectiveness of L-DOPA in patients receiving L-DOPA therapy in the
treatment of Parkinson's disease.
EXAMPLE 3
[0282] GABA and glutamate concentrations in an output nucleus of
basal ganglia, substantia nigra pars reticulata (SNr), are measured
in the 6-hydroxydopamine lesion rats and the chronically
L-DOPA-treated rats after 6-hydroxydopamine lesion. Effect of
adenosine A.sub.2A receptor selective antagonists on GABA and
glutamate levels in SNr and dyskinesias was examined.
[0283] Metohds: 6-hydroxydopamine (8 .mu.g) was injected into the
left medial forebrain bundle in a rat. One week after the lesion,
the rats were then tested for contralateral turning by injecting
apomorphine (0.1 mg/kg s.c.). Only those animals showing robust
contralateral turning were used in subsequent experiments. Three
days after the apomorphine tests, L-DOPA was administrated orally
twice a day at a dose of 20 mg/kg for 1 to 3 weeks.
[0284] For qualification of L-DOPA induced dyskinesia, rats were
observed individually to score severity scale of abnormal
involuntary moments (AIM) including locomotive, axial, limb and
orolingual AIMs, which assigns a score from 0 to 4 to each of the
four AIM subtypes according to the proportion of time/monitoring
period during which the AIM is present. During the chronic
treatment of L-DOPA, recording of severity scale of AIMs were
carried out. In addition, an amplitude-based scale for each limb
and axial AIMs was scored during a microdialysis study. Amplitude
scores of limb or axial AIMs (each ranging from 0 to 4) was rated
based on both the magnitude of paw/limb translocation and of the
visible involvement of distal versus proximal muscle groups or on
the lateral deviation (or torsion) of an animal's neck and trunk
from the longitudinal axis of its body, respectively.
[0285] GABA and glutamate in SNr were measured after
6-hydroxydopamine lesion and four days after terminating the
repeated L-DOPA treatments, with in vivo microdialysis technique.
Rats were placed in each test chamber and the microdialysis probe
inserted into SNr was attached to a fluid swivel (TCS2-23, Eicom)
that allowed free movement (also sustained rotational behavior).
Probes were continuously perfused with a modified Ringer's solution
(1.2 mmol/L CaCl.sub.2, 2.7 mmol/L KCl, 148 mmol/L NaCl, and 0.85
mmol/L MgCl.sub.2; pH 7, artificial cerebrospinal fluid solution)
at a rate of 2 .mu.L/min via a microinjection pump (CMA/100,
Carnegie Medicin AB). After stabilization of basal level of release
for 3-4 h, 4 samples (60 .mu.L each) during 2 h of perfusion were
collected using a fraction collector (CMA/140, Carnegie Medicin).
Sixty .mu.L of perfusate per sample (during 30 min) was divided
into 2.times.30 .mu.L in sampling tubes (sample vial for
Auto-sampling-injector 231XL, Eicom), and the concentrations of
GABA and glutamate were determined from each sample. The samples
were immediately assayed or frozen and stored in a deep freeze
(-80.degree. C.) before assays. GABA and glutamate were analyzed
using reverse phase high-performance liquid chromatograph with
fluorescence detection after pre-column derivatization of the amino
acids with orthophthaldialdehyde reagent. Lindroth and Mopper
(1979).
[0286] Results:
[0287] KW-6002 (1 mg/kg p.o.) caused a marked and sustained
increase of GABA and glutamate levels in the SNr of the
6-hydroxydopamine lesioned rats (FIG. 2A, 2B). L-DOPA also induced
the facilitation of nigral GABA and glutamate in 6-hydroxydopamine
lesioned rats (FIG. 3A, 3B)
[0288] AIMs with 1 week daily repeated treatments of L-DOPA were
still varied in individual rat and maintained the maximum severity
grades for a short time. With 2 to 3 weeks in chronic L-DOPA
treatments, animals produced stable AIMs, and maintained average
maximum AIM scores (9) from 10 min to 3 hrs after L-DOPA
administration.
[0289] The basal nigral glutamate concentration maintained constant
levels until 2week chronic treatment of L-DOPA, and drastically
increase in 3 weeks, whereas nigral GABA levels maintained
unchanged throughout the periods, as shown in Table 3. Table 3
shows the basal level of nigral GABA and glutamate in chronic
L-DOPA-treated rats after 6-hydroxydopamine lesion.
TABLE-US-00003 TABLE 3 Duration of L-DOPA treatment 0 1 week 2
weeks 3 weeks GABA, nmol/L 19.8 .+-. 2.5 19.3 .+-. 2.3 20.9 .+-.
6.8 23.6 .+-. 4.5 (N) (11) (3) (3) (13) Glutamate, 185.0 .+-. 36.5
147.5 .+-. 38.1 112.0 .+-. 47.1 425.4 .+-. 99.6 nmol/L (N) (12) (3)
(3) (13) L-DOPA elicited marked AIMs (sum of the amplitude score of
limb and axial AIMs), whereas KW-6002 induced little or no AIMs in
the chronically treated rats (FIG. 4). L-DOPA increased glutamate
levels without effect on nigral GABA levels, whereas KW-6002 gave
no or little effects on nigral GABA and glutamate levels (FIG.
5).
[0290] The time courses of increase of L-DOPA induced AIMs
amplitude were parallel with the increase of L-DOPA induced nigral
glutamate levels (FIGS. 4 and 5B).
EXAMPLE 4
[0291] To compare in MPTP monkeys rendered parkinsonian by repeated
injections of MPTP and having never received L-DOPA or dopaminergic
agents the effect of chronic treatment with L-DOPA alone or in
combination with KW-6002 or placebo.
[0292] ANIMALS: 8 (eight) female drug-naive cynomologus monkeys
weighing between 3 and 5 kg were used. They were rendered
parkinsonian by subcutaneous infusion of MPTP (0.5 mg daily) until
development of an obvious parkinsonian Syndrome (akinesia, hunched
posture and tremor associated with a disability score on our scale
of 6 or more). The cumulative dose necessary was variable: from 3.5
to 23.5 mg.
[0293] The animals were allowed to recover during at least one
month except an animal who had to be treated earlier because of
marked akinesia. They were scored at least once daily. The
disability score remained stable throughout that period.
[0294] TREATMENT: All animals were treated with L-DOPA/benserazide
100/25 mg (total dose) once daily. The drug was administered orally
with a special capsule handler. The animals in the KW-6002 group
also received this compound (90 mg/kg) by the oral route. The
animals were observed daily (from Monday to Friday) in their cages
through a one-way screen and video recordings were made of
significant events (abnormal behavior--dyskinesias). They were
scored on disability scale and eventually dyskinesia rating scale,
before and during the effect. The treatment with L-DOPA was
continued for one month.
[0295] Results
[0296] The antiparkinsonian response to L-DOPA in terms of
improvement of the parkinsonian score over four weeks was stable
and comparable in the L-DOPA alone group and in the combination
(L-DOPA+KW-6002) treatment group. (FIG. 6).
[0297] The locomotor activity counts increased to a higher level in
the combination treatment group and its level was maintained over
four weeks. (FIG. 7).
[0298] Dyskinesias increased more rapidly and reached a higher
level in the L-DOPA group than in the combination treatment group.
Thus, the onset of dyskinesia was delayed in the presence of
KW-6002. Even after appearance of dyskinesia (week 3 and 4), the
KW-6002 treatment group produced less dyskinesia than L-DOPA alone
group. (FIG. 8).
[0299] At the end of the one-month treatment period, all drugs were
stopped. The following day, the animals of the KW-6002 group were
challenged with a standard dose of L-DOPA/benserazide(100/25 mg),
administered orally. The three animals that had already displayed
dyskinesias had a similar response to the combination.
[0300] In conclusion, the addition of KW-6002 to L-DOPA in the
treatment of previously drug-naive parkinsonian monkeys during one
month delay the onset of dyskinesia and produced less dyskinesia,
while it produced stronger locomotor response, and a similar
improvement of the parkinsonian score.
EXAMPLE 5
[0301] Effect of KW-6002 on L-DOPA induced dyskinesia in MPTP
treated common marmosets that had previously been primed to exhibit
dyskinesia L-DOPA was investigated.
[0302] METHODS: MPTP (Sigma-Aldrich, St. Louis, Mo., USA) was
dissolved in physiological saline and administered at a dose of 2.0
mg/kg s.c daily for 5 days. Then, MPTP 2 mg/kg were further
administered approximately 3 weeks. 8 weeks after exposure to MPTP,
animals showed chronic parkinsonian symptoms such as marked
reduction of basal locomotor activity, slower and less coordinated
movements, abnormal postures of some parts of the body, and reduced
checking movement and eye blinks. The animals, which showed
sufficient chronic parkinsonian symptoms, were selected for this
study.
[0303] L-DOPA (10 mg/kg p.o.) plus benserazide (2.5 mg/kg p.o.) was
then administered twice daily for 28 days to the MPTP-treated
marmosets to induce dyskinesia. The dyskinesia of the animals was
scored using the rating scale described in Table 4. The animals,
which showed high dyskinesia score up to 8 by each L-DOPA
administration, were used in this study. Dyskinesias induced by
L-DOPA (10 mg/kg p.o. plus benserazide 2.5 mg/kg p.o.) were scored
in MPTP-treated marmosets. The score was calculated as the L-DOPA
pre value. On the next day the animals received vehicle for the
vehicle control value. One day later, they were administered with
L-DOPA (2.5 mg/kg, p.o.) to obtain the L-DOPA control value. Then
the effects of KW-6002 on L-DOPA induced dyskinesia were observed.
Administration of KW-6002 (10 mg/kg p.o.) combined with L-DOPA (2.5
mg/kg, p.o.) was started on the following day (day 1) and repeated
once daily for 21 days, followed by a one-week washout period.
Animals were assessed for dyskinesia on days 1, 3, 5, 7, 14, 21 and
28 according to the rating scale. In addition, the L-DOPA post
value was obtained by administration of L-DOPA (10 mg/kg p.o.) to
the marmosets on day 35.
[0304] Table 4 shows the results of quantifying the presence of
limb dystonia, chorea and choreathetoid dyskinesia and
stereotypies. Abnormal movement such as, orofacial movements,
myoclonus and complex stereotypic behaviors (e.g., elaborate
checking, obsessive grooming), are exclude from dyskinesia
rating.
TABLE-US-00004 TABLE 4 Score 0 Absent 1 Mild Fleeting and rare
dyskinetic postures and movements. 2 Moderate More prominent
abnormal movements, but not interfering significantly with normal
behavior. 3 Marked Frequent and at times continuous dyskinesias
intruding upon normal repertory of activity. 4 Severe Virtually
continuous dyskinetic activity, disabling to animal and replacing
normal behavior. Remarks according to dyskinesia. Dystonia (arm,
leg and trunk): abnormal sustained posture (ex. leg elevation).
Stereotypic reaching (arm) Athetosis (arm and leg): writhing
twisting movements. Chorea (arm and leg): abnormal rapid (dance
like) movements of limbs. Akathisia: motor restlessness. Dyskinesia
score is become higher according to severity of dyskinesia. The
maximal score is four points.
[0305] RESULTS: Results was represented on FIG. 9. Oral
administration of L-DOPA (2.5 mg/kg) induced mild dyskinesias in
MPTP-treated common marmosets that had previously been primed to
exhibit dyskinesia by L-DOPA. The L-DOPA (2.5 mg/kg p.o.) induced
dyskinesia was not changed or trended to reduced by KW-6002 (10
mg/kg p.o.) for 21 days compared with L-DOPA alone control. On the
day 21, KW-6002 shows significant reduction of L-DOPA induced
dyskinesias compared with 2.5 mg/kg of L-DOPA alone. The
significant reduction caused by KW-6002 in L-DOPA induced
dyskinesia was observed by acute administration of KW-6002 (10
mg/kg) with L-DOPA (2.5 mg/kg) in 1 week after the repeated
administration for 21 days of KW-6002 and L-DOPA.
[0306] In conclusion, results of these experiments indicate that
KW-6002 suppresses L-DOPA induced dyskinesias.
PREPARATION EXAMPLE 1
Tablets
[0307] Tablets having the following composition are prepared in a
conventional manner.
[0308] KW-6002 (40 g) is mixed with 286.8 g of lactose and 60 g of
potato starch, followed by addition of 120 g of a 10% aqueous
solution of hydroxypropyl cellulose. The resultant mixture is
kneaded, granulated, and then dried by a conventional method. The
granules are refined to give granules used to make tablets. After
mixing the granules with 1.2 g of magnesium stearate, the mixture
is formed into tablets each containing 20 mg of the active
ingredient by using a tablet maker (Model RT-15, Kikusui) having
pestles of 8 mm diameter.
[0309] The prescription is shown in Table 5.
TABLE-US-00005 TABLE 5 Compound (I) 20 mg Lactose 143.4 mg Potato
Starch 30 mg Hydroxypropyl Cellulose 6 mg Magnesium Stearate 0.6 mg
200 mg
PREPARATION EXAMPLE 2
Capsules
[0310] Capsules having the following composition are prepared in a
conventional manner.
[0311] KW-6002 (200 g) is mixed with 995 g of Avicel and 5 g of
magnesium stearate. The mixture is put in hard capsules No. 4 each
having a capacity of 120 mg by using a capsule filler (Model LZ-64,
Zanashi) to give capsules each containing 20 mg of the active
ingredient.
[0312] The prescription is shown in Table 6.
TABLE-US-00006 TABLE 6 Compound (I) 20 mg Avicel 99.5 mg Magnesium
Stearate 0.5 mg 120 mg
PREPARATION EXAMPLE 3
Injections
[0313] Injections having the following composition are prepared in
a conventional manner.
[0314] KW-6002 (1 g) is dissolved in 100 g of purified soybean oil,
followed by addition of 12 g of purified egg yolk lecithin and 25 g
of glycerin for injection. The resultant mixture is made up to
1,000 ml with distilled water for injection, thoroughly mixed, and
emulsified by a conventional method. The resultant dispersion is
subjected to aseptic filtration by using 0.2 .mu.m disposable
membrane filters, and then aseptically put into glass vials in 2 ml
portions to give injections containing 2 mg of the active
ingredient per vial.
[0315] The prescription is shown in Table 7.
TABLE-US-00007 TABLE 7 Compound (I) 2 mg Purified Soybean Oil 200
mg Purified Egg Yolk Lecithin 24 mg Glycerine for Injection 50 mg
Distilled Water for Injection 1.72 ml 2.00 ml
[0316] Although the foregoing invention has been described in some
detail by way of illustration and example for purposes of clarity
and understanding, it will be apparent to those skilled in the art
that certain changes and modifications may be practiced. Therefore,
the description and examples should not be construed as limiting
the scope of the invention.
* * * * *