U.S. patent application number 12/901354 was filed with the patent office on 2011-03-31 for methods and compositions for reduction of side effects of therapeutic treatments.
Invention is credited to Donato Di Monte, J. William Langston, Maryka QUIK.
Application Number | 20110077276 12/901354 |
Document ID | / |
Family ID | 39409946 |
Filed Date | 2011-03-31 |
United States Patent
Application |
20110077276 |
Kind Code |
A1 |
QUIK; Maryka ; et
al. |
March 31, 2011 |
Methods and Compositions for Reduction of Side Effects of
Therapeutic Treatments
Abstract
The invention provides compositions and methods utilizing a
nicotinic receptor modulator, e.g., to reduce or eliminate a side
effect associated with dopaminergic agent treatment. In some
embodiments, the invention provides compositions and methods
utilizing a combination of a dopaminergic agent and a nicotinic
receptor modulator that reduces or eliminates a side effect
associated with dopaminergic agent treatment.
Inventors: |
QUIK; Maryka; (Palo Alto,
CA) ; Di Monte; Donato; (Cupertino, CA) ;
Langston; J. William; (Los Altos Hills, CA) |
Family ID: |
39409946 |
Appl. No.: |
12/901354 |
Filed: |
October 8, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12502992 |
Jul 14, 2009 |
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12901354 |
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12061587 |
Apr 2, 2008 |
7718677 |
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12502992 |
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60909637 |
Apr 2, 2007 |
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60956296 |
Aug 16, 2007 |
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60956657 |
Aug 17, 2007 |
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Current U.S.
Class: |
514/343 |
Current CPC
Class: |
A61P 25/16 20180101;
A61P 25/28 20180101; A61P 43/00 20180101; A61K 9/0053 20130101;
A61K 31/198 20130101; A61K 31/465 20130101; A61P 25/14 20180101;
A61K 45/06 20130101; A61K 31/198 20130101; A61K 2300/00 20130101;
A61K 31/465 20130101; A61K 2300/00 20130101 |
Class at
Publication: |
514/343 |
International
Class: |
A61K 31/465 20060101
A61K031/465; A61P 25/14 20060101 A61P025/14 |
Goverment Interests
GOVERNMENT INTERESTS
[0002] Certain embodiments of the present invention were made under
research grant numbers NIH NS34886 and NS 42091 from the National
Institute of Health, who may have certain rights thereto.
Claims
1-152. (canceled)
153. A method for reducing dopaminergic agent-induced dyskinesia
comprising administering to a human being treated with said
dopaminergic agent an amount of nicotine sufficient to reduce
dyskinesia induced by said dopaminergic agent, wherein said amount
of nicotine is administered such that nicotine or a nicotine
metabolite reaches a critical concentration of about 1 ng/ml to
about 20 ng/ml.
154. The method of claim 153 wherein said critical concentration is
reached about one hour to about three hours after the dopaminergic
agent reaches the bloodstream or brain.
155. The method of claim 153 wherein said critical concentration is
reached about one hour to about three hours before the dopaminergic
agent reaches the bloodstream or brain.
156. The method of claim 153 wherein said critical concentration is
reached at from about one hour to about a minute before the
dopaminergic agent-induced dyskinesia reaches a peak.
157. The method of claim 153 wherein the amount of nicotine is
sufficient to reduce said dyskinesia at least about 30%.
158. The method of claim 153 wherein said dyskinesia is induced by
a Parkinson's disease treatment.
159. The method of claim 153 wherein said dopaminergic agent
comprises a dopamine precursor or a dopamine receptor agonist.
160. The method of claim 153 wherein said dopaminergic agent
comprises levodopa, bromocriptine, pergolide, pramipexole,
cabergoline, ropinirole, apomorphine or a combination thereof.
161. The method of claim 160 wherein said dopaminergic agent is
levodopa.
162. The method of claim 153 wherein said subject suffers from
Parkinson's disease.
163. The method of claim 153 wherein said administration comprises
a single daily dose of nicotine.
164. The method of claim 153 wherein said administration comprises
multiple daily doses of nicotine.
165. The method of claim 153 comprising administering at least one
dose of nicotine in a 24-hour period, wherein said nicotine is
present at about 6 milligrams or less per dose.
166. The method of claim 165 wherein said nicotine is present at
about 4 milligrams or less per dose.
167. The method of claim 165 wherein said nicotine is present at
about 2 milligrams or less per dose.
168. The method of claim 165 wherein said nicotine is present at
about 1 milligrams or less per dose.
169. The method of claim 153 wherein said amount of nicotine
administered in a 24-hour period is about 15 milligrams.
170. The method of claim 153 wherein said amount of nicotine
administered in a 24-hour period is about 8 milligrams.
171. The method of claim 153 wherein said amount of nicotine
administered in a 24-hour period is about 3 milligrams.
172. The method of claim 153 wherein said nicotine is administered
orally.
173. The method of claim 172 wherein said nicotine is administered
in a solid form.
174. The method of claim 153 wherein the dopaminergic agent is
being administered for the treatment of Parkinson's disease or
Parkinsonism in the human and the effective amount of the
dopaminergic agent is 100% to 75% of the effective amount when the
dopaminergic agent is administered without the nicotine.
175. The method of claim 153 wherein said dopaminergic agent is
being administered for the treatment of Parkinson's disease or
Parkinsonism in the human and the amount of the dopaminergic agent
administered is not reduced after nicotine administration.
176. The method of claim 153 wherein the human is suffering from
said dopaminergic agent-induced dyskinesia.
177. The method of claim 153 wherein said amount of nicotine is
maintained for a period of more than six months.
178. The method of claim 153 wherein said amount of nicotine is
maintained for a period of more than one year.
Description
CROSS REFERENCE
[0001] This application claims the benefit of provisional
applications 60/909,637 entitled Methods and Compositions for
Reduction of Side Effects of Therapeutic Treatments filed Apr. 2,
2007; 60/956,296 entitled Methods and Compositions for Reduction of
Side Effects of Therapeutic Treatments filed Aug. 16, 2007; and
60/956,657 entitled Methods and Compositions for Reduction of Side
Effects of Therapeutic Treatments filed Aug. 17, 2007.
BACKGROUND OF THE INVENTION
[0003] Many of the leading treatments for diseases lead to
undesired side effects. For instance, levodopa, the standard for
Parkinson's disease treatment, is associated with debilitating
abnormal involuntary movements or dyskinesias. These motor
abnormalities may occur after only a few months of treatment and
affect the majority of patients within 5-10 years. They can be
quite incapacitating and represent a major complication in
Parkinson's disease management. Currently there are only limited
therapeutic options for dyskinesias.
[0004] Parkinson's disease is extremely common amongst those over
65, and age group that, in North America, is predicted to rise from
12% to 24% over the next 30 year. The overall prevalence of
Parkinson's disease in this population is in the order of 1.5-2%
and increases with age. Therefore, additional treatments are needed
for this disabling complication of levodopa therapy.
SUMMARY OF THE INVENTION
[0005] The invention provides methods, compositions, and kits for
the use of nicotinic receptor modulator. For example the methods,
compositions, and kits described herein are used to reduce or
eliminate a side effect. In some embodiments, the methods,
compositions, and kits described herein are used to reduce or
eliminate a side effect of a dopaminergic agent.
[0006] In one aspect, the invention provides compositions including
a nicotinic receptor modulator. In some embodiments of this aspect,
the invention provides a pharmaceutical composition including a
nicotinic receptor modulator. In some embodiments, the invention
includes pharmaceutical compositions where the nicotinic receptor
modulator is present in an amount sufficient to decrease a side
effect of a dopaminergic agent when the composition is administered
to an animal. In some embodiments, the invention includes
pharmaceutical compositions where the nicotinic receptor modulator
is present in an amount sufficient to reduce or eliminate a side
effect of a dopaminergic agent and to prevent or reduce the
likelihood of addiction to the nicotinic receptor modulator when
the composition is administered to an animal. The pharmaceutical
compositions including a nicotinic receptor modulator are
administered through various routes of delivery further described
herein. In some embodiments, the pharmaceutical compositions
including a nicotinic receptor modulator are administered orally to
an animal. In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing an
effective amount of a nicotinic receptor modulator and a
pharmaceutical excipient suitable for oral administration. In some
embodiments, the invention provides a liquid pharmaceutical
composition for oral administration containing an effective amount
of a nicotinic receptor modulator and a pharmaceutical excipient
suitable for oral administration.
[0007] In some embodiments of this aspect, the invention provides a
pharmaceutical composition including a dopaminergic agent and
nicotinic receptor modulator. In some embodiments, the invention
includes pharmaceutical compositions where the nicotinic receptor
modulator is present in an amount sufficient to decrease a side
effect of the dopaminergic agent when the composition is
administered to an animal.
[0008] In some embodiments of this aspect, the nicotinic receptor
modulator modulates a nicotinic receptor in the brain. In some
embodiments, the nicotinic receptor modulator modulates a nicotinic
receptor in the striatum or substantia niagra. In some embodiments,
the nicotinic receptor modulator modulates a nicotinic receptor
comprising at least one .alpha. subunit or a nicotinic receptor
containing at least one .alpha. subunit and at least one .beta.
subunit. In some embodiments, the .alpha. subunit is selected from
the group consisting of .alpha.2, .alpha.3, .alpha.4, .alpha.5,
.alpha.6, .alpha.7, .alpha.8, .alpha.9, and .alpha.10 and the
.beta. subunit is selected from the group consisting of .beta.2,
.beta.3 and .beta.4. In some embodiments, the nicotinic receptor
modulator modulates a nicotinic receptor comprising subunits
selected from the group consisting of .alpha.4.beta.2,
.alpha.6.beta.2, .alpha.4.alpha.6.beta.2, .alpha.4.alpha.5.beta.2,
.alpha.4.alpha.6.beta.2.beta.3, .alpha.6.beta.2.beta.3 and
.alpha.4.alpha.2.beta.2.
[0009] In some embodiments of the composition, the nicotinic
receptor modulator in the composition includes a nicotinic receptor
agonist. In some embodiments, the nicotinic receptor agonist in the
composition is selected from the group consisting of a simple or
complex organic or inorganic molecule, a peptide, a protein, an
oligonucleotide, an antibody, an antibody derivative, an antibody
fragment, a vitamin derivative, a carbohydrate, and a toxin.
Examples of nicotinic receptor agonists include, but are not
limited to, nicotine, conotoxinMII, epibatidine, A-85380, cytisine,
lobeline, anabasine, SIB-1508Y, SIB-1553A, ABT-418, ABT-594,
ABT-894, TC-2403, TC-2559, RJR-2403, SSR180711, GTS-21 and
varenicline. In some embodiments, the agonist is nicotine.
[0010] In some embodiments of the composition, the dopaminergic
agent is a dopamine precursor or a dopamine receptor agonist.
Examples of dopaminergic agents include, but are not limited to,
levodopa, bromocriptine, pergolide, pramipexole, cabergoline,
ropinorole, apomorphine or a combination thereof. In some
embodiments, the dopaminergic agent is levodopa.
[0011] In some embodiments of the compositions of the invention,
the side effect being treated includes tremors, headache, changes
in motor function, changes in mental status, changes in sensory
functions, seizures, insomnia, paresthesia, dizziness, coma and
dyskinesias. In some embodiments, the side effect is dyskinesias.
In some embodiments of the compositions of the invention, the side
effects are decreased at least 30% compared to the side effects
without the nicotinic receptor modulator. In some embodiments of
the invention, the therapeutic effect of dopaminergic agent is
increased an average of at least about 5% compared to the
therapeutic effect without the nicotinic receptor modulator, when
the composition is administered to an animal.
[0012] In some embodiments of the compositions of the invention,
the nicotinic receptor modulator is administered to an animal
suffering or about to suffer from a dopaminergic agent-induced side
effect such that the nicotinic receptor modulator or a metabolite
reaches an optimal concentration in the blood, plasma and/or target
tissues in the animal so the side effect can be decreased. In some
embodiments the nicotinic receptor modulator or a metabolite is in
the bloodstream of the animal prior to the dopaminergic agent. In
some embodiments, the nicotinic receptor modulator or a metabolite
is in the bloodstream of the animal after the dopaminergic agent
but prior to the beginning of the dopaminergic agent-induced side
effect. In some embodiments, the nicotinic receptor modulator or a
metabolite is in the bloodstream of the animal after the
dopaminergic agent and after the animal is showing the first signs
of a dopaminergic agent-induced side effect. In some embodiments,
the nicotinic receptor modulator or a metabolite is in the
bloodstream of the animal after the dopaminergic agent and after
the animal is suffering of a dopaminergic agent-induced side
effect.
[0013] In some embodiments, the nicotinic receptor modulator is
administered through pulsatile delivery. In some embodiments, the
nicotinic receptor modulator is administered in an extended release
or controlled release formulation. In some embodiments, the
nicotinic receptor modulator and/or the dopaminergic agent are
administered in a multilayer tablet.
[0014] In some embodiments of the compositions of the invention, a
pharmaceutical composition includes the composition of the
invention and a pharmaceutically acceptable excipient. In some
embodiments of the composition, a molar ratio of the dopaminergic
agent and the nicotinic receptor modulator is about 0.001:1 to
about 10:1. In some embodiments of the composition, the
dopaminergic agent is present in an amount of about 0.1 to about
1000 mg and the nicotinic receptor modulator is present in an
amount of about 0.1 to about 2000 mg. In some embodiments, the
nicotinic receptor modulator is nicotine. In some embodiments,
nicotine is present at about 0.1 to about 100 mg. In some
embodiments, nicotine is present at about 0.1 to about 10 mg. In
some embodiments, nicotine is present at about 0.5 mg. In some
embodiments of the compositions of the invention, a pharmaceutical
composition includes an effective amount of levodopa and an amount
of nicotine sufficient to reduce levodopa induced-dyskinesias and a
pharmaceutically acceptable carrier.
[0015] In some embodiments, a pharmaceutical composition includes a
third agent also used for the treatment of a side effect of the
dopaminergic agent. In some embodiments, the side effect treated
with the nicotinic receptor modulator and the third agent is the
same side effect. In some embodiments, the side effects treated
with the nicotinic receptor modulator and the third agent are
different side effects. In some embodiments, the third agent is
amantadine. In some embodiments, the pharmaceutical compositions of
the invention include one or more agents used in the art in
combination with a dopamine agent treatment to achieve a
therapeutic effect. For instance, in some embodiments, the
pharmaceutical compositions of the invention include an agent such
as carbidopa, which blocks the conversion of levodopa to dopamine
in the blood. In some embodiments, the pharmaceutical compositions
of the invention include a COMT Inhibitors, such as entacapone. In
some embodiments, the pharmaceutical compositions of the invention
include a monoamine oxidase type B (MAO-B) inhibitor such as
selegiline.
[0016] In some embodiments of the compositions of the inventions, a
pharmaceutical composition includes an effective amount of
levodopa, an effective amount of carbidopa, an effective amount of
nicotine capable of reducing levodopa-induced dyskinesias and a
pharmaceutically acceptable carrier.
[0017] In some embodiments of the compositions of the inventions, a
pharmaceutical composition includes an effective amount of a
dopaminergic agent, an effective amount of nicotine and a
pharmaceutically acceptable carrier, where nicotine is present at
about 0.01 to about 10 mg.
[0018] In some embodiments of the compositions of the inventions, a
solid pharmaceutical composition for oral administration includes
nicotine and a pharmaceutically acceptable carrier, where nicotine
is present at about 0.01 mg to about 2.8 mg. In some embodiments of
the compositions of the invention, the amount of nicotine present
is less than 3 mg.
[0019] In some embodiments of the compositions of the inventions, a
multilayer tablet includes an immediate release layer and a
sustained release layer, where the immediate release layer
comprises one or more therapeutic agents independently selected
from the group consisting of nicotinic receptor agonist and
dopaminergic agent, and the sustained release layer comprises one
or more therapeutic agents independently selected from the group
consisting of nicotinic receptor agonist and dopaminergic agents.
In some embodiments, the immediate release layer or the sustained
release agent further comprises a third agent. In some embodiments,
the third agent is used to achieve a therapeutic effect in
combination with the dopaminergic agent or to treat a side effect
of the dopaminergic agent.
[0020] In some embodiments of the invention, a kit includes the
composition of the invention and instructions for use of the
composition.
[0021] In another aspect, the invention provides methods utilizing
nicotinic receptor agonist. In some embodiments of this aspect, the
invention provides a method of treating an animal by administering
to an animal an effective amount of a nicotinic receptor agonist
sufficient to reduce or eliminate a side effect of a dopaminergic
agent. In some embodiments of this aspect, the invention provides a
method of treating an animal by administering to an animal an
effective amount of a nicotinic receptor agonist sufficient to
reduce or eliminate a side effect of a dopaminergic agent and to
prevent or reduce the likelihood of addiction to the nicotinic
receptor modulator when the composition is administered to an
animal. In some embodiments, the nicotinic receptor modulator is
administered through various routes of delivery further described
herein. In one embodiment, the nicotinic receptor modulator is
administered orally to an animal.
[0022] In some embodiments of this aspect, the invention provides a
method of treating a condition by administering to an animal
suffering from the condition an effective amount of a dopaminergic
agent and an amount of a nicotinic receptor agonist sufficient to
reduce or eliminate a side effect of the dopaminergic agent. In
some embodiments, the agonist reduces or eliminates a plurality of
side effects of the dopaminergic agent. In some embodiments, the
dopaminergic agent and the nicotinic receptor agonist are
administered in a single composition. In some embodiments, the
dopaminergic agent and the nicotinic receptor agonist are admixed
in the composition.
[0023] In some embodiments of this aspect, the invention provides a
method of decreasing a side effect of treatment with a dopaminergic
agent by administering to a human in need of a treatment with a
dopaminergic agent an effective amount of nicotine in combination
with the dopaminergic agent, where the dopaminergic agent and
nicotine are administered simultaneously to the human in an oral
composition. In some embodiments, the dopaminergic agent and
nicotine are administered in a single composition. In some
embodiments, the dopaminergic agent and nicotine are administered
in different compositions. In some embodiments, the dopaminergic
agent and nicotine are admixed in the composition.
[0024] In some embodiments of this aspect, the invention provides a
method of decreasing levodopa-induced dyskinesias by administering
to a human in need of treatment an effective amount of nicotine in
combination with an effective amount of levodopa and an effective
amount of carbidopa, where the amount of nicotine is sufficient to
reduce the dyskinesias and wherein levodopa and nicotine are
administered orally simultaneously to said human.
[0025] In some embodiments of the methods of the invention, the
dopaminergic agent is present in an amount sufficient to exert a
therapeutic effect and the nicotinic receptor agonist is present in
an amount sufficient to decrease a side effect of the dopaminergic
agent by an average of at least about 30%, compared to the effect
without the nicotinic receptor agonist. In some embodiments, the
administration is oral administration. In some embodiments, the
administration is transdermal administration.
[0026] In some embodiments of the methods of the invention, the
nicotinic receptor modulator is administered to an animal suffering
or about to suffer from a dopaminergic agent-induced side effect
such that the nicotinic receptor modulator or a nicotinic receptor
modulator metabolite reaches an effective concentration in the
blood, plasma and/or target tissues in the animal so as to reduce
or eliminate the side effects associated with the dopaminergic
agent, where the effective concentration is the concentration
necessary to reduce or eliminate the side effect. In some
embodiments, the nicotinic receptor modulator or a metabolite is
present in the bloodstream of the animal prior to the dopaminergic
agent. In some embodiments, the nicotinic receptor modulator or a
metabolite is in the bloodstream of the animal after the
dopaminergic agent but prior to the beginning of the dopaminergic
agent-induced side effect.
[0027] In various embodiments, presence of the dopaminergic agent
and the nicotinic receptor modulator or a metabolite thereof in the
blood is regulated temporally and/or spatially. For example, each
agent can be administered at temporally different times (one before
the other). In addition, the two agents can be administered at the
same time but in a dosage form which functions for regulate release
of one versus the other over a period of time (e.g., bi-layered
tablet dosage form).
[0028] In some embodiments, the nicotinic receptor modulator or a
metabolite is present in the bloodstream of the animal after the
dopaminergic agent and after the animal exhibits the first signs of
a dopaminergic agent-induced side effect. In some embodiments, the
nicotinic receptor modulator or a metabolite is present in the
bloodstream of the animal after the dopaminergic agent and after
the animal exhibits a dopaminergic agent-induced side effect.
[0029] In some embodiments, the nicotinic receptor modulator is
administered through pulsatile delivery. In some embodiments, the
nicotinic receptor modulator is administered in an extended release
or controlled release formulation. In some embodiments, the
nicotinic receptor modulator and the dopaminergic agent are
administered in a multilayer tablet.
[0030] In some embodiments of the methods of the invention, the
nicotinic receptor agonist in the composition is selected from the
group consisting of a simple or complex organic or inorganic
molecule, a peptide, a protein, an oligonucleotide, an antibody, an
antibody derivative, an antibody fragment, a vitamin derivative, a
carbohydrate, and a toxin. Examples of nicotinic receptor agonists
include, but are not limited to, nicotine, conotoxinMII,
epibatidine, A-85380, cytisine, lobeline, anabasine, SIB-1508Y,
SIB-1553A, ABT-418, ABT-594, ABT-894, TC-2403, TC-2559, RJR-2403,
SSR180711, GTS-21 and varenicline. In some embodiments, the agonist
is nicotine. In some embodiments of the invention, the dopaminergic
agent is a dopamine precursor or a dopamine receptor agonist.
Examples of dopaminergic agents include, but are not limited to,
levodopa, bromocriptine, pergolide, pramipexole, cabergoline,
ropinorole, apomorphine or a combination thereof. In some
embodiments, the dopaminergic agent is levodopa.
[0031] In some embodiments, the methods described herein include a
third agent also used for the treatment of a side effect of the
dopaminergic agent. In some embodiments, the side effect treated
with the nicotinic receptor modulator and the third agent is the
same side effect. In some embodiments, the side effects treated
with the nicotinic receptor modulator and the third agent are
different side effects. In some embodiments, the third agent is
amantadine. In some embodiments, the methods described herein
include one or more agents used in the art in combination with a
dopamine agent treatment to achieve a therapeutic effect. For
instance, in some embodiments, the methods described herein include
an agent such as carbidopa, which blocks the conversion of levodopa
to dopamine in the blood. In some embodiments, the methods
described herein include a COMT Inhibitors, such as entacapone. In
some embodiments, the methods described herein include a monoamine
oxidase type B (MAO-B) inhibitor such as selegiline.
[0032] In some embodiments of the methods of the invention, the
individual suffers from a condition including Parkinson's disease,
Alzheimer, dopa-responsive dystonia, cerebral palsy, postischemic
contractile dysfunction, severe ovarian hyperstimulation syndrome,
pediatric movement disorders and non-oliguric renal failure.
[0033] In another aspect, the invention provides methods of
treating dyskinesias by administering to an animal in need of
thereof an amount of a nicotinic receptor agonist sufficient to
reduce or eliminate the dyskinesias.
[0034] In another aspect, the invention provides methods of
treating Parkinson's disease by administering to an animal in need
of thereof an amount of a nicotinic receptor agonist sufficient to
reduce or eliminate Parkinson's disease. In some embodiments, the
invention provides methods of treating Parkinson's disease by
administering to an animal in need of thereof an amount of a
nicotinic receptor agonist sufficient to reduce or eliminate
physiological symptoms associated with Parkinson's disease,
notwithstanding that the patient may still be afflicted with
Parkinson.
[0035] Other objects, features and advantages of the methods and
compositions described herein will become apparent from the
following detailed description. It should be understood, however,
that the detailed description and the specific examples, while
indicating specific embodiments, are given by way of illustration
only, since various changes and modifications within the spirit and
scope of the invention will become apparent to those skilled in the
art from this detailed description.
[0036] All publications, patents, and patent applications mentioned
in this specification are herein incorporated by reference to the
same extent as if each individual publication or patent application
was specifically and individually indicated to be incorporated by
reference.
BRIEF DESCRIPTION OF THE DRAWINGS
[0037] The novel features of the invention are set forth with
particularity in the appended claims. A better understanding of the
features and advantages of the present invention will be obtained
by reference to the following detailed description that sets forth
illustrative embodiments, in which the principles of the invention
are utilized, and the accompanying drawings of which:
[0038] FIG. 1 depicts drug treatments schedule and behavioral
testing periods.
[0039] FIG. 2 depicts a time course of the nicotine-induced decline
in L-dopa-induced dyskinesias.
[0040] FIG. 3 depicts that overall dyskinesias were decreased by
nicotine treatment.
[0041] FIG. 4 depicts a graph showing that nicotine treatment
decreased peak dyskinesias.
[0042] FIG. 5 depicts graphs showing that nicotine administration
decreased total levodopa-induced dyskinesias in levodopa-primed
monkeys.
[0043] FIG. 6 depicts graphs showing that removal of nicotine
increased levodopa-induced dyskinesias in levodopa-primed
monkeys.
[0044] FIG. 7 depicts a graph showing that nicotine administration
does not affect Parkinsonism on or off L-dopa treatment.
[0045] FIG. 8 depicts schedule for treatment paradigms and
behavioral testing in rats.
[0046] FIG. 9 depicts graphs showing time courses of nicotine
treatment on total L-dopa-induced AIMs in
6-hydroxydopamine-lesioned rats.
[0047] FIG. 10 depicts graphs showing that nicotine treatment
differentially reduces L-dopa-induced AIM components.
[0048] FIG. 11 depicts graphs showing that intermittent nicotine
treatment reduces L-dopa-induced abnormal involuntary movements
(AIMs) in rats.
[0049] FIG. 12 depicts graphs showing that intermittent nicotine
treatment reduced individual AIM components in rats after L-dopa
treatment.
[0050] FIG. 13 shows a crossover study depicting the effect of
intermittent nicotine treatment via the drinking water on
L-dopa-induced AIMs in rats.
[0051] FIG. 14 shows that continuous nicotine exposure via minipump
reduces L-dopa-induced AIMs.
[0052] FIG. 15 shows that constant nicotine exposure via minipump
reduced individual AIM components after L-dopa treatment.
[0053] FIG. 16 shows a crossover study depicting the effect of
constant nicotine exposure via minipump on L-dopa-induced AIMs.
DETAILED DESCRIPTION OF THE INVENTION
[0054] Reference will now be made in detail to particularly
preferred embodiments of the invention. Examples of the preferred
embodiments are illustrated in the following Examples section.
[0055] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as is commonly understood by one
of skill in the art to which this invention belongs. All patents
and publications referred to herein are incorporated by
reference.
[0056] The invention provides compositions and methods. In some
embodiments, the invention provides compositions and methods
utilizing a nicotinic receptor modulator, e.g., to reduce or
eliminate a side effect associated with dopaminergic agent
treatment. In some embodiments, the invention provides compositions
and methods utilizing a combination of a dopaminergic agent and a
nicotinic receptor modulator. In some embodiments, the nicotinic
receptor modulator reduces or eliminates a side effect associated
with dopaminergic agent treatment. In some embodiments, the
nicotinic receptor modulator is an agonist. Dopaminergic agents
include a dopamine precursor or a dopamine receptor agonist.
Examples of dopaminergic agents include levodopa, bromocriptine,
pergolide, pramipexole, cabergoline, ropinorole, apomorphine or a
combination thereof.
Nicotinic Receptor System
[0057] A. Striatal Nicotinic Cholinergic System
[0058] Localization of cholinergic neurons in striatum. Cholinergic
neurons in the striatum are large interneurons that comprise about
2% of the neuronal population. Although limited in number, these
interneurons have large axonal arbors that provide for a very dense
local innervation in both the caudate and putamen. Indeed, high
levels of acetylcholine, the acetylcholine synthesizing enzyme
choline acetyltransferase and the acetylcholine degradative enzyme
acetylcholinesterase are expressed in the striatum. These
cholinergic markers overlap with dopaminergic arbors, containing
dopamine, the dopamine synthetic enzyme tyrosine hydroxylase and
other dopaminergic markers that are also expressed at a relatively
high density. Without being limited to any theory, the overlapping
distribution of the cholinergic and dopaminergic system provides
the anatomical basis for a functional interaction between these two
neurotransmitters.
[0059] Nicotinic acetylcholine receptors in striatum. Striatal
cholinergic interneurons are tonically active with a resultant
ongoing release of acetylcholine that is regulated by multiple
striatal systems including glutamatergic, dopaminergic, GABAergic,
serotonergic, and other inputs. Released acetylcholine interacts
with nAChRs present on dopaminergic, as well as other striatal
neurons. These receptors are pentameric ligand-gated ion channels
composed only of .alpha. subunits (homomeric), or of .alpha. and
.beta. subunits (heteromeric receptors). To date, six different
.alpha. (.alpha.2, .alpha.3, .alpha.4, .alpha.5, .alpha.6,
.alpha.7) and three different .beta. (.beta.2, .beta.3, .beta.4)
subunits have been identified in the nigrostriatal pathway. These
subunits combine to form nAChRs, with the primary subtypes in the
striatum composed of .alpha.4.beta.2* and .alpha.3/.alpha.6.beta.2*
subunits as well as a small population of homomeric .alpha.7
nAChRs. (*The asterisks indicate that there are other subunits,
some not yet identified that are also present and may be species
dependent). The .alpha.4.beta.2* receptors are localized on
dopaminergic terminals as well as other neurons in the striatum and
throughout the CNS. However, they are not present in the peripheral
nervous system or skeletal muscle. Interestingly,
.alpha.3/.alpha.6.beta.2* receptor subtypes are selectively
localized to the dopaminergic nigrostriatal pathway, and only a
limited number of other brain areas, suggesting they may be of
particular relevance to nigrostriatal function. These latter
receptors (.alpha.3/.alpha.6.beta.2*) are designated as expressing
.alpha.3 and/or .alpha.6 subunits, because both are present in
monkey striatum, and .alpha.-conotoxinMII, the ligand used to
identify these receptors, interacts with both .alpha.3 and .alpha.6
nAChR subtypes. Without being limited to any theory, the presence
of different receptor populations on dopaminergic neurons raises
the possibility that select subtypes may be more directly linked to
the development of dyskinesias and the antidyskinetic properties of
nicotine. Such knowledge would allow for the development of nAChR
agonists more specifically targeted to ameliorating
dyskinesias.
[0060] Striatal nicotinic receptor activation results in dopamine
release. Endogenously released acetylcholine or exogenously applied
agents such as nicotine and nicotinic agonists are known to
stimulate nAChRs on dopaminergic neurons, with increases in
dopamine release in the striatum under both in vitro and in vivo
conditions. Agonist-evoked dopamine release in striatum occurs in
response to stimulation of nAChR subtypes composed of
.alpha.4.beta.2* and .alpha.3/.alpha.6.beta.2* subunits. Without
being limited to any theory, the antidyskinetic effect of nicotine
as described herein may be associated with changes in dopamine
release after stimulation of .alpha.4.beta.2* and/or
.alpha.3/.alpha.6.beta.2* nAChRs.
[0061] B. Striatal Dopaminergic System and its Involvement in
Reduction of Dopaminergic Agent Treatment Side Effects.
[0062] One of the neurotransmitter systems responsible for the
development of dopaminergic agent treatment side effects, such as
dyskinesias, in parkinsonian animals or individuals with
Parkinson's disease is the dopaminergic system itself. For
instance, D1, D2 and D3 receptor agonists all induce dyskinesias,
indicating that multiple receptor subtypes are involved. There
appears to be an imbalance in activity of the two striatal output
pathways with dyskinesias, possibly through activation of D1 and
inhibition of D2 receptors on the direct and indirect pathway,
respectively, with D3 receptors possibly exerting a modulatory
influence. Despite a clear requirement for dopamine receptor
stimulation, there are no consistent changes in the D1, D2 or D3
receptors themselves with dyskinesias. Without being limited to any
theory, such findings most likely indicate that levodopa-induced
changes may not occur at the receptor level, but involve downstream
signaling events. Recent data suggest that D1 receptors, possibly
through enhanced G-protein coupling, may play a role in
dopaminergic agent-induced dyskinesias, while D2 receptors may be
more relevant in mediating the antiparkinsonian action of
dopaminergic agents. G-proteins are membrane-associated molecules
that couple ligand-activated neurotransmitter receptors to
intracellular second messenger systems. D1 dopamine
receptor-stimulated striatal G-protein coupling was enhanced in
striatal tissue from monkeys with dopaminergic agent-induced
dyskinesias compared to controls. In addition, recent data show
that there is also enhanced .mu.-opioid receptor coupling with
dopaminergic agent-induced dyskinesias, another measure linked to
activation of the D1 direct dopaminergic pathway. Increases have
also been identified in cyclin-dependent kinase 5 (Cdk5) and
dopamine cAMP-regulated phosphoprotein (DARPP-32), an important
site for signal transduction integration in striatum. A
down-regulation of striatal D1 receptor/NMDA receptor complexes has
also been observed with the development of dyskinesias. Without
being limited to any theory, the ability of nicotine to reduce
dopaminergic agent-induced dyskinesias is likely related to
normalization of the imbalance between striatal output pathways and
modulation of signaling mechanisms.
[0063] In addition to changes in molecular markers linked to
activation of the D1 direct dopaminergic pathway, the development
of dopaminergic agent-induced dyskinesias is also associated with
alterations in cellular function. In vivo and in vitro
electrophysiological studies have been used to investigate basal
ganglia function under normal conditions and in animals with
nigrostriatal damage. This approach offers the advantage that it
allows for a determination of changes in synaptic function and
neuronal excitability not readily detectable using biochemical
techniques. One in vitro preparation that has proved particularly
useful to study the cellular mechanisms altered with dopaminergic
agent-induced dyskinesias, are corticostriatal slices from rat
brain. Brain slices at the level of the globus pallidus have
generally been used as they incorporate many of the structures
present in basal ganglia motor circuits. This includes
glutamatergic inputs from the cortex that densely innervate
striatal medium spiny GABAergic neurons and are a determinant of
neuronal activity in striatal projection neurons. Synaptic
plasticity, defined as long-lasting changes in the efficacy of
synaptic transmission, has been identified in corticostriatal
slices in vitro in the form of long-term potentiation (LTP),
long-term depression (LTD) and depotentiation. In slices from
unlesioned rats, high-frequency stimulation (HFS) of glutamatergic
corticostriatal afferent fibers can induce both LTD and LTP in
striatal medium spiny neurons, most likely due to a release of
striatal glutamate which triggers dopamine release. Stimulation of
both D1 and D2 receptors is required for the induction of LTD,
whereas these two receptor subtypes play opposing roles in LTP.
This plasticity at corticostriatal synapses is sensitive to both
dopamine exposure and nigrostriatal damage with a loss of
plasticity with lesioning. Moreover, it has been shown that chronic
L-dopa treatment modulates plasticity. It was found that L-dopa
treatment restores LTP in rats both without and with dyskinesias,
but that low frequency stimulation (LFS)-induced responses
(depotentiation) were specifically lost in dyskinetic rats. In
addition, it was found that exogenous dopamine induced a slow-onset
LTP in corticostriatal slices from L-dopa-treated dyskinetic
animals but LTD in slices from nondyskinetic animals. Without being
limited to any theory, these data suggest that dopamine-mediated
activity-dependent synaptic potentiation may be altered in
dyskinetic compared to nondyskinetic animals. Accumulating evidence
thus suggests that abnormal plasticity at corticostriatal synapses
may be involved in the development of dopaminergic agent-induced
dyskinesias.
[0064] Interestingly, these inventors have recently found that
nicotine treatment modulates synaptic plasticity in corticostriatal
slices from nonhuman primates. In particular, it restores long-term
depression (LTD) that is lost as a result of nigrostriatal damage.
Without being limited to any theory it is possible that that
nicotine modulates synaptic plasticity and promotes functional
restoration also in animals with dopaminergic agent-induced
dyskinesias and that this mechanism underlies its antidyskinetic
effect.
Nicotinic Receptor Modulators
[0065] In one aspect, the invention provides compositions and
methods utilizing a nicotinic receptor modulator, e.g., to reduce
or eliminate a side effect associated with dopaminergic agent
treatment. Modulators may be any suitable modulator.
[0066] In some embodiments, the nicotinic receptor modulator
modulates a nicotinic receptor in the brain. In some embodiments,
the nicotinic receptor modulator modulates a nicotinic receptor in
the striatum or substantia niagra. In some embodiments, the
nicotinic receptor modulator modulates a nicotinic receptor
comprising at least one .alpha. subunit or a nicotinic receptor
containing at least one .alpha. subunit and at least one .beta.
subunit. In some embodiments, the .alpha. subunit is selected from
the group consisting of .alpha.2, .alpha.3, .alpha.4, .alpha.5,
.alpha.6, .alpha.7, .alpha.8, .alpha.9, and .alpha.10 and the
.beta. subunit is selected from the group consisting of .beta.2,
.beta.3 and .beta.4. In some embodiments, the nicotinic receptor
modulator modulates a nicotinic receptor comprising subunits
selected from the group consisting of .alpha.4.beta.2,
.alpha.6.beta.2, .alpha.4.alpha.6.beta.2, .alpha.4.alpha.5.beta.2,
.alpha.4.alpha.6.beta.2.beta.3, .alpha.6.beta.2.beta.3 and
.alpha.4.alpha.2.beta.2. In some embodiments, the nicotinic
receptor modulator modulates a nicotinic receptor comprising at
least one a subunit selected from the group consisting of .alpha.4,
.alpha.6, and .alpha.7.
[0067] In some embodiments, modulators useful in the invention are
nicotinic receptor antagonist. The term "antagonist" as used herein
refers to a molecule having the ability to inhibit a biological
function of a target polypeptide. Accordingly, the term
"antagonist" is defined in the context of the biological role of
the target polypeptide. While preferred antagonists herein
specifically interact with (e.g. bind to) the target, molecules
that inhibit a biological activity of the target polypeptide by
interacting with other members of the signal transduction pathway
of which the target polypeptide is a member are also specifically
included within this definition. Antagonists, as defined herein,
without limitation, include antibodies, antibody derivatives,
antibody fragments and immunoglobulin variants, peptides,
peptidomimetics, simple or complex organic or inorganic molecule,
antisense molecules, oligonucleotide decoys, proteins,
oligonucleotide, vitamin derivatives, carbohydrates, and
toxins.
[0068] In some embodiments, modulators useful in the invention are
nicotinic receptor agonist. The term "agonist" as used herein
refers to a molecule having the ability to initiate or enhance a
biological function of a target polypeptide. Accordingly, the term
"agonist" is defined in the context of the biological role of the
target polypeptide. While preferred agonists herein specifically
interact with (e.g. bind to) the target, molecules that enhance a
biological activity of the target polypeptide by interacting with
other members of the signal transduction pathway of which the
target polypeptide is a member are also specifically included
within this definition. Agonists, as defined herein, without
limitation, include antibodies, antibody derivatives, antibody
fragments and immunoglobulin variants, peptides, peptidomimetics,
simple or complex organic or inorganic molecule, antisense
molecules, oligonucleotide decoys, proteins, oligonucleotide,
vitamin derivatives, carbohydrates, and toxins.
[0069] The nicotinic receptor agonist of the invention may be any
ligand that binds to and activates the nicotinic receptor, thereby
resulting in a biological response. The potential of a given
substance to act as a nicotinic receptor agonist may be determined
using standard in vitro binding assays and/or standard in vivo
functionality tests.
[0070] Nicotinic receptor agonist for use according to the
invention include those substances described in e.g. WO 92/21339
(Abbott), WO 94/08992 (Abbott), WO 96/40682 (Abbott), WO 9746554
(Abbott), WO 99/03859 (AstraZeneca), WO 96/15123 (Salk Institute)
WO 97/19059 (Sibia), WO 00/10997 (Ortho-McNeil), WO 00/44755
(Abbott), WO 00/34284 (Synthelabo), WO 98/42713 (Synthelabo), WO
99/02517 (Synthelabo), WO 00/34279 (Synthelabo), WO 00/34279
(Synthelabo), WO 00/34284 (Synthelabo), EP 955301 (Pfizer), EP
857725 (Pfizer), EP 870768 (Pfizer), EP 311313 (Yamanouchi
Pharmaceutical), WO 97/11072 (Novo Nordisk), WO 97/11073 (Novo
Nordisk), WO 98/54182 (NeuroSearch), WO 98/54181 (NeuroSearch), WO
98/54152 (NeuroSearch), WO 98/54189 (NeuroSearch), WO 99/21834
(NeuroSearch), WO 99/24422 (NeuroSearch), WO 00/32600
(NeuroSearch), WO PCT/DK00/00211 (NeuroSearch), WO PCT/DK00/00202
(NeuroSearch), or their foreign equivalents.
[0071] Examples of nicotinic receptor agonist according to the
invention include nicotine, ethyl nicotine,
3-ethynyl-5-(1-methyl-2-pyrrolidinyl)pyridine (SIB-1765F),
4-[[2-(1-methyl-2-pyrrolidinyl)ethyl]thio]phenol (SIB-1553),
(S)-3-ethynyl-5-(1-methyl-2-pyrrolidinyl)-pyridine (SIB-1508Y),
4'-methylnicotine or
(2S-trans)-3-(1,4-dimethyl-2-pyrrolidinyl)pyridine (Abbott),
2-methyl-3-[(2S)-2-pyrrolidinylmethoxy]-pyridine (ABT-089),
3-methyl-5-[(2S)-1-methyl-2-pyrrolidinyl]-isoxazole (ABT-418),
5-[(2R)-2-azetidinylmethoxy]-2-chloro-Pyridine (ABT-594), 3-PMP or
3-(1-pyrrolidinyl-methyl)pyridine (RJ Reynold),
(3E)-N-methyl-4-(3-pyridinyl)-3-buten-1amine (RJR-2403), anabasine
or 3,4,5,6-tetrahydro-2,3'-bipyridine (RJ Reynold),
5-fluoronicotine or
(S)-5-fluoro-3-(1-methyl-2-pyrrolidinyl)pyridine (RJ Reynold), MCC
or 2-(dimethylamino)ethyl methylcarbamate (Lundbeck), ethyl
arecolone or
1-(1,2,5,6-tetrahydro-1-methyl-3-pyridinyl-)-1-propanone (Lilly),
or isoarecolone or
1-(1,2,3,6-tetrahydro-1-methyl-4-pyridinyl)ethanone (Lilly), AR-R
17779 (AstraZeneca), epibatidine, GTS-21,
1-(6-chloro-3-pyridyl)-homopiperazine, 1-(3-pyridyl)15
homopiperazine, 1-(5-ethynyl-3-pyridyl)-homopiperazine,
conotoxinMII, epibatidine, A-85380, cytisine, lobeline or salts,
free bases, racemates or enantiomers thereof.
[0072] Other nicotinic receptor agonists include choline esterase
inhibitors (e.g., that increase local concentration of
acetylcholine), derivatives of epibatidine that specifically bind
the neuronal type of nicotinic receptors (with reduced binding to
the muscarinic receptor) and having reduced deleterious
side-effects (e.g., Epidoxidine, ABT-154, ABT418, ABT-594; Abbott
Laboratories (Damaj et al. (1998) J. Pharmacol Exp. Ther. 284:1058
65, describing several analogs of epibatidine of equal potency but
with high specificity to the neuronal type of nicotinic receptors).
Further nicotinic receptor agonists of interest include, but are
not necessarily limited to, N-methylcarbamyl and
N-methylthi-O-carbamyl esters of choline (e.g.,
trimethylaminoethanol) (Abood et al. (1988) Pharmacol. Biochem.
Behav. 30:403 8); acetylcholine (an endogenous ligand for the
nicotinic receptor); and the like.
[0073] In one embodiment, the nicotinic receptor agonist is
nicotine (which is understood from to include nicotine derivatives
and like compounds). Nicotine's chemical name is
S-3-(1-methyl-2-pyrrolidinyl)pyridine. Its empirical formula is
C.sub.10H.sub.14N.sub.2, and its structural formula is
##STR00001##
[0074] Nicotine may be isolated and purified from nature or
synthetically produced in any manner. This term "nicotine" is also
intended to encompass the commonly occurring salts containing
pharmacologically acceptable anions, such as hydrochloride,
hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate
or acid phosphate, acetate, lactate, citrate or acid citrate,
tartrate or bitartrate, succinate, maleate, fumarate, gluconate,
saccharate, benzoate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluene sulfonate, camphorate and pamoate
salts. Nicotine is a colorless to pale yellow, strongly alkaline,
oily, volatile, hygroscopic liquid having a molecular weight of
162.23
[0075] Unless specifically indicated otherwise, the term "nicotine"
further includes any pharmacologically acceptable derivative or
metabolite of nicotine which exhibits pharmacotherapeutic
properties similar to nicotine. Such derivatives, metabolites, and
derivatives of metabolites are known in the art, and include, but
are not necessarily limited to, cotinine, norcotinine, nornicotine,
nicotine N-oxide, cotinine N-oxide, 3-hydroxycotinine and
5-hydroxycotinine or pharmaceutically acceptable salts thereof. A
number of useful derivatives of nicotine are disclosed within the
Physician's Desk Reference (most recent edition) as well as
Harrison's Principles of Internal Medicine. Methods for production
of nicotine derivatives and analogues are well known in the art.
See, e.g., U.S. Pat. Nos. 4,590,278; 4,321,387; 4,452,984;
4,442,292; and 4,332,945.
[0076] The compounds of the present invention may have asymmetric
carbon atoms. All isomers, including diastereomeric mixtures such
as racemic mixtures and pure enantiomers are considered as part of
the invention.
[0077] Without being limited to any one theory, one mechanism of
action can be that after a prolong exposure to nicotinic receptor
agonist nicotinic receptors become desensitized and the nicotinic
receptor agonists start working as nicotinic receptor antagonists.
In some embodiments, the nicotinic receptor agonists work as
antagonists to reduce or eliminate a side effect induced by a
dopaminergic agent.
[0078] In some embodiments, the invention provides a composition
for administration of nicotine to an animal. In some embodiments,
the invention provides a composition for administration of nicotine
to an animal to reduce a side effect of a dopaminergic agent, e.g.,
for the oral delivery of nicotine, that contain at least about 1,
5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5, 99.9, or
99.99% nicotine. In some embodiments, the invention provides a
composition for the oral delivery of nicotine that contains no more
than about 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 99, 99.5,
99.9, 99.99, or 100% nicotine. In some embodiments, the invention
provides a composition that contains about 1-100% nicotine, or
about 10-100% nicotine, or about 20-100% nicotine, or about 50-100%
nicotine, or about 80%-100% nicotine, or about 90-100% nicotine, or
about 95-100% nicotine, or about 99-100% nicotine. In some
embodiments, the invention provides a composition that contains
about 1-90% nicotine, or about 10-90% nicotine, or about 20-90%
nicotine, or about 50-90% nicotine, or about 80-90% nicotine. In
some embodiments, the invention provides a composition that
contains about 1-75% nicotine, or about 10-75% nicotine, or about
20-75% nicotine, or about 50-75% nicotine. In some embodiments, the
invention provides a composition that contains about 1-50%
nicotine, or about 10-50% nicotine, or about 20-50% nicotine, or
about 30-50% nicotine, or about 40-50% nicotine. In some
embodiments, the invention provides a composition that contains
about 1-40% nicotine, or about 10-40% nicotine, or about 20-40%
nicotine, or about 30-40% nicotine. In some embodiments, the
invention provides a composition that contains about 1-30%
nicotine, or about 10-30% nicotine, or about 20-30% nicotine. In
some embodiments, the invention provides a composition that
contains about 1-20% nicotine, or about 10-20% nicotine. In some
embodiments, the invention provides a composition that contains
about 1-10% nicotine. In some embodiments, the invention provides a
composition that contains about 1, 2, 5, 10, 20, 30, 40, 50, 60,
70, 80, 90, 95, 96, 97, 98, or 99% nicotine.
[0079] In some of these embodiments, a pharmaceutically acceptable
excipient is also included.
Dopaminergic Agents
[0080] In one aspect, the invention provides compositions and
methods to reduce or eliminate the effects of a dopaminergic agent.
In some embodiments, the compositions and methods retain or enhance
a desired effect of the dopaminergic agent, e.g., antiparkinsonian
effect. The methods and compositions of the invention apply to any
dopaminergic agent for which it is desired to reduce one or more
side effects. In some embodiments, the compositions and methods of
the invention utilize a dopamine precursor. In some embodiments,
the compositions and methods of the invention utilize a dopamine
agonist. In some embodiments, the dopaminergic agent is levodopa,
bromocriptine, pergolide, pramipexole, cabergoline, ropinorole,
apomorphine or a combination thereof. In some embodiments, the
dopaminergic agent is levodopa. In some embodiments, the
compositions and methods of the invention utilize one or more
agents used in the art in combination with a dopamine agent
treatment to achieve a therapeutic effect. For instance, in one
exemplary embodiment the compositions and methods of the invention
utilize levodopa in combination with an agent such as carbidopa,
which blocks the conversion of levodopa to dopamine in the blood.
In another exemplary embodiment, the compositions and methods of
the invention utilize levodopa in combination with a COMT
Inhibitor, such as entacapone. In another exemplary embodiment, the
compositions and methods of the invention utilize levodopa in
combination with a monoamine oxidase type B (MAO-B) inhibitor such
as selegiline. In yet another exemplary embodiment, the
compositions and methods of the invention utilize levodopa in
combination with amantadine.
[0081] Levodopa
[0082] Levodopa, an aromatic amino acid, is a white, crystalline
compound, slightly soluble in water, with a molecular weight of
197.2. It is designated chemically as
(-)-L-a-amino-b-(3,4-dihydroxybenzene)propanoic acid. Its empirical
formula is C.sub.9H.sub.11NO.sub.4, and its structural formula
is
##STR00002##
[0083] Levodopa is used for the treatment of Parkinson's disease.
Parkinson's disease is a progressive, neurodegenerative disorder of
the extrapyramidal nervous system affecting the mobility and
control of the skeletal muscular system. Its characteristic
features include resting tremor, rigidity, and bradykinetic
movements
[0084] Current evidence indicates that symptoms of Parkinson's
disease are related to depletion of dopamine in the corpus
striatum. Administration of dopamine is ineffective in the
treatment of Parkinson's disease apparently because it does not
cross the blood-brain barrier. However, levodopa, the metabolic
precursor of dopamine, does cross the blood-brain barrier, and
presumably is converted to dopamine in the brain. This is thought
to be the mechanism whereby levodopa relieves symptoms of
Parkinson's disease.
[0085] However, although initially very effective, long-term
treatment with levodopa gives rise to multiple complications.
Levodopa treatment may cause nausea, vomiting, involuntary
movements (e.g. dyskinesias), mental disturbances, depression,
syncope, and hallucinations. The precise pathophysiological
mechanisms of levodopa side effects are still enigmatic, but are
thought to be due to increased brain dopamine following
administration of levodopa.
[0086] Previous work has shown that levodopa induced-dyskinesias
(LIDs) arise due to enhanced intermittent stimulation of D1, D2
and/or other dopamine receptor subtypes. This results in an
imbalance in activity of the two major striatal output pathways,
possibly through activation of D1 and inhibition of D2 receptors on
the direct and indirect dopaminergic pathways, respectively,
although there is some overlap between striatal efferents. Recent
data suggest that D1 receptors, through enhanced G-protein
coupling, may play a more prominent role in functional
hypersensitivity associated with levodopa-induced dyskinesias,
while D2 receptor activation may be more closely linked to the
antiparkinsonian action of dopaminergic drugs
Side Effects
[0087] The principal adverse reactions of dopaminergic agent
include headache, diarrhea, hypertension, nausea, vomiting,
involuntary movements (e.g. dyskinesias), mental disturbances,
depression, syncope, hallucinations, and abnormal renal
function.
[0088] The invention provides compositions and methods utilizing a
nicotinic receptor modulator that reduces or eliminates a side
effect associated with dopaminergic agent treatment. In some
embodiments, the invention provides compositions and methods
utilizing a nicotinic receptor modulator that reduces or eliminates
dyskinesias associated with dopaminergic agent treatment. Without
being limited to any theory, one possibility is that nicotinic
receptor modulator exerts its effect by acting at nicotinic
acetylcholine receptors (nAChR), which are expressed in the
striatum. There is a dense cholinergic innervation in striatum that
closely coincides with dopaminergic neurons. Under physiological
conditions, these cholinergic interneurons tonically release
acetylcholine, which stimulates nicotinic receptors on dopaminergic
nerve terminals to release dopamine. Similarly, exogenously applied
agents such as nicotine result in a release of dopamine from
striatal terminals.
[0089] In some embodiments, the invention provides compositions and
methods utilizing a combination of a dopaminergic agent and a
nicotinic receptor modulator that reduces or eliminates a side
effect associated with dopaminergic agent treatment. Typically, the
nicotinic receptor modulator is an agonist. In some embodiments,
the nicotinic receptor agonist modulates a nicotinic receptor
comprising at least one a subunit or a nicotinic receptor
containing at least one .alpha. subunit and at least one .beta.
subunit. In some embodiments, the .alpha. subunit is selected from
the group consisting of .alpha.2, .alpha.3, .alpha.4, .alpha.5,
.alpha.6, .alpha.7, .alpha.8, .alpha.9, and .alpha.10 and the
.beta. subunit is selected from the group consisting of .beta.2,
.beta.3 and .beta.4. In some embodiments, the nicotinic receptor
agonist modulates a nicotinic receptor composed of subunits
selected from the group consisting of .alpha.4.beta.2,
.alpha.6.beta.2, .alpha.4.alpha.6.beta.2, .alpha.4.alpha.5.beta.2,
.alpha.4.alpha.6.beta.2.crclbar.3, .alpha.6.beta.2.beta.3 and
.alpha.4.alpha.2.beta.2. In some embodiments, the nicotinic
receptor modulator modulates a nicotinic receptor comprising at
least one .alpha. subunit selected from the group consisting of
.alpha.4, .alpha.6, and .alpha.7.
[0090] In some embodiments, the dopaminergic agents include a
dopamine precursor or a dopamine receptor agonist Examples of
dopaminergic agents include, but are not limited to, levodopa,
bromocriptine, pergolide, pramipexole, cabergoline, ropinorole,
apomorphine or a combination thereof.
[0091] The nicotinic receptor modulator causing a decrease in the
side effects of the dopaminergic agent may be an agonist or an
antagonist of a protein. The modulatory effect may be
dose-dependent, e.g., some modulators act as agonists in one dosage
range and antagonists in another. In some embodiments, a modulator
of a nicotinic receptor is used in a dosage wherein it acts
primarily as an agonist.
[0092] Typically, the use of the nicotinic receptor modulator,
e.g., agonist, results in a decrease in one or more side effects of
the dopaminergic agent. The therapeutic effect(s) of the
dopaminergic agent may be decreased, remain the same, or increase;
however, in preferred embodiments, if the therapeutic effect is
decreased, it is not decreased to the same degree as the side
effects. It will be appreciated that a given dopaminergic agent may
have more than one therapeutic effects and or one or more side
effects, and it is possible that the therapeutic ratio (in this
case, the ratio of change in desired effect to change in undesired
effect) may vary depending on which effect is measured. However, at
least one therapeutic effect of the dopaminergic agent is decreased
to a lesser degree than at least one side effect of the
dopaminergic agent.
[0093] In addition, in some embodiments, one or more therapeutic
effects of the dopaminergic agent are enhanced by use in
combination with a nicotinic receptor modulator, while one or more
side effects of the dopaminergic agent is reduced or substantially
eliminated. For example, in some embodiments, the antiparkinsonian
effect of the dopaminergic agent is enhanced while one or more side
effects of the dopaminergic agent is reduced or substantially
eliminated.
[0094] Hence, in some embodiments the invention provides
compositions that include a dopaminergic agent and a nicotinic
receptor modulator, where the dopaminergic agent is present in an
amount sufficient to exert a therapeutic effect and the nicotinic
receptor modulator is present in an amount sufficient to decrease
side effect of the dopaminergic agent when compared to the side
effect without the nicotinic receptor modulator, when the
composition is administered to an animal.
[0095] In some embodiments, compositions of the invention include
one or more dopaminergic agent with one or more nicotinic receptor
modulators. One or more of the dopaminergic agent may have one or
more side effects which are desired to be decreased. In some
embodiments, compositions of the invention include one or more
agents, one or more dopaminergic agent with one or more nicotinic
receptor modulators. The one or more agents are agents used in the
art in combination with a dopamine agent treatment to achieve a
therapeutic effect and/or reduce a side effect. In some
embodiments, the compositions of the invention include an agent
such as carbidopa, which blocks the conversion of levodopa to
dopamine in the blood. In some embodiments, the compositions of the
invention include a COMT Inhibitor, such as entacapone. In some
embodiments, the compositions of the invention include a monoamine
oxidase type B (MAO-B) inhibitor such as selegiline. In some
embodiments, the compositions of the invention include
amantadine.
[0096] Compositions of the invention may be prepared in any
suitable form for administration to an animal. In some embodiments,
the invention provides pharmaceutical compositions.
[0097] In some embodiments, the invention provides compositions
suitable for oral administration. In some embodiments, compositions
are suitable for transdermal administration. In some embodiments,
compositions are suitable for injection by any standard route of
injection, e.g., intravenous, subcutaneous, intramuscular, or
intraperitoneal. Compositions suitable for other routes of
administration, such and inhalation, are also encompassed by the
invention, as described herein.
[0098] In some embodiments the invention provides methods of
decreasing a side effect of a dopaminergic agent in an animal, e.g.
a human, that has received an amount of the dopaminergic agent
sufficient to produce a side effect by administering to the animal,
e.g., human, an amount of a nicotinic receptor modulator sufficient
to reduce or eliminate the side effect.
[0099] The side effect may be acute or chronic. The effect may be
biochemical, cellular, at the tissue level, at the organ level, at
the multi-organ level, or at the level of the entire organism. The
effect may manifest in one or more objective or subjective manners,
any of which may be used to measure the effect. If an effect is
measured objectively or subjectively (e.g., dyskinesias and the
like), any suitable method for evaluation of objective or
subjective effect may be used. Examples include visual and numeric
scales and the like for evaluation by an individual. A further
example includes sleep latency for measurement of drowsiness, or
standard tests for measurement of concentration, mentation, memory,
and the like. These and other methods of objective and subjective
evaluation of side effects by an objective observer, the
individual, or both, are well-known in the art.
[0100] A "therapeutic effect," as that term is used herein,
encompasses a therapeutic benefit and/or a prophylactic benefit. By
therapeutic benefit is meant eradication or amelioration of the
underlying disorder being treated. Also, a therapeutic benefit is
achieved with the eradication or amelioration of one or more of the
physiological symptoms associated with the underlying disorder such
that an improvement is observed in the patient, notwithstanding
that the patient may still be afflicted with the underlying
disorder. For prophylactic benefit, the compositions may be
administered to a patient at risk of developing a particular
disease, or to a patient reporting one or more of the physiological
symptoms of a disease, even though a diagnosis of this disease may
not have been made. A prophylactic effect includes delaying or
eliminating the appearance of a disease or condition, delaying or
eliminating the onset of symptoms of a disease or condition,
slowing, halting, or reversing the progression of a disease or
condition, or any combination thereof.
Compositions
[0101] In one aspect the invention provides compositions that
include a nicotinic receptor modulator, e.g., that reduces or
eliminates a side effect of one or more dopaminergic agent. In some
embodiments, a dopaminergic agent is co-administered with the
nicotinic receptor modulator. "Co-administration," "administered in
combination with," and their grammatical equivalents, as used
herein, encompasses administration of two or more agents to an
animal so that both agents and/or their metabolites are present in
the animal at the same time. Co-administration includes
simultaneous administration in separate compositions,
administration at different times in separate compositions, or
administration in a composition in which both agents are
present.
[0102] In some embodiments, the invention provides compositions
containing a nicotinic receptor modulator. In further embodiments
the invention provides pharmaceutical compositions that further
include a pharmaceutically acceptable excipient.
[0103] In some embodiments, the invention includes pharmaceutical
compositions wherein the nicotinic receptor modulator is present in
an amount sufficient to decrease a side effect of a dopaminergic
agent when the composition is administered to an animal. In some
embodiments, the invention includes pharmaceutical compositions
where the nicotinic receptor modulator is present in an amount
sufficient to decrease a side effect of a dopaminergic agent and to
prevent addiction to the nicotinic receptor modulator when the
composition is administered to an animal. For example, the
pharmaceutical compositions including a nicotinic receptor
modulator are administered through various routes of delivery
further described herein.
[0104] In one embodiment, the pharmaceutical compositions including
a nicotinic receptor modulator are administered orally to an
animal. In various embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing an
effective amount of a nicotinic receptor modulator and a
pharmaceutical excipient suitable for oral administration; or a
liquid pharmaceutical composition for oral administration
containing an effective amount of a nicotinic receptor modulator
and a pharmaceutical excipient suitable for oral
administration.
[0105] In some embodiments, the pharmaceutical compositions are
suitable for transdermal administration.
[0106] In some embodiments, the invention provides a composition
containing a nicotinic receptor modulator, where nicotinic receptor
modulator is present in an amount sufficient to decrease a side
effect of a dopaminergic agent by a measurable amount, compared to
the side effect without the nicotinic receptor modulator, when the
composition is administered to an animal. In some embodiments, a
side effect of the dopaminergic agent is decreased by an average of
at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,
70, 75, 80, 85, 90, 95, or more than 95%, compared to the side
effect without the nicotinic receptor modulator. In some
embodiments, a side effect of the dopaminergic agent is decreased
by an average of at least about 5%, compared to the side effect
without the nicotinic receptor modulator. In some embodiments, a
side effect of the dopaminergic agent is decreased by an average of
at least about 10%, compared to the side effect without the
nicotinic receptor modulator. In some embodiments, a side effect of
the dopaminergic agent is decreased by an average of at least about
15%, compared to the side effect without the nicotinic receptor
modulator. In some embodiments, a side effect of the dopaminergic
agent is decreased by an average of at least about 20%, compared to
the side effect without the nicotinic receptor modulator. In some
embodiments, a side effect of the dopaminergic agent is decreased
by an average of at least about 30%, compared to the side effect
without the nicotinic receptor modulator. In some embodiments, a
side effect is substantially eliminated compared to the side effect
without the nicotinic receptor modulator. "Substantially
eliminated" as used herein encompasses no measurable or no
statistically significant side effect (one or more side effects) of
the dopaminergic agent, when a nicotinic receptor modulator is
administered.
[0107] In some embodiments, the invention provides compositions
that contain a nicotinic receptor agonist, e.g., nicotine, where
the nicotinic receptor agonist, e.g., nicotine is present in an
amount sufficient to decrease a side effect of the dopaminergic
agent by a measurable amount, compared to the side effect without
the nicotinic receptor agonist, e.g., nicotine when the composition
is administered to an animal. The measurable amount may be an
average of at least about 5%, 10%, 15%, 20%, 30% or more than 30%
as described herein. The side effect may be any side effect as
described herein. In some embodiments, the side effect is
dyskinesias.
[0108] In exemplary embodiments, the invention provides a
composition that contains nicotine, where nicotine is present in an
amount effective to decrease a side effect of a dopaminergic agent
by a measurable amount (e.g., an average of at least about 5, 10,
15, 20, 30 or more than 30%, as described herein). In some
exemplary embodiments, the invention provides a composition that
contains nicotine, where nicotine is present in an amount effective
to decrease a side effect of a dopaminergic agent by a measurable
amount (e.g., an average of at least about 5, 10, 15, 20, or more
than 20%, as described herein) and to increase the therapeutic
effect of the dopaminergic agent by a measurable amount (e.g., an
average of at least about 5, 10, 15, 20, 30 or more than 30%, as
described herein). In some embodiments, the invention provides a
composition that contains nicotine, where nicotine is present in
amount effective to decrease a side effect of a dopaminergic agent
by a measurable amount (e.g., an average of at least about 5, 10,
15, 20, 30 or more than 30%, as described herein) and to prevent
addition to nicotine. In some exemplary embodiments, the invention
provides a composition that contains nicotine, where nicotine is
present in an amount effective to decrease a side effect of a
dopaminergic agent by a measurable amount (e.g., an average of at
least about 5, 10, 15, 20, 30 or more than 30%, as described
herein), and to increase the therapeutic effect of the dopaminergic
agent by a measurable amount (e.g., an average of at least about 5,
10, 15, 20, 30 or more than 30%, as described herein), and to
prevent addiction to nicotine. The side effect may be any side
effect as described herein. In some embodiments, the side effect is
dyskinesias.
[0109] In some embodiments, the invention provides compositions
containing a combination of a dopaminergic agent and a nicotinic
receptor modulator that reduces or eliminates a side effect of the
dopaminergic agent. In some embodiments, the invention provides
compositions containing a combination of a dopaminergic agent and a
nicotinic receptor modulator that reduces or eliminates a side
effect of the dopaminergic agent, where the nicotine receptor
modulator is present in an amount that prevents addiction to the
nicotine receptor modulator. In some embodiments, the invention
provides pharmaceutical compositions that further include a
pharmaceutically acceptable excipient. In some embodiments, the
pharmaceutical compositions are suitable for oral administration.
In some embodiments, the pharmaceutical compositions are suitable
for transdermal administration. In some embodiments, the
pharmaceutical compositions are suitable for injection. Other forms
of administration are also compatible with embodiments of the
pharmaceutical compositions of the invention, as described
herein.
[0110] In some embodiments, the nicotinic receptor modulator
comprises an agonist or antagonist as described herein. In some
embodiments, after prolong exposure to an agonist the nicotinic
receptors become desensitized and the nicotinic receptor agonists
described herein work as antagonists.
[0111] In some embodiments, the side effect of the dopaminergic
agent that is reduced is selected from the group consisting of
involuntary movements (e.g. dyskinesias), mental disturbances,
depression, syncope, hallucinations, or combinations thereof. In
some embodiments, the side effect of the dopaminergic agent that is
reduced is dyskinesias.
[0112] In some embodiments the dopaminergic agent is a dopamine
precursor or a dopamine agonist. Examples of dopaminergic agents
include, but are not limited to, levodopa, bromocriptine,
pergolide, pramipexole, cabergoline, ropinorole, apomorphine or a
combination thereof
[0113] In some embodiments, compositions of the invention include
one or more agents, one or more dopaminergic agent with one or more
nicotinic receptor modulators. The one or more agents are agents
used in the art in combination with a dopamine agent treatment to
achieve a therapeutic effect and/or reduce a side effect. In some
embodiments, the compositions of the invention include an agent
such as carbidopa, which blocks the conversion of levodopa to
dopamine in the blood. In some embodiments, the compositions of the
invention include a COMT Inhibitor, such as entacapone. In some
embodiments, the compositions of the invention include a monoamine
oxidase type B (MAO-B) inhibitor such as selegiline. In some
embodiments, the compositions of the invention include
amantadine.
[0114] In some embodiments, the invention provides a composition
containing a dopaminergic agent and a nicotinic receptor modulator,
where the dopaminergic agent is present in an amount sufficient to
exert a therapeutic effect and the nicotinic receptor modulator is
present in an amount sufficient to decrease side effect of the
dopaminergic agent by a measurable amount, compared to the side
effect without the nicotinic receptor modulator, when the
composition is administered to an animal. In some embodiments, a
side effect of the dopaminergic agent is decreased by an average of
at least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65,
70, 75, 80, 85, 90, 95, or more than 95%, compared to the side
effect without the nicotinic receptor modulator. In some
embodiments, a side effect of the dopaminergic agent is decreased
by an average of at least about 5%, compared to the side effect
without the nicotinic receptor modulator. In some embodiments, a
side effect of the dopaminergic agent is decreased by an average of
at least about 10%, compared to the side effect without the
nicotinic receptor modulator. In some embodiments, a side effect of
the dopaminergic agent is decreased by an average of at least about
15%, compared to the side effect without the nicotinic receptor
modulator. In some embodiments, a side effect of the dopaminergic
agent is decreased by an average of at least about 20%, compared to
the side effect without the nicotinic receptor modulator. In some
embodiments, a side effect of the dopaminergic agent is decreased
by an average of at least about 30%, compared to the side effect
without the nicotinic receptor modulator. In some embodiments, a
side effect is substantially eliminated compared to the side effect
without the nicotinic receptor modulator. "Substantially
eliminated" as used herein encompasses no measurable or no
statistically significant side effect (one or more side effects) of
the dopaminergic agent, when administered in combination with the
nicotinic receptor modulator.
[0115] Thus, in some embodiments, the invention provides
compositions that contain a nicotinic receptor agonist, e.g.,
nicotine, and a dopaminergic agent, where the dopaminergic agent is
present in an amount sufficient to exert an therapeutic effect and
the nicotinic receptor agonist, e.g., nicotine is present in an
amount sufficient to decrease a side effect of the dopaminergic
agent by a measurable amount, compared to the side effect without
the nicotinic receptor agonist, e.g., nicotine when the composition
is administered to an animal. The measurable amount may be an
average of at least about 5%, 10%, 15%, 20%, 30% or more than 30%
as described herein. The side effect may be any side effect as
described herein. In some embodiments, the side effect is
dyskinesias.
[0116] In some embodiments, the invention provides compositions
that contain a nicotinic receptor agonist that is nicotine, and a
dopaminergic agent that is levodopa, where the levodopa is present
in an amount sufficient to exert a therapeutic effect and nicotine
is present in an amount sufficient to decrease side effect of
levodopa by a measurable amount, compared to the side effect
without nicotine when the composition is administered to an animal.
The measurable amount may be an average of at least about 5%, 10%,
15%, 20%, 30% or more than 30% as described herein. The side effect
may be any side effect as described herein. In some embodiments,
the side effect is dyskinesias.
[0117] In some embodiments, the nicotinic receptor modulator is
present in an amount sufficient to decrease a side effect of the
dopaminergic agent by a measurable amount and to increase a
therapeutic effect of the dopaminergic agent by a measurable
amount, compared to the side effect and therapeutic effect without
the nicotinic receptor modulator, when the composition is
administered to an animal. In some embodiments, a therapeutic
effect of the dopaminergic agent is increased by an average of at
least about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70,
75, 80, 85, 90, 95, or more than 95%, compared to the therapeutic
effect without the nicotinic receptor modulator. In some
embodiments, a therapeutic effect of the dopaminergic agent is
increased by an average of at least about 5%, compared to the
therapeutic effect without the nicotinic receptor modulator. In
some embodiments, a therapeutic effect of the dopaminergic agent is
increased by an average of at least about 10%, compared to the
therapeutic effect without the nicotinic receptor modulator. In
some embodiments, a therapeutic effect of the dopaminergic agent is
increased by an average of at least about 15%, compared to the
therapeutic effect without the nicotinic receptor modulator. In
some embodiments, a therapeutic effect of the dopaminergic agent is
increased by an average of at least about 20%, compared to the
therapeutic effect without the nicotinic receptor modulator. In
some embodiments, a therapeutic effect of the dopaminergic agent is
increased by an average of at least about 30%, compared to the
therapeutic effect without the nicotinic receptor modulator. In
some embodiments, a therapeutic effect of the dopaminergic agent is
increased by an average of at least about 40%, compared to the
therapeutic effect without the nicotinic receptor modulator. In
some embodiments, a therapeutic effect of the dopaminergic agent is
increased by an average of at least about 50%, compared to the
therapeutic effect without the nicotinic receptor modulator.
[0118] Thus, in some embodiments, the invention provides
compositions containing a nicotinic receptor modulator present in
an amount sufficient to decrease a side effect of a dopaminergic
agent by an average of at least about 5% and to increase a
therapeutic effect of the dopaminergic agent by an average of at
least about 5%, compared to the side effect and therapeutic effect
without the nicotinic receptor modulator, when the composition is
administered to an animal in combination with the dopaminergic
agent. In some embodiments, the invention provides compositions
containing a nicotinic receptor modulator present in an amount
sufficient to decrease a side effect of a dopaminergic agent by an
average of at least about 10% and to increase a therapeutic effect
of the dopaminergic agent by an average of at least about 10%,
compared to the side effect and therapeutic effect without the
nicotinic receptor modulator, when the composition is administered
to an animal in combination with the dopaminergic agent. In some
embodiments, the invention provides compositions containing a
nicotinic receptor modulator present in an amount sufficient to
decrease a side effect of a dopaminergic agent by an average of at
least about 20% and to increase a therapeutic effect of the
dopaminergic agent by an average of at least about 20%, compared to
the side effect and therapeutic effect without the nicotinic
receptor modulator, when the composition is administered to an
animal in combination with the dopaminergic agent. In some
embodiments, the invention provides compositions containing a
nicotinic receptor modulator present in an amount sufficient to
decrease a side effect of a dopaminergic agent by an average of at
least about 10% and to increase a therapeutic effect of the
dopaminergic agent by an average of at least about 20%, compared to
the side effect and therapeutic effect without the nicotinic
receptor modulator, when the composition is administered to an
animal in combination with the dopaminergic agent. In some
embodiments, the invention provides compositions containing a
nicotinic receptor modulator present in an amount sufficient to
decrease a side effect of a dopaminergic agent by an average of at
least about 10% and to increase a therapeutic effect of the
dopaminergic agent by an average of at least about 30%, compared to
the side effect and therapeutic effect without the nicotinic
receptor modulator, when the composition is administered to an
animal in combination with the dopaminergic agent. In some
embodiments, the invention provides compositions containing a
nicotinic receptor modulator present in an amount sufficient to
decrease a side effect of a dopaminergic agent by an average of at
least about 10% and to increase a therapeutic effect of the
dopaminergic agent by an average of at least about 40%, compared to
the side effect and therapeutic effect without the nicotinic
receptor modulator, when the composition is administered to an
animal in combination with the dopaminergic agent. In some
embodiments, the invention provides compositions containing a
nicotinic receptor modulator present in an amount sufficient to
decrease a side effect of a dopaminergic agent by an average of at
least about 10% and to increase a therapeutic effect of the
dopaminergic agent by an average of at least about 50%, compared to
the side effect and therapeutic effect without the nicotinic
receptor modulator, when the composition is administered to an
animal in combination with the dopaminergic agent.
[0119] In some embodiments, the invention provides compositions
containing a nicotinic receptor agonist, e.g., nicotine, present in
an amount sufficient to decrease a side effect of a dopaminergic
agent by an average of at least about 5% and to increase a
therapeutic effect of the dopaminergic agent by an average of at
least about 5%, when the composition is administered to an animal
in combination with the dopaminergic agent, compared to the side
effect and therapeutic effect without the nicotinic receptor
agonist, e.g., nicotine. In some embodiments, the invention
provides compositions containing a nicotinic receptor agonist,
e.g., nicotine present in an amount sufficient to decrease a side
effect of a dopaminergic agent by an average of at least about 10%
and to increase a therapeutic effect of the dopaminergic agent by
an average of at least about 10%, when the composition is
administered to an animal in combination with the dopaminergic
agent, compared to the side effect and therapeutic effect when the
dopaminergic agent is administered without the a nicotinic receptor
agonist, e.g., nicotine. In some embodiments, the invention
provides compositions containing a nicotinic receptor agonist,
e.g., nicotine present in an amount sufficient to decrease a side
effect of a dopaminergic agent by an average of at least about 20%
and to increase a therapeutic effect of the dopaminergic agent by
an average of at least about 20%, when the composition is
administered to an animal in combination with the dopaminergic
agent, compared to the side effect and therapeutic effect when the
dopaminergic agent is administered without the a nicotinic receptor
agonist, e.g., nicotine. In some embodiments, the invention
provides compositions containing a nicotinic receptor agonist,
e.g., nicotine present in an amount sufficient to decrease a side
effect of a dopaminergic agent by an average of at least about 10%
and to increase a therapeutic effect of the dopaminergic agent by
an average of at least about 20%, when the composition is
administered to an animal in combination with the dopaminergic
agent, compared to the side effect and therapeutic effect when the
dopaminergic agent is administered without the a nicotinic receptor
agonist, e.g., nicotine. In some embodiments, the invention
provides compositions containing a nicotinic receptor agonist,
e.g., nicotine present in an amount sufficient to decrease a side
effect of a dopaminergic agent by an average of at least about 10%
and to increase a therapeutic effect of the dopaminergic agent by
an average of at least about 30%, when the composition is
administered to an animal in combination with the dopaminergic
agent, compared to the side effect and therapeutic effect when the
dopaminergic agent is administered without the nicotinic receptor
agonist, e.g., nicotine. In some embodiments, the invention
provides compositions containing a nicotinic receptor agonist,
e.g., nicotine present in an amount sufficient to decrease a side
effect of a dopaminergic agent by an average of at least about 10%
and to increase a therapeutic effect of the dopaminergic agent by
an average of at least about 40%, when the composition is
administered to an animal in combination with the dopaminergic
agent, compared to the side effect and therapeutic effect when the
dopaminergic agent is administered without the nicotinic receptor
agonist, e.g., nicotine. In some embodiments, the invention
provides compositions containing a nicotinic receptor agonist,
e.g., nicotine present in an amount sufficient to decrease a side
effect of a dopaminergic agent by an average of at least about 10%
and to increase a therapeutic effect of the dopaminergic agent by
an average of at least about 50%, when the composition is
administered to an animal in combination with the dopaminergic
agent, compared to the side effect and therapeutic effect when the
dopaminergic agent is administered without the a nicotinic receptor
agonist, e.g., nicotine.
[0120] In exemplary embodiments, the invention provides a
composition that contains nicotine and a dopaminergic agent, such
as levodopa or a dopamine agonist, where the dopaminergic agent is
present in an amount sufficient to exert a therapeutic effect, and
nicotine is present in an amount effective to decrease a side
effect of the dopaminergic agent by a measurable amount (e.g., an
average of at least about 5, 10, 15, 20, 30 or more than 30%, as
described herein) and to increase the therapeutic effect of the
dopaminergic agent by a measurable amount (e.g., an average of at
least about 5, 10, 15, 20, 30 or more than 30%, as described
herein). The side effect may be any side effect as described
herein. In some embodiments, the side effect is dyskinesias.
[0121] An "average" as used herein is preferably calculated in a
set of normal human subjects, this set being at least about 3 human
subjects, preferably at least about 5 human subjects, preferably at
least about 10 human subjects, even more preferably at least about
25 human subjects, and most preferably at least about 50 human
subjects.
[0122] In some embodiments, the invention provides a composition
that contains a dopaminergic agent and a nicotinic receptor
modulator, e.g. an agonist such as nicotine. In some embodiments,
the a concentration of one or more of the dopaminergic agents
and/or nicotinic receptor modulator, e.g. an agonist such as a
nicotine is less than 100%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,
19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%,
5%, 4%, 3%, 2%, 1%, 0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%,
0.07%, 0.06%, 0.05%, 0.04%, 0.03%, 0.02%, 0.01%, 0.009%, 0.008%,
0.007%, 0.006%, 0.005%, 0.004%, 0.003%, 0.002%, 0.001%, 0.0009%,
0.0008%, 0.0007%, 0.0006%, 0.0005%, 0.0004%, 0.0003%, 0.0002%, or
0.0001% w/w, w/v or v/v.
[0123] In some embodiments, a concentration of one or more of the
dopaminergic agents and/or nicotinic receptor modulator, e.g. an
agonist such as a nicotine is greater than 90%, 80%, 70%, 60%, 50%,
40%, 30%, 20%, 19.75%, 19.50%, 19.25% 19%, 18.75%, 18.50%, 18.25%
18%, 17.75%, 17.50%, 17.25% 17%, 16.75%, 16.50%, 16.25%, 16%,
15.75%, 15.50%, 15.25% 15%, 14.75%, 14.50%, 14.25% 14%, 13.75%,
13.50%, 13.25%, 13%, 12.75%, 12.50%, 12.25% 12%, 11.75%, 11.50%,
11.25% 11%, 10.75%, 10.50%, 10.25% 10%, 9.75%, 9.50%, 9.25%, 9%,
8.75%, 8.50%, 8.25% 8%, 7.75%, 7.50%, 7.25% 7%, 6.75%, 6.50%, 6.25%
6%, 5.75%, 5.50%, 5.25%, 5%, 4.75%, 4.50%, 4.25%, 4%, 3.75%, 3.50%,
3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 125%, 1%, 0.5%,
0.4%, 0.3%, 0.2%, 0.1%, 0.09%, 0.08%, 0.07%, 0.06%, 0.05%, 0.04%,
0.03%, 0.02%, 0.01%, 0.009%, 0.008%, 0.007%, 0.006%, 0.005%,
0.004%, 0.003%, 0.002%, 0.001%, 0.0009%, 0.0008%, 0.0007%, 0.0006%,
0.0005%, 0.0004%, 0.0003%, 0.0002%, or 0.0001% w/w, w/v, or
v/v.
[0124] In some embodiments, a concentration of one or more of the
dopaminergic agents and/or nicotinic receptor modulator, e.g. an
agonist such as a nicotine is in the range from approximately
0.0001% to approximately 50%, approximately 0.001% to approximately
40%, approximately 0.01% to approximately 30%, approximately 0.02%
to approximately 29%, approximately 0.03% to approximately 28%,
approximately 0.04% to approximately 27%, approximately 0.05% to
approximately 26%, approximately 0.06% to approximately 25%,
approximately 0.07% to approximately 24%, approximately 0.08% to
approximately 23%, approximately 0.09% to approximately 22%,
approximately 0.1% to approximately 21%, approximately 0.2% to
approximately 20%, approximately 0.3% to approximately 19%,
approximately 0.4% to approximately 18%, approximately 0.5% to
approximately 17%, approximately 0.6% to approximately 16%,
approximately 0.7% to approximately 15%, approximately 0.8% to
approximately 14%, approximately 0.9% to approximately 12%,
approximately 1% to approximately 10% w/w, w/v or v/v. v/v.
[0125] In some embodiments, a concentration of one or more of the
dopaminergic agents and/or nicotinic receptor modulator, e.g. a an
agonist such as a nicotine is in the range from approximately
0.001% to approximately 10%, approximately 0.01% to approximately
5%, approximately 0.02% to approximately 4.5%, approximately 0.03%
to approximately 4%, approximately 0.04% to approximately 3.5%,
approximately 0.05% to approximately 3%, approximately 0.06% to
approximately 2.5%, approximately 0.07% to approximately 2%,
approximately 0.08% to approximately 1.5%, approximately 0.09% to
approximately 1%, approximately 0.1% to approximately 0.9% w/w, w/v
or v/v.
[0126] In some embodiments, the amount of one or more of the
dopaminergic agents and/or nicotinic receptor modulator, e.g. an
agonist such as a nicotine is equal to or less than 10 g, 9.5 g,
9.0 g, 8.5 g, 8.0 g, 7.5 g, 7.0 g, 6.5 g, 6.0 g, 5.5 g, 5.0 g, 4.5
g, 4.0 g, 3.5 g, 3.0 g, 2.5 g, 2.0 g, 1.5 g, 1.0 g, 0.95 g, 0.9 g,
0.85 g, 0.8 g, 0.75 g, 0.7 g, 0.65 g, 0.6 g, 0.55 g, 0.5 g, 0.45 g,
0.4 g, 0.35 g, 0.3 g, 0.25 g, 0.2 g, 0.15 g, 0.1 g, 0.09 g, 0.08 g,
0.07 g, 0.06 g, 0.05 g, 0.04 g, 0.03 g, 0.02 g, 0.01 g, 0.009 g,
0.008 g, 0.007 g, 0.006 g, 0.005 g, 0.004 g, 0.003 g, 0.002 g,
0.001 g, 0.0009 g, 0.0008 g, 0.0007 g, 0.0006 g, 0.0005 g, 0.0004
g, 0.0003 g, 0.0002 g, or 0.0001 g.
[0127] In some embodiments, the amount of one or more of the
dopaminergic agents and/or nicotinic receptor modulator, e.g. a an
agonist such as a nicotine is more than 0.0001 g, 0.0002 g, 0.0003
g, 0.0004 g, 0.0005 g, 0.0006 g, 0.0007 g, 0.0008 g, 0.0009 g,
0.001 g, 0.0015 g, 0.002 g, 0.0025 g, 0.003 g, 0.0035 g, 0.004 g,
0.0045 g, 0.005 g, 0.0055 g, 0.006 g, 0.0065 g, 0.007 g, 0.0075 g,
0.008 g, 0.0085 g, 0.009 g, 0.0095 g, 0.01 g, 0.015 g, 0.02 g,
0.025 g, 0.03 g, 0.035 g, 0.04 g, 0.045 g, 0.05 g, 0.055 g, 0.06 g,
0.065 g, 0.07 g, 0.075 g, 0.08 g, 0.085 g, 0.09 g, 0.095 g, 0.1 g,
0.15 g, 0.2 g, 0.25 g, 0.3 g, 0.35 g, 0.4 g, 0.45 g, 0.5 g, 0.55 g,
0.6 g, 0.65 g, 0.7 g, 0.75 g, 0.8 g, 0.85 g, 0.9 g, 0.95 g, 1 g,
1.5 g, 2 g, 2.5, 3 g, 3.5, 4 g, 4.5 g, 5 g, 5.5 g, 6 g, 6.5 g, 7 g,
7.5 g, 8 g, 8.5 g, 9 g, 9.5 g, or 10 g.
[0128] In some embodiments, the amount of one or more of the
dopaminergic agents and/or nicotinic receptor modulator, e.g. a an
agonist such as a nicotine is in the range of 0.0001-10 g, 0.0005-9
g, 0.001-8 g, 0.005-7 g, 0.01-6 g, 0.05-5 g, 0.1-4 g, 0.5-4 g, or
1-3 g.
[0129] In exemplary embodiments, compositions of the invention
include nicotine, where nicotine is present in an amount from about
0.1-1000 mg, or about 1-1000 mg, or about 5-1000 mg, or about
10-1000 mg, or about 1-500 mg, or about 5-500 mg, or about 50-500
mg, or about 100-500 mg, or about 200-1000 mg, or about 200-800 mg,
or about 200-700 mg, or about 0.01 mg, or about 0.1 mg, or about
0.5 mg, or about 1 mg, or about 10 mg, or about 25 mg, or about 50
mg, or about 100 mg, or about 200 mg, or about 250 mg, or about 300
mg, or about 400 mg, or about 500 mg, or about 600 mg, or about 700
mg, or about 800 mg, or about 900 mg, or about 1000 mg. In some
embodiments, compositions of the invention include nicotine, where
nicotine is present in an amount from about 0.1-10 mg. In some
embodiments, compositions of the invention include nicotine, where
nicotine is present in an amount from about 0.1 to about 5 mg. In
some embodiments, compositions of the invention include nicotine,
where nicotine is present in an amount from about 0.1 to about 2.8
mg. In some embodiments, compositions of the invention include
nicotine, where nicotine is present in an amount that is less than
3 mg. In some embodiments, compositions of the invention include
nicotine, where nicotine is present in an amount from about 0.5
mg.
[0130] In exemplary embodiments, compositions of the invention
include nicotine and levodopa, where nicotine is present in an
amount from about 1-1000 mg, or about 10-1000 mg, or about 50-1000
mg, or about 100-1000 mg, or about 1-500 mg, or about 5-500 mg, or
about 50-500 mg, or about 100-500 mg, or about 200-1000 mg, or
about 200-800 mg, or about 200-700 mg, or about 1 mg, or about 10
mg, or about 25 mg, or about 50 mg, or about 100 mg, or about 200
mg, or about 250 mg, or about 300 mg, or about 400 mg, or about 500
mg, or about 600 mg, or about 700 mg, or about 800 mg, or about 900
mg, or about 1000 mg, and levodopa is present in an amount from
0.01 to 1000 mg, or about 0.1-800 mg, or about 0.1, 0.5, 1, 5, 10,
20, 50, 80, 100, 150, 200, 300, 400, or 500 mg.
[0131] In some embodiments, nicotine/levodopa is present at about
0.1/50 mg (nicotine/levodopa). In some embodiments, nicotine is
present at about 0.5 mg and levodopa is present at about 50 mg. In
some embodiments, nicotine is present at about 0.5 mg and levodopa
is present at about 100 mg. In some embodiments, nicotine is
present at about 0.5 mg and levodopa is present at about 150 mg. In
some embodiments, nicotine is present at about 0.5 mg and levodopa
is present at about 300 mg. In some embodiments, nicotine is
present at about 0.5 mg and levodopa is present at about 1000 mg.
In some embodiments, nicotine is present at about 1 mg and levodopa
is present at about 50 mg. In some embodiments, nicotine is present
at about 1 mg and levodopa is present at about 100 mg. In some
embodiments, nicotine is present at about 1 mg and levodopa is
present at about 150 mg. In some embodiments, nicotine is present
at about 1 mg and levodopa is present at about 300 mg. In some
embodiments, nicotine is present at about 1 mg and levodopa is
present at about 1000 mg. In some embodiments, nicotine is present
at about 5 mg and levodopa is present at about 50 mg. In some
embodiments, nicotine is present at about 5 mg and levodopa is
present at about 100 mg. In some embodiments, nicotine is present
at about 5 mg and levodopa is present at about 150 mg. In some
embodiments, nicotine is present at about 5 mg and levodopa is
present at about 500 mg. In some embodiments, nicotine is present
at about 1 mg and levodopa is present at about 50 mg.
[0132] In some embodiments, nicotine is present at about 0.5 mg and
levodopa is present at about 100 mg. In some embodiments, nicotine
is present at about 0.5 mg and levodopa is present at about 150 mg.
In some embodiments, nicotine is present at about 0.5 mg and
levodopa is present at about 500 mg. In some embodiments, nicotine
is present at about 1 mg and levodopa is present at about 100 mg.
In some embodiments, nicotine is present at about 1 mg and levodopa
is present at about 150 mg. In some embodiments, nicotine is
present at about 1 mg and levodopa is present at about 500 mg. In
some embodiments, nicotine is present at about 7 mg and levodopa is
present at about 50 mg. In some embodiments, nicotine is present at
about 7 mg and levodopa is present at about 100 mg. In some
embodiments, nicotine is present at about 7 mg and levodopa is
present at about 150 mg. In some embodiments, nicotine is present
at about 7 mg and levodopa is present at about 500 mg. In some
embodiments, nicotine is present at about 10 mg and levodopa is
present at about 100 mg. In some embodiments, nicotine is present
at about 10 mg and levodopa is present at about 200 mg. In some
embodiments, nicotine is present at about 10 mg and levodopa is
present at about 300 mg. In some embodiments, levodopa is nicotine
at about 10 mg and levodopa is present at about 1000 mg. In some
embodiments, nicotine is present at about 14 mg and levodopa is
present at about 50 mg. In some embodiments, nicotine is present at
about 14 mg and levodopa is present at about 100 mg. In some
embodiments, nicotine is present at about 14 mg and levodopa is
present at about 150 mg. In some embodiments, nicotine is present
at about 14 mg and levodopa is present at about 500 mg. In some
embodiments, nicotine is present at about 21 mg and levodopa is
present at about 50 mg. In some embodiments, nicotine is present at
about 21 mg and levodopa is present at about 100 mg. In some
embodiments, nicotine is present at about 21 mg and levodopa is
present at about 150 mg. In some embodiments, nicotine is present
at about 21 mg and levodopa is present at about 500 mg. In some
embodiments, levodopa is present at an amount that is 100 percent
to about 75% of the effective amount when levodopa is administered
alone.
[0133] In another exemplary embodiment, compositions of the
invention include nicotine, levodopa and carbidopa. In some
embodiments, nicotine is present at about 0.5 mg, levodopa is
present at about 25 mg, and carbidopa is present at about 100 mg.
In some embodiments, nicotine is present at about 0.5 mg, levodopa
is present at about 25 mg, and carbidopa is present at about 250
mg. In some embodiments, nicotine is present at about 0.5 mg,
levodopa is present at about 12.5 mg, and carbidopa is present at
about 50 mg. In some embodiments, nicotine is present at about 0.5
mg, levodopa is present at about 6.5 mg, and carbidopa is present
at about 25 mg. In some embodiments, nicotine is present at about
0.5 mg, levodopa is present at about 12.5 mg, and carbidopa is
present at about 125 mg. In some embodiments, nicotine is present
at about 0.5 mg, levodopa is present at about 6.25 mg, and
carbidopa is present at about 62.5 mg. In some embodiments,
nicotine is present at about 0.5 mg, levodopa is present at about
12.5 mg, and carbidopa is present at about 125 mg. In some
embodiments, nicotine is present at about 0.5 mg, levodopa is
present at about 100 mg, and carbidopa is present at about 10 mg.
In some embodiments, nicotine is present at about 0.5 mg, levodopa
is present at about 100 mg, and carbidopa is present at about 25
mg. In some embodiments, nicotine is present at about 0.5 mg,
levodopa is present at about 250 mg, and carbidopa is present at
about 25 mg. In some embodiments, nicotine is present at about 1
mg, levodopa is present at about 25 mg, and carbidopa is present at
about 100 mg. In some embodiments, nicotine is present at about 1
mg, levodopa is present at about 25 mg, and carbidopa is present at
about 250 mg. In some embodiments, nicotine is present at about 1
mg, levodopa is present at about 12.5 mg, and carbidopa is present
at about 50 mg. In some embodiments, nicotine is present at about 1
mg, levodopa is present at about 6.5 mg, and carbidopa is present
at about 25 mg. In some embodiments, nicotine is present at about 1
mg, levodopa is present at about 12.5 mg, and carbidopa is present
at about 125 mg. In some embodiments, nicotine is present at about
1 mg, levodopa is present at about 6.25 mg, and carbidopa is
present at about 62.5 mg. In some embodiments, nicotine is present
at about 1 mg, levodopa is present at about 100 mg, and carbidopa
is present at about 10 mg. In some embodiments, nicotine is present
at about 1 mg, levodopa is present at about 100 mg, and carbidopa
is present at about 25 mg. In some embodiments, nicotine is present
at about 1 mg, levodopa is present at about 250 mg, and carbidopa
is present at about 25 mg. In some embodiments, nicotine is present
at about 4 mg, levodopa is present at about 25 mg, and carbidopa is
present at about 100 mg. In some embodiments, nicotine is present
at about 7 mg, levodopa is present at about 25 mg, and carbidopa is
present at about 250 mg. In some embodiments, nicotine is present
at about 7 mg, levodopa is present at about 12.5 mg, and carbidopa
is present at about 50 mg. In some embodiments, nicotine is present
at about 7 mg, levodopa is present at about 6.5 mg, and carbidopa
is present at about 25 mg. In some embodiments, nicotine is present
at about 7 mg, levodopa is present at about 12.5 mg, and carbidopa
is present at about 125 mg. In some embodiments, nicotine is
present at about 7 mg, levodopa is present at about 6.25 mg, and
carbidopa is present at about 62.5 mg. In some embodiments,
nicotine is present at about 7 mg, levodopa is present at about 100
mg, and carbidopa is present at about 10 mg. In some embodiments,
nicotine is present at about 7 mg, levodopa is present at about 100
mg, and carbidopa is present at about 25 mg. In some embodiments,
nicotine is present at about 7 mg, levodopa is present at about 250
mg, and carbidopa is present at about 25 mg.
[0134] In liquid preparations, levodopa can be present at about
1-1000 mg/ml, or 1-500 mg/ml, or 1-200 mg/ml, or about 1, 5, 10,
20, 50, 50 or 100 mg/ml and nicotine at about 0.001-1000 mg/ml, or
about 0.010-1000 mg/ml, or about 0.050-1000 mg/ml, or about
0.1-1000 mg/ml, or about 0.1-500 mg/ml, or about 0.05-500 mg/ml, or
about 0.010-500 mg/ml, or about 0.001-500 mg/ml, or about 1-1000
mg/ml, or about 1-500 mg/ml, or about 1-200 mg/ml, or about 0.001
mg/ml, or about 0.025 mg/ml, or about 0.050 mg/ml, or about 0.1
mg/ml, or about 0.2 mg/ml, or about 0.25 mg/ml, or about 0.3 mg/ml,
or about 0.4 mg/ml, or about 0.5 mg/ml, or about 0.6mg/ml, or about
0.7 mg/ml, or about 0.8 mg/ml, or about 0.9 mg/ml, or about 1
mg/ml. At higher levels of nicotine, solubility can be enhanced by
adjusting the type of diluent. In some embodiments, levodopa is
present at an amount that is 100 percent to about 75% of the
effective amount when levodopa is administered alone.
[0135] In some embodiments, a molar ratio of one or more of the
dopaminergic agents to the nicotinic receptor modulator, e.g. an
agonist such as nicotine can be 0.0001:1 to 1:1. Without limiting
the scope of the invention, the molar ratio of one or more of the
dopaminergic agents to the nicotinic receptor modulator, e.g. an
agonist such as nicotine can be about 0.0001:1 to about 10:1, or
about 0.001:1 to about 5:1, or about 0.01:1 to about 5:1, or about
0.1:1 to about 2:1, or about 0.2:1 to about 2:1, or about 0.5:1 to
about 2:1, or about 0.1:1 to about 1:1. In some embodiments,
levadopa is present at an amount that is 100 percent to about 75%
of the effective amount when levodopa is administered alone.
[0136] Without limiting the scope of the present invention, the
molar ratio of one or more of the dopaminergic agents to the
nicotinic receptor agonist can be about 0.03.times.10-5:1,
0.1.times.10-5:1, 0.04.times.10-3:1, 0.03.times.10-5:1,
0.02.times.10-5:1, 0.01.times.10-3:1, 0.1.times.10-3:1,
0.15.times.10-3:1, 0.2.times.10-3:1, 0.3.times.10-3:1,
0.4.times.10-3:1, 0.5.times.10-3:1, 0.15.times.10-2:1,
0.1.times.10-2:1, 0.2.times.10-2:1, 0.3.times.10-2:1,
0.4.times.10-2:1, 0.5.times.10-2:1, 0.6.times.10-2:1,
0.8.times.10-2:1, 0.01:1, 0.1:1; or 0.2:1 per dose. In one
embodiment, the dopaminergic agent is levodopa. In one embodiment,
the nicotinic receptor agonist is nicotine.
[0137] Without limiting the scope of the present invention, the
molar ratio of one or more of the dopaminergic agents to the
nicotinic receptor modulator, e.g. an agonist such as nicotine can
be about 0.001:1, 0.002:1, 0.003:1, 0.004:1, 0.005:1, 0.006:1,
0.007:1, 0.008:1, 0.009:1, 0.01:1, 0.02:1, 0.03:1, 0.04:1, 0.05:1,
0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.2:1, 0.3:1, 0.4:1, 0.5:1,
0.6:1, 0.7:1, 0.8:1, 0.9:1, 1:1, 2:1, 3:1, 4:1, or 5:1 per dose. In
one embodiment, the dopaminergic agent is levodopa. In one
embodiment, the nicotinic receptor agonist is nicotine.
[0138] A. Pharmaceutical Compositions
[0139] The nicotinic receptor modulators of the invention are
usually administered in the form of pharmaceutical compositions.
The drugs described above are also administered in the form of
pharmaceutical compositions. When the nicotinic receptor modulators
and the drugs are used in combination, both components may be mixed
into a preparation or both components may be formulated into
separate preparations to use them in combination separately or at
the same time.
[0140] This invention therefore provides pharmaceutical
compositions that contain, as the active ingredient, a nicotinic
receptor modulator or a pharmaceutically acceptable salt and/or
coordination complex thereof, and one or more pharmaceutically
acceptable excipients, carriers, including inert solid diluents and
fillers, diluents, including sterile aqueous solution and various
organic solvents, permeation enhancers, solubilizers and
adjuvants.
[0141] This invention further provides pharmaceutical compositions
that contain, as the active ingredient, a nicotinic receptor
modulator or a pharmaceutically acceptable salt and/or coordination
complex thereof, a dopaminergic agent or a pharmaceutically
acceptable salt and/or coordination complex thereof, and one or
more pharmaceutically acceptable excipients, carriers, including
inert solid diluents and fillers, diluents, including sterile
aqueous solution and various organic solvents, permeation
enhancers, solubilizers and adjuvants.
[0142] The dopaminergic agent and/or the nicotinic receptor
modulator may be prepared into pharmaceutical compositions in
dosages as described herein (see, e.g., Compositions). Such
compositions are prepared in a manner well known in the
pharmaceutical art.
[0143] Pharmaceutical compositions for oral administration. In some
embodiments, the invention provides a pharmaceutical composition
for oral administration containing a nicotinic receptor modulator
that reduces or eliminates a side effect of a dopaminergic agent,
and a pharmaceutical excipient for oral administration. In some
embodiments, the invention provides a pharmaceutical composition
for oral administration containing a combination of a dopaminergic
agent and a nicotinic receptor modulator that reduces or eliminates
a side effect of the dopaminergic agent, and a pharmaceutical
excipient suitable for oral administration. In some embodiments,
the nicotinic receptor modulator that reduces or eliminates the
side effect of the dopaminergic agent is a nicotinic receptor
agonist, e.g. nicotine, as described elsewhere herein. In some
embodiments, the nicotinic receptor modulator is present in amount
to prevent addiction to the nicotinic receptor modulator.
[0144] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of a nicotinic receptor modulator capable of
reducing or eliminating one or more side effects of the
dopaminergic agent; and (ii) a pharmaceutical excipient suitable
for oral administration. In some embodiments, the nicotinic
receptor modulator is present in amount to prevent addiction to the
nicotinic receptor modulator.
[0145] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of a dopaminergic agent; (ii) an effective
amount of a nicotinic receptor modulator capable of reducing or
eliminating one or more side effects of the dopaminergic agent; and
(iii) a pharmaceutical excipient suitable for oral administration.
In some embodiments, the nicotinic receptor modulator is present in
amount to prevent addiction to the nicotinic receptor
modulator.
[0146] In some embodiments, the composition further contains: (iv)
an effective amount of a second dopaminergic agent. In some
embodiments, the composition further contains: (iv) an effective
amount of an agent such as carbidopa, which blocks the conversion
of levodopa to dopamine in the blood. In some embodiments, the
composition further contains: (iv) an effective amount of a COMT
Inhibitor, such as entacapone. In some embodiments, the composition
further contains: (iv) an effective amount of a monoamine oxidase
type B (MAO-B) inhibitor such as selegiline. In some embodiments,
the composition further contains: (iv) an effective amount of
amantadine.
[0147] In some embodiments, the pharmaceutical composition may be a
liquid pharmaceutical composition suitable for oral
consumption.
[0148] In some embodiments, the dopaminergic agent is levodopa. In
some embodiments, the dopaminergic agent is a dopamine agonist. In
some embodiments, the nicotinic receptor modulator capable of
reducing or eliminating one or more side effects of the
dopaminergic agent is a nicotinic receptor agonist, e.g.,
nicotine.
[0149] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of a nicotinic receptor agonist that is
nicotine; and (ii) a pharmaceutical excipient suitable for oral
administration. In some embodiments, the nicotinic receptor
modulator is present in amount to prevent or reduce addiction to
the nicotinic receptor modulator.
[0150] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing: (i)
an effective amount of a dopaminergic agent that is levodopa or a
dopamine agonist; (ii) an effective amount of a nicotinic receptor
agonist that is nicotine; and (iii) a pharmaceutical excipient
suitable for oral administration. In some embodiments, the
nicotinic receptor modulator is present in amount to prevent or
reduce addiction to the nicotinic receptor modulator.
[0151] In some embodiments, the composition further contains (iv)
an effective amount of a second dopaminergic agent. In some
embodiments, the composition further contains: (iv) an effective
amount of an agent such as carbidopa, which blocks the conversion
of levodopa to dopamine in the blood. In some embodiments, the
composition further contains: (iv) an effective amount of a COMT
Inhibitor, such as entacapone. In some embodiments, the composition
further contains: (iv) an effective amount of a monoamine oxidase
type B (MAO-B) inhibitor such as selegiline. In some embodiments,
the composition further contains: (iv) an effective amount of
amantadine.
[0152] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing an
effective amount of levodopa, an amount of nicotine that is
effective in reducing or eliminating a side effect of levodopa, and
a pharmaceutically acceptable excipient. In some embodiments, the
invention provides a liquid pharmaceutical composition for oral
administration containing an effective amount of levodopa, an
amount of nicotine that is effective in reducing or eliminating a
side effect of levodopa, and a pharmaceutically acceptable
excipient. In some embodiments, nicotine is present in amount to
prevent or reduce addiction to nicotine.
[0153] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing
levodopa at about 40-800 mg, nicotine at about 0.01-200 mg and a
pharmaceutically acceptable excipient. In some embodiments, the
invention provides a solid pharmaceutical composition for oral
administration containing levodopa at about 40-800 mg, nicotine at
about 0.1-10 mg and a pharmaceutically acceptable excipient. In
some embodiments, the invention provides a liquid pharmaceutical
composition for oral administration containing levodopa at about
0.1-800 mg/ml, nicotine at about 0.005-100 mg/ml and a
pharmaceutically acceptable excipient.
[0154] In some embodiments, the invention provides a solid
pharmaceutical composition for oral administration containing an
effective amount of levodopa, an effective amount of nicotine, and
a pharmaceutically acceptable excipient, wherein the release of
nicotine from said pharmaceutical composition reduces or eliminates
a side effect of levodopa. In some embodiments, the invention
provides a liquid pharmaceutical composition for oral
administration containing an effective amount of levodopa, an
effective amount of nicotine, and a pharmaceutically acceptable
excipient, wherein the release of nicotine from said pharmaceutical
composition reduces or eliminates a side effect of levodopa.
[0155] Pharmaceutical compositions of the invention suitable for
oral administration can be presented as discrete dosage forms, such
as capsules, cachets, or tablets, or liquids or aerosol sprays each
containing a predetermined amount of an active ingredient as a
powder or in granules, a solution, or a suspension in an aqueous or
non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil
liquid emulsion. Such dosage forms can be prepared by any of the
methods of pharmacy, but all methods include the step of bringing
the active ingredient into association with the carrier, which
constitutes one or more necessary ingredients. In general, the
compositions are prepared by uniformly and intimately admixing the
active ingredient with liquid carriers or finely divided solid
carriers or both, and then, if necessary, shaping the product into
the desired presentation. For example, a tablet can be prepared by
compression or molding, optionally with one or more accessory
ingredients. Compressed tablets can be prepared by compressing in a
suitable machine the active ingredient in a free-flowing form such
as powder or granules, optionally mixed with an excipient such as,
but not limited to, a binder, a lubricant, an inert diluent, and/or
a surface active or dispersing agent. Molded tablets can be made by
molding in a suitable machine a mixture of the powdered compound
moistened with an inert liquid diluent.
[0156] This invention further encompasses anhydrous pharmaceutical
compositions and dosage forms comprising an active ingredient,
since water can facilitate the degradation of some compounds. For
example, water may be added (e.g., 5%) in the pharmaceutical arts
as a means of simulating long-term storage in order to determine
characteristics such as shelf-life or the stability of formulations
over time. Anhydrous pharmaceutical compositions and dosage forms
of the invention can be prepared using anhydrous or low moisture
containing ingredients and low moisture or low humidity conditions.
Pharmaceutical compositions and dosage forms of the invention which
contain lactose can be made anhydrous if substantial contact with
moisture and/or humidity during manufacturing, packaging, and/or
storage is expected. An anhydrous pharmaceutical composition may be
prepared and stored such that its anhydrous nature is maintained.
Accordingly, anhydrous compositions may be packaged using materials
known to prevent exposure to water such that they can be included
in suitable formulary kits. Examples of suitable packaging include,
but are not limited to, hermetically sealed foils, plastic or the
like, unit dose containers, blister packs, and strip packs.
[0157] An active ingredient can be combined in an intimate
admixture with a pharmaceutical carrier according to conventional
pharmaceutical compounding techniques. The carrier can take a wide
variety of forms depending on the form of preparation desired for
administration. In preparing the compositions for an oral dosage
form, any of the usual pharmaceutical media can be employed as
carriers, such as, for example, water, glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents, and the like in
the case of oral liquid preparations (such as suspensions,
solutions, and elixirs) or aerosols; or carriers such as starches,
sugars, micro-crystalline cellulose, diluents, granulating agents,
lubricants, binders, and disintegrating agents can be used in the
case of oral solid preparations, in some embodiments without
employing the use of lactose. For example, suitable carriers
include powders, capsules, and tablets, with the solid oral
preparations. If desired, tablets can be coated by standard aqueous
or nonaqueous techniques.
[0158] Binders suitable for use in pharmaceutical compositions and
dosage forms include, but are not limited to, corn starch, potato
starch, or other starches, gelatin, natural and synthetic gums such
as acacia, sodium alginate, alginic acid, other alginates, powdered
tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl
cellulose, cellulose acetate, carboxymethyl cellulose calcium,
sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl
cellulose, pre-gelatinized starch, hydroxypropyl methyl cellulose,
microcrystalline cellulose, and mixtures thereof.
[0159] Examples of suitable fillers for use in the pharmaceutical
compositions and dosage forms disclosed herein include, but are not
limited to, talc, calcium carbonate (e.g., granules or powder),
microcrystalline cellulose, powdered cellulose, dextrates, kaolin,
mannitol, silicic acid, sorbitol, starch, pre-gelatinized starch,
and mixtures thereof.
[0160] Disintegrants may be used in the compositions of the
invention to provide tablets that disintegrate when exposed to an
aqueous environment. Too much of a disintegrant may produce tablets
which may disintegrate in the bottle. Too little may be
insufficient for disintegration to occur and may thus alter the
rate and extent of release of the active ingredient(s) from the
dosage form. Thus, a sufficient amount of disintegrant that is
neither too little nor too much to detrimentally alter the release
of the active ingredient(s) may be used to form the dosage forms of
the compounds disclosed herein. The amount of disintegrant used may
vary based upon the type of formulation and mode of administration,
and may be readily discernible to those of ordinary skill in the
art. About 0.5 to about 15 weight percent of disintegrant, or about
1 to about 5 weight percent of disintegrant, may be used in the
pharmaceutical composition. Disintegrants that can be used to form
pharmaceutical compositions and dosage forms of the invention
include, but are not limited to, agar-agar, alginic acid, calcium
carbonate, microcrystalline cellulose, croscarmellose sodium,
crospovidone, polacrilin potassium, sodium starch glycolate, potato
or tapioca starch, other starches, pre-gelatinized starch, other
starches, clays, other algins, other celluloses, gums or mixtures
thereof.
[0161] Lubricants which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, calcium stearate, magnesium stearate, mineral oil,
light mineral oil, glycerin, sorbitol, mannitol, polyethylene
glycol, other glycols, stearic acid, sodium lauryl sulfate, talc,
hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil,
sunflower oil, sesame oil, olive oil, corn oil, and soybean oil),
zinc stearate, ethyl oleate, ethyl laureate, agar, or mixtures
thereof. Additional lubricants include, for example, a syloid
silica gel, a coagulated aerosol of synthetic silica, or mixtures
thereof. A lubricant can optionally be added, in an amount of less
than about 1 weight percent of the pharmaceutical composition.
[0162] When aqueous suspensions and/or elixirs are desired for oral
administration, the essential active ingredient therein may be
combined with various sweetening or flavoring agents, coloring
matter or dyes and, if so desired, emulsifying and/or suspending
agents, together with such diluents as water, ethanol, propylene
glycol, glycerin and various combinations thereof.
[0163] The tablets can be uncoated or coated by known techniques to
delay disintegration and absorption in the gastrointestinal tract
and thereby provide a sustained action over a longer period. For
example, a time delay material such as glyceryl monostearate or
glyceryl distearate can be employed. Formulations for oral use can
also be presented as hard gelatin capsules wherein the active
ingredient is mixed with an inert solid diluent, for example,
calcium carbonate, calcium phosphate or kaolin, or as soft gelatin
capsules wherein the active ingredient is mixed with water or an
oil medium, for example, peanut oil, liquid paraffin or olive oil.
The tablets can be disintegrating tablets for fast release of the
therapeutic agent.
[0164] Surfactant which can be used to form pharmaceutical
compositions and dosage forms of the invention include, but are not
limited to, hydrophilic surfactants, lipophilic surfactants, and
mixtures thereof. That is, a mixture of hydrophilic surfactants may
be employed, a mixture of lipophilic surfactants may be employed,
or a mixture of at least one hydrophilic surfactant and at least
one lipophilic surfactant may be employed.
[0165] A suitable hydrophilic surfactant may generally have an HLB
value of at least 10, while suitable lipophilic surfactants may
generally have an HLB value of or less than about 10. An empirical
parameter used to characterize the relative hydrophilicity and
hydrophobicity of non-ionic amphiphilic compounds is the
hydrophilic-lipophilic balance ("HLB" value). Surfactants with
lower HLB values are more lipophilic or hydrophobic, and have
greater solubility in oils, while surfactants with higher HLB
values are more hydrophilic, and have greater solubility in aqueous
solutions. Hydrophilic surfactants are generally considered to be
those compounds having an HLB value greater than about 10, as well
as anionic, cationic, or zwitterionic compounds for which the HLB
scale is not generally applicable. Similarly, lipophilic (i.e.,
hydrophobic) surfactants are compounds having an HLB value equal to
or less than about 10.
[0166] However, HLB value of a surfactant is merely a rough guide
generally used to enable formulation of industrial, pharmaceutical
and cosmetic emulsions.
[0167] Hydrophilic surfactants may be either ionic or non-ionic.
Suitable ionic surfactants include, but are not limited to,
alkylammonium salts; fusidic acid salts; fatty acid derivatives of
amino acids, oligopeptides, and polypeptides; glyceride derivatives
of amino acids, oligopeptides, and polypeptides; lecithins and
hydrogenated lecithins; lysolecithins and hydrogenated
lysolecithins; phospholipids and derivatives thereof;
lysophospholipids and derivatives thereof; carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acyl lactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[0168] Within the aforementioned group, preferred ionic surfactants
include, by way of example: lecithins, lysolecithin, phospholipids,
lysophospholipids and derivatives thereof; carnitine fatty acid
ester salts; salts of alkylsulfates; fatty acid salts; sodium
docusate; acyl lactylates; mono- and di-acetylated tartaric acid
esters of mono- and di-glycerides; succinylated mono- and
di-glycerides; citric acid esters of mono- and di-glycerides; and
mixtures thereof.
[0169] Ionic surfactants may be the ionized forms of lecithin,
lysolecithin, phosphatidylcholine, phosphatidylethanolamine,
phosphatidylglycerol, phosphatidic acid, phosphatidylserine,
lysophosphatidylcholine, lysophosphatidylethanolamine,
lysophosphatidylglycerol, lysophosphatidic acid,
lysophosphatidylserine, PEG-phosphatidylethanolamine,
PVP-phosphatidylethanolamine, lactylic esters of fatty acids,
stearoyl-2-lactylate, stearoyl lactylate, succinylated
monoglycerides, mono/diacetylated tartaric acid esters of
mono/diglycerides, citric acid esters of mono/diglycerides,
cholylsarcosine, caproate, caprylate, caprate, laurate, myristate,
palmitate, oleate, ricinoleate, linoleate, linolenate, stearate,
lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitines,
palmitoyl carnitines, myristoyl carnitines, and salts and mixtures
thereof.
[0170] Hydrophilic non-ionic surfactants may include, but not
limited to, alkylglucosides; alkylmaltosides; alkylthioglucosides;
lauryl macrogolglycerides; polyoxyalkylene alkyl ethers such as
polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such
as polyethylene glycol alkyl phenols; polyoxyalkylene alkyl phenol
fatty acid esters such as polyethylene glycol fatty acids
monoesters and polyethylene glycol fatty acids diesters;
polyethylene glycol glycerol fatty acid esters; polyglycerol fatty
acid esters; polyoxyalkylene sorbitan fatty acid esters such as
polyethylene glycol sorbitan fatty acid esters; hydrophilic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids, and sterols; polyoxyethylene sterols,
derivatives, and analogues thereof; polyoxyethylated vitamins and
derivatives thereof; polyoxyethylene-polyoxypropylene block
copolymers; and mixtures thereof; polyethylene glycol sorbitan
fatty acid esters and hydrophilic transesterification products of a
polyol with at least one member of the group consisting of
triglycerides, vegetable oils, and hydrogenated vegetable oils. The
polyol may be glycerol, ethylene glycol, polyethylene glycol,
sorbitol, propylene glycol, pentaerythritol, or a saccharide.
[0171] Other hydrophilic-non-ionic surfactants include, without
limitation, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32
laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 oleate, PEG-20
oleate, PEG-20 dioleate, PEG-32 oleate, PEG-200 oleate, PEG-400
oleate, PEG-15 stearate, PEG-32 distearate, PEG-40 stearate,
PEG-100 stearate, PEG-20 dilaurate, PEG-25 glyceryl trioleate,
PEG-32 dioleate, PEG-20 glyceryl laurate, PEG-30 glyceryl laurate,
PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl
oleate, PEG-30 glyceryl laurate, PEG-40 glyceryl laurate, PEG-40
palm kernel oil, PEG-50 hydrogenated castor oil, PEG-40 castor oil,
PEG-35 castor oil, PEG-60 castor oil, PEG-40 hydrogenated castor
oil, PEG-60 hydrogenated castor oil, PEG-60 corn oil, PEG-6
caprate/caprylate glycerides, PEG-8 caprate/caprylate glycerides,
polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phyto sterol,
PEG-30 soya sterol, PEG-20 trioleate, PEG-40 sorbitan oleate,
PEG-80 sorbitan laurate, polysorbate 20, polysorbate 80, POE-9
lauryl ether, POE-23 lauryl ether, POE-10 oleyl ether, POE-20 oleyl
ether, POE-20 stearyl ether, tocopheryl PEG-100 succinate, PEG-24
cholesterol, polyglyceryl-10oleate, Tween 40, Tween 60, sucrose
monostearate, sucrose monolaurate, sucrose monopalmitate, PEG
10-100 nonyl phenol series, PEG 15-100 octyl phenol series, and
poloxamers.
[0172] Suitable lipophilic surfactants include, by way of example
only: fatty alcohols; glycerol fatty acid esters; acetylated
glycerol fatty acid esters; lower alcohol fatty acids esters;
propylene glycol fatty acid esters; sorbitan fatty acid esters;
polyethylene glycol sorbitan fatty acid esters; sterols and sterol
derivatives; polyoxyethylated sterols and sterol derivatives;
polyethylene glycol alkyl ethers; sugar esters; sugar ethers;
lactic acid derivatives of mono- and di-glycerides; hydrophobic
transesterification products of a polyol with at least one member
of the group consisting of glycerides, vegetable oils, hydrogenated
vegetable oils, fatty acids and sterols; oil-soluble
vitamins/vitamin derivatives; and mixtures thereof. Within this
group, preferred lipophilic surfactants include glycerol fatty acid
esters, propylene glycol fatty acid esters, and mixtures thereof,
or are hydrophobic transesterification products of a polyol with at
least one member of the group consisting of vegetable oils,
hydrogenated vegetable oils, and triglycerides.
[0173] In one embodiment, the composition may include a solubilizer
to ensure good solubilization and/or dissolution of the
dopaminergic agent and/or nicotinic receptor modulator and to
minimize precipitation of the dopaminergic agent and/or nicotinic
receptor modulator. This can be especially important for
compositions for non-oral use, e.g., compositions for injection. A
solubilizer may also be added to increase the solubility of the
hydrophilic drug and/or other components, such as surfactants, or
to maintain the composition as a stable or homogeneous solution or
dispersion.
[0174] Examples of suitable solubilizers include, but are not
limited to, the following: alcohols and polyols, such as ethanol,
isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene
glycol, butanediols and isomers thereof, glycerol, pentaerythritol,
sorbitol, mannitol, transcutol, dimethyl isosorbide, polyethylene
glycol, polypropylene glycol, polyvinylalcohol, hydroxypropyl
methylcellulose and other cellulose derivatives, cyclodextrins and
cyclodextrin derivatives; ethers of polyethylene glycols having an
average molecular weight of about 200 to about 6000, such as
tetrahydrofurfuryl alcohol PEG ether (glycofurol) or methoxy PEG;
amides and other nitrogen-containing compounds such as
2-pyrrolidone, 2-piperidone, .epsilon.-caprolactam,
N-alkylpyrrolidone, N-hydroxyalkylpyrrolidone, N-alkylpiperidone,
N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone;
esters such as ethyl propionate, tributylcitrate, acetyl
triethylcitrate, acetyl tributyl citrate, triethylcitrate, ethyl
oleate, ethyl caprylate, ethyl butyrate, triacetin, propylene
glycol monoacetate, propylene glycol diacetate,
.epsilon.-caprolactone and isomers thereof, .delta.-valerolactone
and isomers thereof, .beta.-butyrolactone and isomers thereof; and
other solubilizers known in the art, such as dimethyl acetamide,
dimethyl isosorbide, N-methyl pyrrolidones, monooctanoin,
diethylene glycol monoethyl ether, and water.
[0175] Mixtures of solubilizers may also be used. Examples include,
but not limited to, triacetin, triethylcitrate, ethyl oleate, ethyl
caprylate, dimethylacetamide, N-methylpyrrolidone,
N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropyl
methylcellulose, hydroxypropyl cyclodextrins, ethanol, polyethylene
glycol 200-100, glycofurol, transcutol, propylene glycol, and
dimethyl isosorbide. Particularly preferred solubilizers include
sorbitol, glycerol, triacetin, ethyl alcohol, PEG-400, glycofurol
and propylene glycol.
[0176] The amount of solubilizer that can be included is not
particularly limited. The amount of a given solubilizer may be
limited to a bioacceptable amount, which may be readily determined
by one of skill in the art. In some circumstances, it may be
advantageous to include amounts of solubilizers far in excess of
bioacceptable amounts, for example to maximize the concentration of
the drug, with excess solubilizer removed prior to providing the
composition to a patient using conventional techniques, such as
distillation or evaporation. Thus, if present, the solubilizer can
be in a weight ratio of 10%, 25%, 50%, 100%, or up to about 200% by
weight, based on the combined weight of the drug, and other
excipients. If desired, very small amounts of solubilizer may also
be used, such as 5%, 2%, 1% or even less. Typically, the
solubilizer may be present in an amount of about 1% to about 100%,
more typically about 5% to about 25% by weight.
[0177] The composition can further include one or more
pharmaceutically acceptable additives and excipients. Such
additives and excipients include, without limitation, detackifiers,
anti-foaming agents, buffering agents, polymers, antioxidants,
preservatives, chelating agents, viscomodulators, tonicifiers,
flavorants, colorants, odorants, opacifiers, suspending agents,
binders, fillers, plasticizers, lubricants, and mixtures
thereof.
[0178] In addition, an acid or a base may be incorporated into the
composition to facilitate processing, to enhance stability, or for
other reasons. Examples of pharmaceutically acceptable bases
include amino acids, amino acid esters, ammonium hydroxide,
potassium hydroxide, sodium hydroxide, sodium hydrogen carbonate,
aluminum hydroxide, calcium carbonate, magnesium hydroxide,
magnesium aluminum silicate, synthetic aluminum silicate, synthetic
hydrocalcite, magnesium aluminum hydroxide, disopropylethylamine,
ethanolamine, ethylenediamine, triethanolamine, triethylamine,
trisopropanolamine, trimethylamine, tris(hydroxymethyl)aminomethane
(TRIS) and the like. Also suitable are bases that are salts of a
pharmaceutically acceptable acid, such as acetic acid, acrylic
acid, adipic acid, alginic acid, alkanesulfonic acid, amino acids,
ascorbic acid, benzoic acid, boric acid, butyric acid, carbonic
acid, citric acid, fatty acids, formic acid, fumaric acid, gluconic
acid, hydroquinosulfonic acid, isoascorbic acid, lactic acid,
maleic acid, oxalic acid, para-bromophenylsulfonic acid, propionic
acid, p-toluenesulfonic acid, salicylic acid, stearic acid,
succinic acid, tannic acid, tartaric acid, thioglycolic acid,
toluenesulfonic acid, uric acid, and the like. Salts of polyprotic
acids, such as sodium phosphate, disodium hydrogen phosphate, and
sodium dihydrogen phosphate can also be used. When the base is a
salt, the cation can be any convenient and pharmaceutically
acceptable cation, such as ammonium, alkali metals, alkaline earth
metals, and the like. Example may include, but not limited to,
sodium, potassium, lithium, magnesium, calcium and ammonium.
[0179] Suitable acids are pharmaceutically acceptable organic or
inorganic acids. Examples of suitable inorganic acids include
hydrochloric acid, hydrobromic acid, hydriodic acid, sulfuric acid,
nitric acid, boric acid, phosphoric acid, and the like. Examples of
suitable organic acids include acetic acid, acrylic acid, adipic
acid, alginic acid, alkanesulfonic acids, amino acids, ascorbic
acid, benzoic acid, boric acid, butyric acid, carbonic acid, citric
acid, fatty acids, formic acid, fumaric acid, gluconic acid,
hydroquinosulfonic acid, isoascorbic acid, lactic acid, maleic
acid, methanesulfonic acid, oxalic acid, para-bromophenylsulfonic
acid, propionic acid, p-toluenesulfonic acid, salicylic acid,
stearic acid, succinic acid, tannic acid, tartaric acid,
thioglycolic acid, toluenesulfonic acid, uric acid and the
like.
[0180] Pharmaceutical compositions for injection In some
embodiments, the invention provides a pharmaceutical composition
for injection containing an agent that reduces or eliminate a side
effect of a dopaminergic agent. In some embodiments, the invention
provides a pharmaceutical composition for injection containing a
combination of a dopaminergic agent and an agent that reduces or
eliminates a side effect of the dopaminergic agent, and a
pharmaceutical excipient suitable for injection. Components and
amounts of agents in the compositions are as described herein.
[0181] The forms in which the novel compositions of the present
invention may be incorporated for administration by injection
include aqueous or oil suspensions, or emulsions, with sesame oil,
corn oil, cottonseed oil, or peanut oil, as well as elixirs,
mannitol, dextrose, or a sterile aqueous solution, and similar
pharmaceutical vehicles.
[0182] Aqueous solutions in saline are also conventionally used for
injection. Ethanol, glycerol, propylene glycol, liquid polyethylene
glycol, and the like (and suitable mixtures thereof), cyclodextrin
derivatives, and vegetable oils may also be employed. The proper
fluidity can be maintained, for example, by the use of a coating,
such as lecithin, by the maintenance of the required particle size
in the case of dispersion and by the use of surfactants. The
prevention of the action of microorganisms can be brought about by
various antibacterial and antifungal agents, for example, parabens,
chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
[0183] Sterile injectable solutions are prepared by incorporating
the nicotinic receptor modulator and/or the dopaminergic agent in
the required amount in the appropriate solvent with various other
ingredients as enumerated above, as required, followed by filtered
sterilization. Generally, dispersions are prepared by incorporating
the various sterilized active ingredients into a sterile vehicle
which contains the basic dispersion medium and the required other
ingredients from those enumerated above. In the case of sterile
powders for the preparation of sterile injectable solutions, the
preferred methods of preparation are vacuum-drying and
freeze-drying techniques which yield a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered solution thereof.
[0184] Pharmaceutical compositions for topical (e.g., transdermal)
delivery In some embodiments, the invention provides a
pharmaceutical composition for transdermal delivery containing a
nicotinic receptor modulator that reduces or eliminates a side
effect of a dopaminergic agent, and a pharmaceutical excipient
suitable for transdermal delivery. In some embodiments, the
invention provides a pharmaceutical composition for transdermal
delivery containing a combination of a dopaminergic agent and a
nicotinic receptor modulator that reduces or eliminates a side
effect of the dopaminergic agent, and a pharmaceutical excipient
suitable for transdermal delivery. In some embodiments, the
nicotinic receptor modulator that reduces or eliminates the side
effect of the dopaminergic agent is a nicotinic receptor agonist,
e.g. nicotine, as described elsewhere herein. Components and
amounts of nicotinic receptor modulators in the compositions are as
described herein.
[0185] Compositions of the present invention can be formulated into
preparations in solid, semi-solid, or liquid forms suitable for
local or topical administration, such as gels, water soluble
jellies, creams, lotions, suspensions, foams, powders, slurries,
ointments, solutions, oils, pastes, suppositories, sprays,
emulsions, saline solutions, dimethylsulfoxide (DMSO)-based
solutions. In general, carriers with higher densities are capable
of providing an area with a prolonged exposure to the active
ingredients. In contrast, a solution formulation may provide more
immediate exposure of the active ingredient to the chosen area.
[0186] The pharmaceutical compositions also may comprise suitable
solid or gel phase carriers or excipients, which are compounds that
allow increased penetration of, or assist in the delivery of,
therapeutic molecules across the stratum corneum permeability
barrier of the skin. There are many of these penetration-enhancing
molecules known to those trained in the art of topical formulation.
Examples of such carriers and excipients include, but are not
limited to, humectants (e.g., urea), glycols (e.g., propylene
glycol), alcohols (e.g., ethanol), fatty acids (e.g., oleic acid),
surfactants (e.g., isopropyl myristate and sodium lauryl sulfate),
pyrrolidones, glycerol monolaurate, sulfoxides, terpenes (e.g.,
menthol), amines, amides, alkanes, alkanols, water, calcium
carbonate, calcium phosphate, various sugars, starches, cellulose
derivatives, gelatin, and polymers such as polyethylene
glycols.
[0187] Another formulation for use in the methods of the present
invention employs transdermal delivery devices (e.g. patches or
minipumps). Such transdermal devices may be used to provide
continuous or discontinuous infusion of the nicotinic receptor
modulator in controlled amounts, either with or without
dopaminergic agent. Thus, in some embodiments the invention
provides a transdermal device incorporating a nicotinic receptor
modulator, e.g., an agonist such as nicotine. In some embodiments
the invention provides a transdermal device incorporating a
nicotinic receptor modulator, e.g., an agonist such as nicotine in
combination with a dopaminergic agent, e.g. levodopa.
[0188] The construction and use of transdermal devices for the
delivery of pharmaceutical agents is well known in the art. See,
e.g., U.S. Pat. Nos. 5,023,252, 4,992,445 and 5,001,139. Such
devices may be constructed for continuous, pulsatile, or on demand
delivery of pharmaceutical agents.
[0189] Pharmaceutical compositions for inhalation. Compositions for
inhalation or insufflation include solutions and suspensions in
pharmaceutically acceptable, aqueous or organic solvents, or
mixtures thereof, and powders. The liquid or solid compositions may
contain suitable pharmaceutically acceptable excipients as
described supra. Preferably the compositions are administered by
the oral or nasal respiratory route for local or systemic effect.
Compositions in preferably pharmaceutically acceptable solvents may
be nebulized by use of inert gases. Nebulized solutions may be
inhaled directly from the nebulizing device or the nebulizing
device may be attached to a face mask tent, or intermittent
positive pressure breathing machine. Solution, suspension, or
powder compositions may be administered, preferably orally or
nasally, from devices that deliver the formulation in an
appropriate manner.
[0190] Other pharmaceutical compositions Pharmaceutical
compositions may also be prepared from compositions described
herein and one or more pharmaceutically acceptable excipients
suitable for sublingual, buccal, rectal, intraosseous, intraocular,
intranasal, epidural, or intraspinal administration. Preparations
for such pharmaceutical compositions are well-known in the art.
See, e.g., See, e.g., Anderson, Philip O.; Knoben, James E.;
Troutman, William G, eds., Handbook of Clinical Drug Data, Tenth
Edition, McGraw-Hill, 2002; Pratt and Taylor, eds., Principles of
Drug Action, Third Edition, Churchill Livingston, New York, 1990;
Katzung, ed., Basic and Clinical Pharmacology, Ninth Edition,
McGraw Hill, 20037ybg; Goodman and Gilman, eds., The
Pharmacological Basis of Therapeutics, Tenth Edition, McGraw Hill,
2001; Remingtons Pharmaceutical Sciences, 20th Ed., Lippincott
Williams & Wilkins, 2000; Martindale, The Extra Pharmacopoeia,
Thirty-Second Edition (The Pharmaceutical Press, London, 1999); all
of which are incorporated by reference herein in their
entirety.
[0191] B. Kits
[0192] The invention also provides kits. The kits include a
nicotinic receptor modulator that reduces or eliminates a side
effect of a dopaminergic agent, in suitable packaging, and written
material that can include instructions for use, discussion of
clinical studies, listing of side effects, and the like. The kit
may further contain a dopaminergic agent that has a side effect. In
some embodiments, the dopaminergic agent and the nicotinic receptor
modulator that reduces or eliminates a side effect of the
dopaminergic agent are provided as separate compositions in
separate containers within the kit. In some embodiments, the
dopaminergic agent and the nicotinic receptor modulator that
reduces or eliminates a side effect of the dopaminergic agent are
provided as a single composition within a container in the kit.
Suitable packaging and additional articles for use (e.g., measuring
cup for liquid preparations, foil wrapping to minimize exposure to
air, and the like) are known in the art and may be included in the
kit.
Methods
[0193] In another aspect, the invention provides methods, including
methods of treatment and methods of enhancing a therapeutic effect
of a substance.
[0194] The term "animal" or "animal subject" as used herein
includes humans as well as other mammals. The methods generally
involve the administration of one or more drugs for the treatment
of one or more diseases. Combinations of agents can be used to
treat one disease or multiple diseases or to modulate the
side-effects of one or more agents in the combination.
[0195] The term "treating" and its grammatical equivalents as used
herein includes achieving a therapeutic benefit and/or a
prophylactic benefit. By therapeutic benefit is meant eradication
or amelioration of the underlying disorder being treated. Also, a
therapeutic benefit is achieved with the eradication or
amelioration of one or more of the physiological symptoms
associated with the underlying disorder such that an improvement is
observed in the patient, notwithstanding that the patient may still
be afflicted with the underlying disorder. For prophylactic
benefit, the compositions may be administered to a patient at risk
of developing a particular disease, or to a patient reporting one
or more of the physiological symptoms of a disease, even though a
diagnosis of this disease may not have been made.
[0196] In some embodiments, the invention provides a method of
treating a condition by administering to an animal suffering from
the condition an effective amount of a nicotinic receptor modulator
sufficient to reduce or eliminate a side effect associated with a
dopaminergic agent. In some embodiments, the nicotinic receptor
modulator reduces or eliminates a plurality of side effects
associated with the dopaminergic agent. In some embodiments the
animal is a mammal, e.g., a human.
[0197] In some embodiments, the invention provides a method of
treating a condition by administering to an animal suffering from
the condition an effective amount of a dopaminergic agent and an
amount of a nicotinic receptor modulator sufficient to reduce or
eliminate a side effect of the dopaminergic agent. In some
embodiments, the modulator reduces or eliminates a plurality of
side effects of the dopaminergic agent. In some embodiments the
animal is a mammal, e.g., a human.
[0198] The dopaminergic agent and the nicotinic receptor modulator
are co-administered. "Co-administration," "administered in
combination with," and their grammatical equivalents, as used
herein, encompasses administration of two or more agents to an
animal so that both agents and/or their metabolites are present in
the animal at the same time. Co-administration includes
simultaneous administration in separate compositions,
administration at different times in separate compositions, or
administration in a composition in which both agents are present.
Thus, in some embodiments, the nicotinic receptor modulator and the
dopaminergic agent are administered in a single composition. In
some embodiments, the dopaminergic agent and the nicotinic receptor
modulator are admixed in the composition. Typically, the
dopaminergic agent is present in the composition in an amount
sufficient to produce a therapeutic effect, and the nicotinic
receptor modulator is present in the composition in an amount
sufficient to reduce a side effect of the dopaminergic agent. In
some embodiments, the dopaminergic agent is present in an amount
sufficient to exert a therapeutic effect and the nicotinic receptor
modulator is present in an amount sufficient to decrease a side
effect of the dopaminergic agent by an average of at least about 5,
10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, more than 90%, or
substantially eliminate a side effect, compared to the effect
without nicotinic receptor modulator. In some embodiments the
dopaminergic agent and the nicotinic receptor modulator are
co-administered to an individual every time than a therapeutic
effect from said dopaminergic agent is desired in said individual.
In some embodiment, co-administration comprises simultaneous
administration of said dopaminergic agent and nicotine in the same
dosage form or simultaneous administration in separate dosage
forms. In some embodiments, the dopaminergic agent is present at an
amount that is 100 percent to about 75% of the effective amount
when the dopaminergic agent is administered alone.
[0199] In some embodiments, the dopaminergic agent is present in an
amount sufficient to exert a therapeutic effect and the nicotinic
receptor modulator is present in an amount sufficient to reduce or
eliminate a side effect of the dopaminergic agent within at least
about 1, 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 minutes
after administration of the dopaminergic agent.
[0200] In some embodiments, the dopaminergic agent and/or the
nicotinic receptor modulator are co-administered with an effective
amount of an agent such as carbidopa, which blocks the conversion
of levodopa to dopamine in the blood. In some embodiments, the
dopaminergic agent and/or the nicotinic receptor modulator are
co-administered with an effective amount of a COMT Inhibitor, such
as entacapone. In some embodiments, the dopaminergic agent and/or
the nicotinic receptor modulator are co-administered with an
effective amount of a monoamine oxidase type B (MAO-B) inhibitor
such as selegiline. In some embodiments, the dopaminergic agent and
the nicotinic receptor modulator are co-administered with an
effective amount of amantadine.
[0201] Administration of the dopaminergic agent and the nicotinic
receptor modulator that reduces or eliminates at least one side
effect of the dopaminergic agent may be any suitable means. If the
agents are administered as separate compositions, they may be
administered by the same route or by different routes. If the
agents are administered in a single composition, they may be
administered by any suitable route. In some embodiments, the agents
are administered as a single composition by oral administration. In
some embodiments, the agents are administered as a single
composition by transdermal administration. In some embodiments, the
agents are administered as a single composition by injection. In
some embodiments the dopaminergic agent and the nicotinic receptor
modulator are administered as a single composition to an individual
every time than a therapeutic effect from said dopaminergic agent
is desired in said individual. In some embodiments, the
dopaminergic agent is present at an amount that is 100 percent to
about 75% of the effective amount when the dopaminergic agent is
administered alone. In some embodiments, the dopaminergic agent is
administered in an amount sufficient to exert a therapeutic effect
and the nicotinic receptor modulator is administered in an amount
sufficient to reduce or eliminate a side effect of the dopaminergic
agent within at least about 1, 5, 10, 15, 20, 25, 30, 40, 50, 60,
70, 80, or 90 minutes after administration of the dopaminergic
agent.
[0202] In some embodiments, the nicotinic receptor modulator that
reduces or eliminates a side effect of a dopaminergic agent is a
nicotinic receptor agonist, nicotinic receptor agonists are as
described herein. In some embodiments, nicotine is used. Dosages
are as provided for compositions. Typically, the daily dosage of
the nicotinic receptor modulator will be about 0.05 to about 100
mg/kg. In some embodiments, the daily dosage of the nicotinic
receptor modulator is less than 93 mg per day.
[0203] The dopaminergic agent may be any dopaminergic agent
described herein. In some embodiments, the dopaminergic agent is
levodopa or a dopamine agonist, as described herein.
[0204] The methods of the invention may be used for treatments of
any suitable condition where one or more dopaminergic agents are
used that have side effects. Examples of conditions include, but
are not limited to, Parkinson's disease, Alzheimer, dopa-responsive
dystonia, cerebral palsy, postischemic contractile dysfunction,
severe ovarian hyperstimulation syndrome, pediatric movement
disorders and non-oliguric renal failure.
[0205] For example, in some embodiments, the methods of the
invention include the treatment of Parkinson's disease patient to
prevent dyskinesias by administering to an animal in need of
treatment an effective amount of a dopaminergic agent, such as
levodopa, and an effective amount of an agent that reduces or
eliminates a dyskinesias induced by the dopaminergic agent.
[0206] In other embodiments, the methods of the invention include
the treatment of postischemic contractile dysfunction by
administering to an animal in need of treatment an effective amount
of a dopaminergic agent, such as levodopa, and an effective amount
of nicotinic receptor modulator that reduces or eliminates a side
effect of the dopaminergic agent.
[0207] In yet other embodiments, the methods of the invention
include the treatment of severe ovarian hyperstimulation syndrome
by administering to an animal in need of treatment an effective
amount of a dopaminergic agent, such as levodopa, and an effective
amount of an agent that reduces or eliminates a side effect of the
dopaminergic agent.
[0208] In other embodiments, the methods of the invention include
the treatment of pediatric movement disorders by administering to
an animal in need of treatment an effective amount of a
dopaminergic agent, such as levodopa, and an effective amount of an
agent that reduces or eliminates a side effect of the dopaminergic
agent.
[0209] In some embodiments, the methods of the invention include
the treatment of non-oliguric renal failure by administering to an
animal in need of treatment an effective amount of a dopaminergic
agent, such as levodopa, and an effective amount of an agent that
reduces or eliminates a side effect of the dopaminergic agent.
[0210] When a dopaminergic agent and a nicotinic receptor modulator
that reduces or eliminates a side effect of the dopaminergic agent
are used in combination, any suitable ratio of the two agents,
e.g., molar ratio, w/w ratio, w/v ratio, or v/v ratio, as described
herein, may be used. In some embodiments, the dopaminergic agent is
present at an amount that is 100 percent to about 75% of the
effective amount when the dopaminergic agent is administered
alone.
[0211] The invention further provides methods of reversing one or
more side effects of a dopaminergic agent by administering
nicotinic receptor modulator to an animal that has received an
amount of the dopaminergic agent sufficient to produce one or more
side effects. The methods are especially useful in a situation
where it is desired to rapidly reverse one or more side effects of
a dopaminergic agent. Any suitable nicotinic receptor modulator
described herein may be used.
[0212] In some embodiments, the invention provides a method for
reversing a side effect of a dopaminergic agent in a human by
administering to the human an amount of a nicotinic receptor
modulator sufficient to partially or completely reverse a side
effect of the dopaminergic agent, where the human has received an
amount of said dopaminergic agent sufficient to produce a side
effect. In some embodiments, the human has received an overdose of
the dopaminergic agent producing the side effect. In some
embodiments, the nicotinic receptor modulator is an agonist, such
as nicotine. Typically, the agonist will be administered by oral
administration or transdermal delivery, in a dose sufficient to
partially or completely reverse a side effect of the dopaminergic
agent. In some embodiments, the agonist will be delivered by
pulsatile delivery. In some embodiments, the agonist is
administered in an amount sufficient to reduce or eliminate a side
effect of the dopaminergic agent within at least about 1, 5, 10,
15, 20, 25, 30, 40, 50, 60, 70, 80, or 90 minutes after
administration of the dopaminergic agent.
[0213] In another aspect, the invention includes method for the
reducing dyskinesias comprising administering an animal suffering
from dyskinesias an amount of a nicotinic receptor modulator
sufficient to reduce the dyskinesias.
[0214] In some embodiments, the nicotinic receptor modulator is an
agonist or an antagonist as described herein. In some embodiments,
the nicotinic receptor agonist modulates a nicotinic receptor
comprising at least one .alpha. subunit or a nicotinic receptor
containing at least one .alpha. subunit and at least one .beta.
subunit. In some embodiments, the .alpha. subunit is selected from
the group consisting of .alpha.2, .alpha.3, .alpha.4, .alpha.5,
.alpha.6, .alpha.7, .alpha.8, .alpha.9, and .alpha.10 and the
.beta. subunit is selected from the group consisting of .beta.2,
.beta.3 and .beta.4. In some embodiments, the nicotinic receptor
agonist modulates a nicotinic receptor composed of subunits
selected from the group consisting of .alpha.4.beta.2,
.alpha.6.beta.2, .alpha.4.alpha.6.beta.2, .alpha.4.alpha.5.beta.2,
.alpha.4.alpha.6.beta.2.beta.3, .alpha.6.beta.2.beta.3 and
.alpha.4.alpha.2.beta.2. In some embodiments, the nicotinic
receptor modulator modulates a nicotinic receptor comprising at
least one .alpha. subunit selected from the group consisting of
.alpha.4, .alpha.6, and .alpha.7.
Administration
[0215] The methods involve the administration of a nicotinic
receptor modulator, e.g., to reduce or eliminate a side effect of a
dopaminergic agent. In some embodiments, a dopaminergic agent that
produces a side effect is administered in combination with a
nicotinic receptor modulator that reduces the effects of a side
effect of the dopaminergic agent. In some embodiments, other agents
are also administered, e.g., other dopaminergic agents or other
therapeutic agent. When two or more agents are co-administered,
they may be co-administered in any suitable manner, e.g., as
separate compositions, in the same composition, by the same or by
different routes of administration. In some embodiments, the
nicotine receptor modulator and/or the dopaminergic agent are
administered to the upper gastrointestinal tract of a subject.
[0216] In some embodiments, the nicotinic receptor modulator that
reduces or eliminates a side effect of a dopaminergic agent is
administered in a single dose. This may be the case where the agent
is introduced into an animal to quickly lower the side effect of a
dopaminergic agent already present in the body. Typically, such
administration will be by injection, e.g., intravenous injection,
in order to introduce the nicotinic receptor modulator quickly.
However, other routes may be used as appropriate. A single dose of
an agent that reduces or eliminates a side effect of a dopaminergic
agent may also be used when it is administered with the
dopaminergic agent (e.g., a dopaminergic agent that produces a side
effect) for treatment of an acute condition.
[0217] In some embodiments, the nicotinic receptor modulator that
reduces or eliminates a side effect of a dopaminergic agent is
administered in multiple doses. Dosing may be about once, twice,
three times, four times, five times, six times, or more than six
times per day. Dosing may be about once a month, once every two
weeks, once a week, or once every other day. In one embodiment the
dopaminergic agent is levodopa. In another embodiment the
dopaminergic agent and the nicotinic receptor modulator are
administered together about once per day to about 6 times per day.
In some embodiments, the nicotinic receptor modulator and the
dopaminergic agent are administered to an individual every time
than a therapeutic effect from said dopaminergic agent is desired
in said individual. In another embodiment the administration of the
dopaminergic agent and the nicotinic receptor modulator continues
for less than about 7 days. In yet another embodiment the
administration continues for more than about 6, 10, 14, 28 days,
two months, six months, or one year. In some cases, continuous
dosing is achieved and maintained as long as necessary. In some
embodiments, the nicotinic receptor modulator that reduces or
eliminates a side effect of a substance and/or dopaminergic agent
is administered continually or in a pulsatile manner, e.g. with a
minipump, patch or stent.
[0218] Administration of the nicotinic receptor modulator of the
invention may continue as long as necessary. In some embodiments,
an agent of the invention is administered for more than 1, 2, 3, 4,
5, 6, 7, 14, 28 days or 1 year. In some embodiments, an agent of
the invention is administered for less than 28, 14, 7, 6, 5, 4, 3,
2, or 1 day. In some embodiments, an agent of the invention is
administered chronically on an ongoing basis, e.g., for the
treatment of chronic effects.
[0219] In some embodiments, a composition comprising a nicotinic
receptor modulator is administered to an individual to reduce or
eliminate a side effect of a dopaminergic agent in said individual,
wherein the release of the nicotinic receptor modulator from a
composition reduces or eliminates the side effect the dopaminergic
agent. In some embodiments, in order to eliminate or reduce the
side effects of a dopaminergic agent the nicotinic receptor
modulator or a metabolite of the nicotinic receptor modulator can
be present in the bloodstream prior to the dopaminergic agent. For
example, this may be accomplished by administering the nicotinic
receptor modulator separately from the dopaminergic agent or by
administering the nicotinic receptor modulator and the dopaminergic
agent in the same composition that is formulated so that the
nicotinic receptor modulator reaches the bloodstream before the
dopaminergic agent. For example, as desired a dosage form can be
used wherein one active agent is immediate release and the other
agent is slow/delayed release (e.g., bilayered tablet comprising
both agents). Examples of multidrug dosage forms for differential
release are known, such as disclosed in U.S. Pat. Nos. 7,011,849;
6,221,394; 5,073,380; 20070104787; 20060204578; 20060057202;
20050276852 and 20050266032.
[0220] In some embodiments, the nicotinic receptor modulator and/or
the dopaminergic agent are formulated into orally disintegrating
tablets that dissolve rapidly. These tablets can be swallowed with
or without water. Examples of orally disintegrating tablets are
known, such as disclosed in U.S. Pat. Nos. 7,282,217; 7,229,641;
6,368,625; 6,365,182; 6,221,392; and 6,024,981.
[0221] In some embodiments, the nicotinic receptor modulator or a
metabolite of the nicotinic receptor modulator is in the blood 48,
36, 24, 12, 10, 8, 6, 5, 4, 3, 2, 1 hours before the dopaminergic
agent. In other embodiments, the nicotinic receptor modulator or a
metabolite of the nicotinic receptor modulator is in the blood
stream 59, 50, 40, 35, 30, 25 20, 10, 5, 4, 3, 2, 1 minutes before
the dopaminergic agent.
[0222] In another aspect of the invention, in order to eliminate or
reduces the side effects of a dopaminergic agent the nicotinic
receptor modulator or a metabolite of the nicotinic receptor
modulator may be in the bloodstream after the dopaminergic agent.
This may be accomplished by administering the nicotinic receptor
modulator separately from the dopaminergic agent or by
administering the nicotinic receptor modulator and the dopaminergic
agent in the same composition that is formulated so that the
nicotinic receptor modulator reaches the bloodstream after the
dopaminergic agent.
[0223] In some embodiments, the nicotinic receptor modulator or a
metabolite of the nicotinic receptor modulator is present in the
blood 48, 36, 24, 12, 10, 8, 6, 5, 4, 3, 2, 1 hours after the
dopaminergic agent. In some embodiments, the nicotinic receptor
modulator or a metabolite of the nicotinic receptor modulator is in
the blood stream 59, 50, 40, 35, 30, 25 20, 10, 5, 4, 3, 2, 1
minutes after the dopaminergic agent.
[0224] In one embodiment, nicotinic receptor modulator or a
metabolite has a second plasma half-life that differs from the
first plasma half-life by at least about 3 hours, wherein a dosage
form administered provides a plasma concentration within a
therapeutic range of the dopaminergic agent over a period which is
coextensive with at least about 70% of a period over which the
dosage form provides a plasma concentration within a therapeutic
range of nicotinic receptor modulator or a metabolite. In some
embodiments the nicotinic receptor modulator or a metabolite and
the dopaminergic agent have a similar half-life. In some
embodiments, the half life of the nicotinic receptor modulator or a
metabolite of the nicotinic receptor modulator is 48, 36, 24, 12,
10, 8, 6, 5, 4, 3, 2, 1.5, 1 hours.
[0225] In some embodiments, a dosage form of the invention
comprises a multi-layered tablet. In one embodiment, a dosage form
of the invention comprises a bi-layered tablet which comprises a
first layer and a second layer, the first layer comprising
nicotinic receptor modulator or a metabolite and has a first plasma
half-life, and the second layer comprising the dopaminergic agent
which has a second plasma half-life that differs from the first
plasma half-life by at least about 3 hours, wherein the bi-layered
tablet provides a plasma concentration within a therapeutic range
of the dopaminergic agent over a period which is coextensive with
at least about 70% of a period over which the bi-layered tablet
provides a plasma concentration within a therapeutic range of the
nicotinic receptor modulator or a metabolite.
[0226] In yet other embodiments, the second and first plasma
half-life differ by at least 48, 36, 24, 12, 10, 8, 6, 5, 4, 3, 2,
or 1 hour. In some embodiments the second and first plasma
half-life are similar.
[0227] In some embodiments, the invention includes a multilayer
tablet comprising an immediate release layer and a sustained
release layer. In some embodiments, the immediate release layer
comprises a nicotinic receptor modulator or a metabolite and the
sustained release layer comprises a dopaminergic agent. In some
embodiments, the immediate release layer comprises one or more
therapeutic agents independently selected from the group consisting
of nicotinic receptor agonist and dopaminergic agent, and the
sustained release layer comprises one or more therapeutic agents
independently selected from the group consisting of nicotinic
receptor agonist and dopaminergic agents. In some embodiments, the
immediate release layer comprises a dopaminergic agent and the
sustain release layer comprises a nicotinic receptor modulator or a
metabolite. In some embodiments, the immediate release layer or the
sustained release layer comprises a third therapeutic agent such as
the ones described herein. Examples of agents include, but are not
limited to, amantadine, carbidopa and entacapone.
[0228] An effective amount of a nicotinic receptor modulator and/or
an effective amount of a dopaminergic agent may be administered in
either single or multiple doses by any of the accepted modes of
administration of agents having similar utilities, including
rectal, buccal, intranasal and transdermal routes, by
intra-arterial injection, intravenously, intraperitoneally,
parenterally, intramuscularly, subcutaneously, orally, topically,
as an inhalant, or via an impregnated or coated device such as a
stent.
[0229] In some embodiments, an effective amount of a nicotinic
receptor modulator is administered such that the nicotinic receptor
modulator reaches a critical concentration in the bloodstream,
plasma, or the tissue where the side effect need to be eliminated,
wherein the critical concentration is the concentration necessary
to reduce or eliminate the dopaminergic agent induced-side effect.
Examples of different forms of administration include, but are not
limited to, administration in a single dose, multiple doses or
through pulsatile administration. In some embodiments, after the
nicotinic receptor modulator or a metabolite of the nicotinic
receptor modulator has reduced or eliminated the dopaminergic agent
induced-side effect, the concentration of the nicotine receptor
modulator or a metabolite of the nicotine receptor modulator will
decrease at the site of side effects occur (e.g., systemically,
such as in the bloodstream; or the tissue where the side effect
occurs).
[0230] In some embodiments, the nicotinic receptor modulator is
administered such that the nicotinic receptor modulator or a
metabolite of a receptor modulator reaches a critical concentration
in the bloodstream, plasma or tissue where the side effect needs to
be eliminated 48, 36, 24, 12, 10, 8, 6, 5, 4, 3, 2, 1 hours before
the dopaminergic agent reaches the bloodstreams or the tissue where
the side effects are generated. In some embodiments, the nicotinic
receptor modulator is administered such that the nicotinic receptor
modulator or a metabolite of the nicotinic receptor modulator
reaches a critical concentration in the bloodstream, plasma or
tissue where the side effect needs to be eliminated 59, 50, 40, 35,
30, 25 20, 10, 5, 4, 3, 2, 1 minutes before the dopaminergic agent
reaches the bloodstreams or the tissue where the side effects are
generated.
[0231] In some embodiments, the nicotinic receptor modulator is
administered such that the nicotinic receptor modulator or a
metabolite of a receptor modulator reaches a critical concentration
in the bloodstream, plasma or tissue where the side effect needs to
be eliminated 48, 36, 24, 12, 10, 8, 6, 5, 4, 3, 2, 1 hours after
the dopaminergic agent reaches the bloodstreams or the tissue where
the side effects are generated. In some embodiments, the nicotinic
receptor modulator is administered such that the nicotinic receptor
modulator or a metabolite of the nicotinic receptor modulator
reaches a critical concentration in the bloodstream, plasma or
tissue where the side effect needs to be eliminated 59, 50, 40, 35,
30, 25 20, 10, 5, 4, 3, 2, 1 minutes after the dopaminergic agent
reaches the bloodstream, plasma or the tissue where the side
effects are generated.
[0232] In some embodiments, the nicotinic receptor modulator is
administered such that a critical concentration of the nicotinic
receptor modulator and or a metabolite of the nicotinic receptor
modulator is reached in the bloodstream, plasma or a tissue where
the side effect needs to be eliminated when the side effect reaches
a peak. In some embodiments, is administered such that a critical
concentration of the nicotinic receptor modulator and or a
metabolite of the nicotinic receptor modulator is reached in the
bloodstream, plasma or a tissue where the side effect needs to be
eliminated 48, 36, 24, 12, 10, 8, 6, 5, 4, 3, 2, 1 hours before the
side effect eliminated reaches a peak. In some embodiments, is
administered such that a critical concentration of the nicotinic
receptor modulator and or a metabolite of the nicotinic receptor
modulator is reached in the bloodstream, plasma or a tissue where
the side effect needs to be eliminated 59, 50, 40, 35, 30, 25 20,
10, 5, 4, 3, 2, 1 minutes before the side effect eliminated reaches
a peak.
[0233] In some embodiment, the critical concentration of the
nicotinic receptor modulator or a nicotinic receptor modulator
metabolite is about 1 pg/ml to about 1 mg/ml. In some embodiments
the critical concentration nicotinic receptor modulator or
nicotinic receptor modulator metabolite is about 1 pg/ml to about 1
ng/ml, or about 50 pg/ml to about 1 ng/ml, or about 100 pg/ml to
about 1 ng/ml, or about 500 pg/ml to about 1 ng/ml, or about 1
ng/ml to about 500 ng/ml, or about 10 ng/ml to about 500 ng/ml, or
about 100 ng/ml to about 500 ng/ml, or about 200 ng/ml to about 500
ng/ml, or about 300 ng/ml to about 500 ng/ml, or about 400 ng/ml to
about 500 ng/ml, or about 500 ng/ml to about 1 ug/ml, or about 600
ng/ml to about 1 ug/ml, or about 700 ng/ml to about 1 ug/ml, or
about 800 ng/ml to about 1 ug/ml, or about 900 ng/ml to about 1
ug/ml, or about 1 ug/ml to about 1 mg/ml, or about 10 ug/ml to
about 1 mg/ml, or about 100 ug/ml to about 1 mg/ml, or about 500
ug/ml to about 1 mg/ml, or about 600 ug/ml to about 1 mg/ml, or
about 700 ug/ml to about 1 mg/ml, or about 800 ug/ml to about 1
mg/ml, or about 900 ug/ml to about 1 mg/ml. In some embodiment, the
critical concentration of the nicotinic receptor modulator or a
nicotinic receptor modulator metabolite is about 200 ng/ml to about
420 ng/ml. In some embodiment, the critical concentration of the
nicotinic receptor modulator or a nicotinic receptor modulator
metabolite is about 1 ng/ml to about 20 ng/ml. In some embodiment,
the critical concentration of the nicotinic receptor modulator or a
nicotinic receptor modulator metabolite is about 1 ng/ml to about 5
ng/ml. In some embodiment, the critical concentration of the
nicotinic receptor modulator or a nicotinic receptor modulator
metabolite is about 20 ng/ml to about 100 ng/ml.
[0234] In some embodiments, the nicotinic receptor modulator is
administered such that the nicotinic receptor modulator or a
metabolite reduce or eliminate a side effect of a dopaminergic
agent within at least about 1, 5, 10, 15, 20, 25, 30, 40, 50, 60,
70, 80, or 90 minutes after administration of the dopaminergic
agent.
[0235] The nicotinic receptor modulator and the dopaminergic agent
may be administered in dosages as described herein (see, e.g.,
Compositions). Dosing ranges for dopaminergic agents are known in
the art. It is also known in the art that due to intersubject
variability in dopaminergic agents, such as levodopa,
pharmacokinetics, individualization of dosing regimen is necessary
for optimal therapy. Dosing for the nicotinic receptor modulator
may be found by routine experimentation. For an nicotinic receptor
agonist, e.g., nicotine, typical daily dose ranges are, e.g. about
1-5000 mg, or about 1-3000 mg, or about 1-2000 mg, or about 1-1000
mg, or about 1-500 mg, or about 1-100 mg, or about 10-5000 mg, or
about 10-3000 mg, or about 10-2000 mg, or about 10-1000 mg, or
about 10-500 mg, or about 10-200 mg, or about 10-100 mg, or about
20-2000 mg or about 20-1500 mg or about 20-1000 mg or about 20-500
mg, or about 20-100 mg, or about 50-5000 mg, or about 50-4000 mg,
or about 50-3000 mg, or about 50-2000 mg, or about 50-1000 mg, or
about 50-500 mg, or about 50-100 mg, about 100-5000 mg, or about
100-4000 mg, or about 100-3000 mg, or about 100-2000 mg, or about
100-1000 mg, or about 100-500 mg. In some embodiments, the daily
dose of nicotine is about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50,
100, 200, 300, 400, 500, 600, 700, 800, 900, or 1000 mg. In some
embodiments, the daily dose of nicotine is 0.9 mg. In some
embodiments, the daily dose of nicotine is 1.8 mg. In some
embodiments, the daily dose of nicotine is 2.4 mg. In some
embodiments, the daily dose of nicotine is 3 mg. In some
embodiments, the daily dose of nicotine is 6 mg. In some
embodiments, the daily dose of nicotine is 7 mg. In some
embodiments, the daily dose of nicotine is 8 mg. In some
embodiments, the daily dose of nicotine is 9 mg. In some
embodiments, the daily dose of nicotine is 12 mg. In some
embodiments, the daily dose of nicotine is 14 mg. In some
embodiments, the daily dose of nicotine is 18 mg. In some
embodiments, the daily dose of nicotine is 21 mg. In some
embodiments, the daily dose of nicotine is 24 mg. In some
embodiments, the daily dose of nicotine is 32 mg. In some
embodiments, the daily dose of nicotine is 50 mg. In some
embodiments, the daily dose of nicotine is less than 93 mg. Daily
dose range may depend on the form of nicotinic receptor agonist
and/or factors with which the nicotinic receptor agonist is
administered, as described herein.
[0236] In some embodiment the daily dose of nicotine is such that
the plasma level of nicotine or a nicotine metabolite is about 1
pg/ml to about 1 mg/ml. In some embodiments the daily dose of
nicotine is such that the plasma level or nicotine or nicotine
metabolite is about 1 pg/ml to about 1 ng/ml, or about 50 pg/ml to
about 1 ng/ml, or about 100 pg/ml to about 1 ng/ml, or about 500
pg/ml to about 1 ng/ml, or about 1 ng/ml to about 500 ng/ml, or
about 10 ng/ml to about 500 ng/ml, or about 100 ng/ml to about 500
ng/ml, or about 200 ng/ml to about 500 ng/ml, or about 300 ng/ml to
about 500 ng/ml, or about 400 ng/ml to about 500 ng/ml, or about
500 ng/ml to about 1 ug/ml, or about 600 ng/ml to about 1 ug/ml, or
about 700 ng/ml to about 1 ug/ml, or about 800 ng/ml to about 1
ug/ml, or about 900 ng/ml to about 1 ug/ml, or about 1 ug/ml to
about 1 mg/ml, or about 10 ug/ml to about 1 mg/ml, or about 100
ug/ml to about 1 mg/ml, or about 500 ug/ml to about 1 mg/ml, or
about 600 ug/ml to about 1 mg/ml, or about 700 ug/ml to about 1
mg/ml, or about 800 ug/ml to about 1 mg/ml, or about 900 ug/ml to
about 1 mg/ml. In some embodiment, the daily dose of nicotine is
such that the plasma level of nicotine or a nicotine metabolite is
about 200 ng/ml to about 420 ng/ml. In some embodiment, the daily
dose of nicotine is such that the plasma level of nicotine or a
nicotine metabolite is about 1 ng/ml to about 20 ng/ml. In some
embodiment, the daily dose of nicotine is such that the plasma
level of nicotine or a nicotine metabolite is about 1 ng/ml to
about 5 ng/ml. In some embodiment, the daily dose of nicotine is
such that the plasma level of nicotine or a nicotine metabolite is
about 20 ng/ml to about 100 ng/ml.
[0237] When a nicotinic receptor modulator, e.g., an agonist such
as nicotine, is administered in a composition that comprises one or
more dopaminergic agents and the dopaminergic agent has a shorter
half-life than nicotinic receptor modulator, unit dose forms of the
dopaminergic agent and the nicotinic receptor modulator may be
adjusted accordingly.
EXAMPLES
Example 1
Nicotine Reduced Levodopa-Induced Dyskinesias in Monkeys with
Nigrostriatal Damage
Materials and Methods
[0238] Animals: Squirrel (Saimiri sciureus) monkeys (n=7) were
purchased from World Wide Primates (Miami, Fla.). The animals
weighed between 0.6-0.9 kg and were in mid to late adulthood as
determined from their general appearance (dentition, fur, other).
Female monkeys were used since older animals were available that
may better model Parkinson's disease. The animals were placed in
quarantine upon arrival, and maintained in a temperature-controlled
room (27.+-.3.degree. C.) with a relative humidity>30%, under a
13/11-hour light/dark cycle. Monkey food chow and fruits/vegetables
were provided once daily, with water provided ad libitum. The
monkeys were housed in separate cages to allow for clear behavioral
assessments. The animals were released from quarantine after 1
month and treatments initiated. All procedures conformed to the
National Institutes of Health Guide for the Care and Use of
Laboratory Animals and were approved by the Institutional Animal
Care and Use Committee at the Parkinson's Institute.
[0239] 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)
administration: Prior to lesioning, the animals were allowed to
acclimate to the colony and rated for parkinsonism as described
(Langston et al. Ann Neurol. 2000; 47:579-89). All values were
within the normal range. The monkeys were then injected
subcutaneously with 2.0 mg/kg MPTP (Sigma, St-Louis, Mo.) dissolved
in saline. The animals were rated for parkinsonism 3-4 weeks after
MPTP administration. The disability scores ranged from 0 (normal)
to 28 for a severely parkinsonian animal. Animals were assessed for
1) spatial hypokinesia (reduction in use of the available cage
space), 2) body bradykinesia (increased slowness in body movement),
3) left and 4) right manual dexterity, 5) balance, 6) freezing and
7) action tremor. If they were not parkinsonian, MPTP injection
(1.0-2.0 mg/kg) was repeated from 2-5 times for total doses of 3.5
to 13.5 mg/kg. Despite multiple MPTP dosing, two of the animals
were not stably parkinsonian. These two monkeys did exhibit
reliable dyskinesias in response to levodopa treatment.
[0240] Nicotine treatment: All monkeys (n=7) were then given a
drinking solution for 3 weeks consisting of commercially available
orange Gatorade.RTM. to mask nicotine's bitter taste (FIG. 1). The
control group (n=4) was continued on Gatorade.RTM. only, while
nicotine (free base) was added to the Gatorade of the treated group
(n=3). Nicotine dosing was started at 50 .mu.g/ml for 1 week, 150
.mu.g/ml for 1 week, with the concentration increased by 150 .mu.g
increments/week over the next few weeks, up to 650 .mu.g/ml (FIG.
1). Since the animals were relatively old and exhibited poor
dentition, the dried food pellets were softened with .about.25 ml
of either Gatorade.RTM. or the nicotine-Gatorade.RTM. (for the
treated animals) to ensure adequate nicotine intake. There were no
significant effects of nicotine treatment on body weight or fluid
intake, and the monkeys appeared in good health.
[0241] Levodopa administration: Monkeys were administered
levodopa/carbidopa (5 mg/kg and 1.25 mg/kg, respectively), prepared
by crushing a tablet of Sinemet.RTM. CR 100/25 (DuPont Pharma) and
dissolving it in water. This dose of levodopa is within the range
of that prescribed to Parkinson's disease patients. The monkeys
were gavaged twice daily at 3.5-hour intervals for 8 weeks at a
time using a 5-day-on/2-day-off schedule (Hsu et al., J Pharmacol
Exp Ther. 2004; 311:770-777). During levodopa treatment, the
monkeys were given fruits in the morning and food pellets 3.5 hours
after the afternoon levodopa dose to optimize gastrointestinal
absorption.
[0242] Dyskinesias were rated from videotapes, as described (Hsu et
al., J Pharmacol Exp Ther. 2004; 311:770-777). This included a one
hour baseline period (no drugs) from .about.8:00-9:00 AM, followed
by two 3.5-hour treatment periods with levodopa starting at
.about.9:00 AM and .about.12:30 PM. Dyskinesias were rated for
2-minute periods at 30-minute intervals by two independent raters
blinded to treatment. They were rated on a scale of 0 (no
dyskinesias) to 4; a score of 1 was indicative of subtle
dyskinesias that were not sustained; 2, mild dyskinesias that were
sustained; 3, moderate dyskinesias that impaired the ability to
remain stationary; 4, severe dyskinesias that were generalized and
incapacitating.
[0243] Data analyses: The levodopa treatment protocol used in the
present study involved a 5-day-on/2-day-off schedule. Parkinsonian
ratings were done on Monday and Friday of each week, with the score
averaged over the two days. Dyskinesias ratings were determined by
averaging the scores on Wednesday and Thursday of each week. All
values are expressed as the mean.+-.SE of the indicated number of
animals. Results were compared using paired t-tests or analysis of
variance (ANOVA) followed by Bonferroni multiple comparison post
hoc test, using Prism.RTM. program (GraphPad Software, Inc, San
Diego, Calif.). A level of 0.05 was considered significant.
[0244] Measurement of plasma cotinine levels: Plasma cotinine, a
major (75%) nicotine metabolite, was measured as an index of
nicotine intake (Hukkanen et al., Pharmacol Rev. 2005; 57:79-115
and Matta et al., Psychopharmacology (Berl). 2007; 190:269-319).
Blood (1-2 ml) was drawn from the femoral vein under ketamine
sedation (15-20 mg/kg intramuscularly) at .about.3 PM. The blood
samples were centrifuged at 1,000.times.g for 12 minutes, and the
plasma stored at -80.degree. C. Plasma cotinine levels were
measured using an ELISA kit (OraSure Technologies Inc, Bethleham,
Pa.). Plasma cotinine levels were 303+25 (n=7), and fell within the
range observed in cigarette smokers (Hukkanen et al., Pharmacol
Rev. 2005; 57:79-115 and Matta et al., Psychopharmacology (Berl).
2007; 190:269-319).
Results
[0245] Time course of the nicotine-induced decline in
levodopa-induced dyskinesias in monkeys with nigrostriatal damage:
Nicotine treatment (n=3) resulted in a reduction in
levodopa-induced dyskinesias over the course of the day as compared
to non-nicotine-treated animals (n=4). This decline was observed
over the entire 8-week period investigated, with the data for weeks
2, 4, 6 and 8 depicted in FIG. 2. In monkeys not receiving
nicotine, dyskinesias developed rapidly following levodopa
administration, were maximal after 30-90 minutes, and declined over
the remaining two hours (FIG. 2). Dyskinesias were significantly
reduced in nicotine-treated animals compared to monkeys not
receiving nicotine. For instance at 8 weeks, ANOVA yielded a
significant main effect of nicotine treatment (F[1, 80]=54.24,
p<0.0001) There also was a significant main effect of time
(F[15, 80]=8.95, p<0.0001).
[0246] Decline in total dyskinesias in monkeys receiving nicotine
treatment: It was next examined the effect of nicotine treatment on
the total dyskinetic response by evaluating the area under the
curve of the time course. A significant decrease was observed in
nicotine-treated animals at all time points compared to monkeys not
receiving nicotine (FIG. 3). For instance at the 8 week time point,
there was a significant main effect of nicotine by ANOVA (F[1,
10]=11.41, p=0.007), with no effect of time.
[0247] Nicotine treatment decreases peak dose dyskinesias: Peak
dyskinesias, defined as the maximal dyskinetic score during the
morning or afternoon, were decreased throughout the 8-week levodopa
treatment period in nicotine-treated animals compared to control
(FIG. 4). For instance at 8 weeks, there was a significant main
effect of nicotine by ANOVA (F[1, 10]=7.90, p=0.0184), with no main
effect of time.
[0248] Nicotine shortened the duration of dyskinesias: Dyskinesias
were still evident in the non-nicotine-treated monkeys 3 hours
after the second daily levodopa administration, but not in animals
treated with nicotine (FIG. 2, Table 1). ANOVA showed there was a
main effect of nicotine treatment (F[1, 20]=18.33, p=0.0004), but
not time indicating no difference across the 8-week rating period
(Table 1).
TABLE-US-00001 TABLE 1 Nicotine administration shortens the
duration of levodopa-induced dyskinesias Nicotine Week of levodopa
treatment Treatment N 2/3 4 6 8 No 4 0.5 .+-. 0.3 1.0 .+-. 0.4 1.1
.+-. 0.2 0.9 .+-. 0.1 Yes 3 0.3 .+-. 0.3 0* 0* 0.2 .+-. 0.2 Each
value is the mean .+-. SE of dyskinetic ratings 3 hours after the
afternoon levodopa treatment. *p < 0.05 as compared to no
nicotine treatment using ANOVA followed by a Bonferroni post-hoc
test.
Example 2
Nicotine Reduced Dyskinesias in Levodopa-Primed Monkeys
Materials and Methods
[0249] Materials and methods were the same as in example 1.
Results
[0250] Crossover study: The data depicted in FIG. 2-4 and Table 1
clearly showed that nicotine administration attenuated
levodopa-induced dyskinesias. A crossover study, was then
conducted, in which the animals originally receiving nicotine were
given vehicle (n=3), while the vehicle-treated animals were now
administered nicotine (n=4). Levodopa treatment was stopped. The
concentration of nicotine was gradually increased in the drinking
water (see FIG. 1) to 650 .mu.g/ml, at which the animals were
maintained for 4 weeks. Monkeys that had previously received
nicotine were placed on vehicle drinking water for the same time
period. All monkeys were then treated with levodopa (5 mg/kg, twice
daily 3.5 hours apart) for a subsequent 8-week period. Since both
groups of monkeys had previously received levodopa, they were
termed levodopa-primed.
[0251] Nicotine administration decreased levodopa-induced
dyskinesias in levodopa-primed monkeys: For these analyses, the
ratings obtained for each animal on the new treatment were compared
to the score of the same animal in the previous treatment period,
that is, prior to crossover. The results in FIG. 5 show that
nicotine administration significantly reduced total dyskinesias at
all time points using paired t-tests. Analyses of the dyskinetic
time course also showed a main effect of nicotine throughout
levodopa treatment by ANOVA (for example, week 8, F[1, 114]=15.89,
p=0.0001). Peak dyskinesias were significantly reduced during the
last 4 weeks of levodopa treatment (week 6, p=0.0354; and week 8,
p=0.0138 by paired t-tests). There was also a decrease in the
duration of dyskinesias with nicotine treatment, with a significant
main effect of nicotine by ANOVA (F[1, 24]=18.00, p=0.0003). Thus,
nicotine administration reduced levodopa-induced dyskinesias in
animals previously exposed to levodopa.
[0252] Removal of nicotine increases levodopa-induced dyskinesias
in levodopa-primed monkeys: By contrast, in animals removed from
nicotine treatment, total dyskinetic scores were significantly
enhanced at week 4, 6 and 8 of levodopa treatment (FIG. 6).
Analyses of the time course of dyskinesias also showed an increase
in dyskinesias over the 8-week levodopa treatment, with ANOVA
yielding a significant main effect of nicotine (for example, week
8, F[1, 76]=15.94, p=0.0001). In addition, there was a significant
increase in the duration of dyskinesia assessed 3 hours after the
afternoon levodopa dose, with a significant main effect of nicotine
by two-way ANOVA (F[1, 16]=5.33, p=0.0346). Thus, removal of
nicotine enhanced levodopa-induced dyskinesias.
[0253] Nicotine administration does not affect parkinsonism on or
off levodopa treatment: Levodopa administration reduced
parkinsonism ratings, which were measured 1.5-2 hours after
levodopa dosing when its effects are maximal (FIG. 7 and Table 2).
Nicotine treatment did not affect parkinsonism either on of off
levodopa treatment (F[1, 16]=0.03, p=0.8718).
TABLE-US-00002 TABLE 2 Nicotine administration does not affect
parkinsonism on or off levodopa treatment levodopa Nicotine
Parkinson Ratings Treat- Treat- Expt 2 ment ment Expt 1 (crossover)
Mean .+-. SE (n) No No 3.7, 6.1, 6.0 6.8, 7.4 6.0 .+-. 0.6 (5) No
Yes 5.2, 6.6 4.1, 6.4, 5.9 5.6 .+-. 0.5 (5) Yes No 0.4, 0.4, 0.6
1.8, 0.9 0.8 .+-. 0.3 (5) Yes Yes 1.7, 1.5 0.8, 0.4, 0.8 1.0 .+-.
0.2 (5)
[0254] FIG. 7 shows the effect of nicotine administration on
parkinsonism. White bars indicate no nicotine treatment and black
bars indicate nicotine treatment. Parkinsonism was evaluated
immediately before the afternoon L-dopa dose and 1.5 to 2 hours
after L-dopa treatment, when a maximal antiparkinsonian effect is
anticipated. Two of the seven animals in the study were not
parkinsonian, and therefore were not included in this analysis.
Error bars are the means.+-.standard error of five animals before
and after crossover of nicotine treatment. **p<0.01, as compared
with the same group with no L-dopa treatment by a Mann-Whitney
test. These results suggest that nicotine treatment influenced only
dyskinetic behavior and not parkinsonism.
[0255] The results from example 1 and 2 are the first to show that
nicotine treatment attenuates levodopa-induced dyskinesias in
nonhuman primates. Nicotine treatment significantly reduced both
the peak and duration of the dyskinetic response. Importantly, this
was not accompanied by a worsening of parkinsonism either on or off
levodopa. In animals pretreated with nicotine, that is, levodopa
naive monkeys, there was .about.60% decline in levodopa-induced
dyskinesias. In addition, nicotine treatment reduced dyskinesias by
.about.35% in monkeys that had received previously been treated
with levodopa, that is, in levodopa-primed monkeys.
Example 3
Effect of Continuous Delivery of Nicotine on its Antidyskinetic
Effect
[0256] Animals: Two groups of experimental animals (see Table 3)
are required for these experiments to determine the effectiveness
of minipump administration in reducing dyskinesias in lesioned
monkeys
TABLE-US-00003 TABLE 3 Groups for experiments in example 3 L-dopa
treatment Groups n Nicotine (5 mg/kg orally) (1) MPTP-lesioned 8 No
Yes (2) MPTP-lesioned 8 Yes Yes
[0257] MPTP treatment. All animals are lesioned with an injection
of MPTP (1.5-2.0 mg/kg, sc). The animals are rated for parkinsonism
3-4 weeks after lesioning according to methods described in example
1. If an animal is not parkinsonian, MPTP injection will be
repeated up to 4 times. The lesioning process may therefore require
up to 4 months to generate animals with parkinsonism. Eight animals
are required per group as our objective is to obtain stably
parkinsonian animals. In general .about.80% of the animals develop
stable parkinsonism. The animals are then allowed to recover from
the last MPTP injection for 1 month to ensure they are stably
parkinsonian before the minipumps are surgically implanted.
[0258] Minipump delivery: Nicotine is delivered via a minipump
according to standard procedure, using the 0.2 ml pump (ALZET) to
release nicotine over a 4-week period. Nicotine is administered at
a dose of 0.5 mg/kg/day (free base). This dose is chosen based on
previous data in nonhuman primates known in the art. Surgically
implanted minipumps containing nicotine and the treatment appears
to be well tolerated, with no appreciable weight loss or adverse
effects. The non-nicotine treated group will receive vehicle in the
pump. Plasma nicotine and cotinine levels will be measured 1-2
weeks after minipump implantation to ensure adequate nicotine
dosing as described in example 1. The objective is to achieve
levels similar to those in our current study involving nicotine
administration in the drinking water (.about.500 ng/ml). The pumps
are replaced monthly to ensure that the supply of nicotine remains
constant. The animals receive nicotine for 2 months prior to the
initiation of L-dopa treatment.
[0259] L-Dopa: After 2 months of nicotine infusion, both groups of
monkeys (either vehicle or nicotine) are gavaged with
L-dopa/carbidopa (5 mg/kg/1.25 mg/kg) twice daily at 9:00 AM and
1:00 PM. Treatment is performed on a 5-day-on 2-day-off schedule
and is done for at least 4 weeks. If nicotine treatment reduces
dyskinesias, L-dopa treatment is continued (up to 2 months) to
allow us to determine how long the decrease in dyskinesias is
maintained.
[0260] Parkinsonism will be rated using a modified nonhuman primate
parkinsonian rating scale as described in example 1. Dyskinesias
are monitored from videotapes, using the rating system detailed in
example 1. Parkinsonian ratings are done throughout the entire
treatment period (.about.9 months) 3 times weekly. Dyskinesia
ratings are done when the animals are being treated with
L-dopa.
[0261] These studies will test the effect of constant nicotine
administration which may enhance the antidyskinetic effect of
nicotine. Without being limited to any theory, continuous nicotine
application results in an initial receptor activation that is
followed by receptor desensitization or inactivation that remains
until the nicotine dissipates. Receptor desensitization or blockade
is then thought to result in compensatory changes in striatal
nAChRs, with the receptor changes possibly being more pronounced
depending on the period of desensitization. Thus, one might expect
a more sustained-desensitization and receptor changes with
continuous nicotine treatment.
Example 4
Nicotine Treatment Reduces L-Dopa-Induced Dyskinetic-Like Movements
in Rats
Materials and Methods
[0262] Animal model--6-Hydroxydopamine lesioning. We used the
6-hydroxydopamine lesioned rat model of nigrostriatal damage
described by Cenci and colleagues (Cenci et al., 1998 Eur J
Neurosci 10:2694-2706; Cenci et al., 2002 Nat Rev Neurosci
3:574-579). Adult male Sprague-Dawley rats were anesthetized with
isofluorane, and then placed in a Kopf stereotaxic instrument. Burr
holes were drilled through the skull and an intracranial injection
of 6 .mu.g 6-hydroxydopamine (2 .mu.g/.mu.l) stereotaxically
injected at two separate sites into the right ascending dopamine
fiber bundle, for a total of 12 .mu.g 6-hydroxydopamine. The
coordinates for the position of these two lesion sites were as
follows relative to the Bregma and dural surface: (1)
anteroposterior, -4.4; lateral, 1.2; ventral, 7.8; tooth bar at
-2.4; (2) anteroposterior, -4.0; lateral, 0.75; ventral, 8.0; tooth
bar at +3.4 (Cenci et al., 1998 Eur J Neurosci 10:2694-2706; Cenci
et al., 2002 Nat Rev Neurosci 3:574-579). All procedures conformed
to the NIH Guide for the Care and Use of Laboratory Animals and
were approved by the Institutional Animal Care and Use
Committee.
[0263] Behavioral assessment of the lesion. As an index of
nigrostriatal damage, the rats were tested for rotational behavior
3 and 4 weeks after lesioning. This was done using an automated
behavioral measurement apparatus that has four cylindrical chambers
(50 cm height.times.34 cm diameter) (ROTOMAX, AccuScan Instruments
Inc. Columbus, Ohio, USA). A rat was placed in one of the chambers
for 30 min for acclimatization, after which time amphetamine (4
mg/kg ip) was administered as previously described (Visanji et al.,
2006, Neuropharmacology 51:506-516). The rats were observed for
circling behavior for 90 min after injection. The rats were tested
a second time one week later and the data from the two testing
periods pooled.
[0264] Nicotine treatment regimen. The rats were first given a
drinking solution containing 1% saccharin for 3-4 days (FIG. 8).
Nicotine was then added at a concentration of 25 .mu.g/ml, and
increased to 50 .mu.g/ml 3-4 days later. Animals were maintained on
this dose for 3 weeks. L-dopa treatment was then initiated, as
below, with the nicotine dosing continued.
[0265] L-dopa treatment and behavioral testing for AIMs. Rats
received single daily intraperitoneal injections of 8 mg/kg L-dopa
methyl ester plus 15 mg/kg benserazide for 3 weeks (FIG. 8), as
described (Cenci et al., 1998 Eur J Neurosci 10:2694-2706; Cenci et
al., 2002 Nat Rev Neurosci 3:574-579). Abnormal involuntary
movements (AIMs) after daily LDOPA injection were then quantified
using the scale developed by Cenci and colleagues (Cenci et al.,
1998 Eur J Neurosci 10:2694-2706; Cenci et al., 2002 Nat Rev
Neurosci 3:574-579), as previously done in our laboratory (Cox et
al., 2007, Exp. Neurol.). Rats were placed in a Rotomax test
chamber. They were then scored on a scale from 0 to 4:
1=occasional; 2=frequent; 3=continuous but interrupted by sensory
distraction; 4=continuous, severe, not interrupted by sensory
distraction. The rating categories were as follows; (1) axial
dystonia, consisting of twisting posturing of the head and neck;
(2) orolingual dyskinesia, with stereotyped jaw movements and
contralateral tongue protrusion and (3) forelimb movements, with
dystonic movements of the contralateral forelimb. They were also
assessed for locomotive dyskinesia, or increased locomotion with
contralateral side bias; however, these scores were not included
because the interpretation of this motor response is not clear
(Papa et al., 1994 Brain Res 662;69-74; Cenci et al., 1998 Eur J
Neurosci 10:2694-2706).
[0266] Locomotive dyskinesias are distinct from turning behavior
described above. Rats were observed individually every 20 min for 3
h following L-dopa treatment. The maximum possible score in each
session was thus 108 (maximum score per observation=12; number of
observations per session=9). Rats were evaluated by two raters, one
blinded to treatment.
[0267] Data analyses. Statistical significance was determined using
Student's t-tests or ANOVA followed by Bonferroni post hoc tests,
as appropriate. Data are mean.+-.SEM. A p level of 0.05 was
considered significant.
Results
[0268] Nicotine treatment reduces total AIM scores. The time course
of the effect of 50 .mu.g/ml nicotine on the total number of AIMs
after 3 weeks of L-dopa treatment is shown in FIG. 9 (left panel)
Each value in FIG. 9 represents the mean.+-.SEM of 9-10 rats.
*p<0.05 using a Bonferroni post hoc test. A reduction in AIMs
scores was observed throughout the entire 3-hour period, with a
significant main effect of nicotine treatment (F(1, 153)=15.83,
p=0.0001) and time (F(8, 153)=4.12, p=0.0002), with no significant
interaction (F(8,153)=0.388, p=0.93). Experiments were next done to
determine whether a lower dose of nicotine also decreased AIMs. The
nicotine concentration in the drinking water was therefore reduced
from 50 to 25 .mu.g/ml with continued L-dopa administration (see
FIG. 8). The rats were tested for AIMs two and four weeks after
initiation of the lower dose of nicotine (25 .mu.g/ml). Since
results at two and four weeks were similar, the data were pooled.
FIG. 9 (right panel) shows that the nicotine-induced reduction in
AIMs was sustained using 25 .mu.g/ml nicotine in the drinking
water. Two-way ANOVA demonstrated a significant main effect of
nicotine treatment (F(1, 153)=35.32, p<0.0001) and time (F(8,
153)=2.06, p=0.0428), with no significant interaction (F(8,
153)=0.41, p=0.92).
[0269] Nicotine treatment reduces different AIM components. As
indicated earlier, AIMs consist of several different components
including (1) axial dystonia; (2) orolingual dyskinesia; and (3)
limb dyskinesia. Results shown are for the 3 and 6-8 week time
points (FIG. 10). Each value of FIG. 10 represents the mean.+-.SEM
of 9-10 rats, *p<0.05 and **p<0.01 using a t-test. There were
significant decreases in forelimb dyskinesias at both time points
with both doses of nicotine, and in axial dyskinesias at the 6-8
week time point. There was a trend for a decrease in oral
dyskinesias, although this was not significant. Thus, nicotine
treatment reduces some AIMs, but not others. These results may
imply that nicotine differentially affects molecular mechanisms
linked to AIMs. To evaluate this possibility, correlation analyses
can be done between nicotine-mediated reduction in AIMs components
and molecular mechanisms.
[0270] Effect of nicotine on behavior related to parkinsonism. Our
studies in monkeys showed that nicotine treatment reduced
L-dopa-induced dyskinesias without affecting parkinsonism. In our
preliminary studies in rats, we found that nicotine treatment did
not affect turning behavior, which is used as an index of
nigrostriatal damage (Mabandla et al., 2004 Metab Brain Dis
19;43-50; Howells et al., 2005 Behav Brain Res 165:210-220; Steiner
et al., 2006 Exp Neurol 199:291-300). The extent of turning was
quantified using the ROTOMAX, AccuScan System, with no difference
between rats receiving saccharin (8.2+3.7, n=10) compared to
nicotine (8.4+6.7, n=9). The effect on nicotine on rotarod
performance can also be tested. This is another approach used to
evaluate effects of drugs on motor performance in parkinsonian rats
(Lundblad et al., 2003 J Neurochem 84:1398-1410; Dekundy et al.,
2007 Behav Brain Res 179:76-89).
[0271] The present data show that nicotine treatment significantly
reduces L-dopa-induced AIMs in a 6-hydroxydopamine-lesioned rat
model. They demonstrate a decline in AIMs at nicotine doses of 25
and 50 .mu.g/ml in the drinking water. This effect of nicotine
persists with at least 2 months of L-dopa treatment. These results
are important as they further support the idea that nicotine may be
useful for the treatment of L-dopa-induced dyskinesias in
Parkinson's disease.
Example 5
Effects of Nicotinic Receptor Agonist on L-Dopa-Induced Dyskinetic
Movements
[0272] The effect of nicotinic receptor agonist such as
conotoxinMII, epibatidine, A-85380, cytisine, lobeline, anabasine,
SIB-1508Y, SIB-1553A, ABT-418, ABT-594, ABT-894, TC-2403, TC-2559,
RJR-2403, SSR180711, GTS-21 and varenicline can be tested using the
models described in the previous examples. The effect of nicotinic
receptor agonist in L-dopa-induced dyskinesias can be tested in the
rodent model described in Example 4. The compounds can in addition
be tested in a nonhuman primate model, which exhibits parkinsonian
symptoms and dyskinesias that closely resemble those in Parkinson's
disease such as the model described in Examples 1-3. Nicotinic
receptor agonist can be tested using both models. Alternatively,
nicotinic receptor agonist can be tested using either one of the
models described herein as well as any model known in the art.
Rodent Model
[0273] 6-Hydroxydopamine lesion. Rats (30) can be first be lesioned
with 6-hydroxydopamine as described in Example 4.
[0274] Behavioral assessment of the lesion. As an index of
nigrostriatal damage, the rats will be tested for rotational
behavior two (2) weeks after the lesion. This will be done using an
automated behavioral measurement apparatus. Baseline activity will
be monitored for thirty (30) minutes, after which time amphetamine
(4 mg/kg i.p.) will be administered. Because amphetamine induces a
greater dopamine release from the unlesioned as compared to the
lesioned striatum, the animals turn to the ipsilateral side.
Rotation will be monitored for ninety (90) minutes. The rats will
be retested one (1) week later, and the results from the two (2)
testing periods pooled. Rats with scores over 100 rotations will be
retained for further study (generally 20-25 animals out of 30).
[0275] L-dopa treatment. Rats (20) can be injected i.p. with 8-12
mg/kg L-dopa methyl ester plus 15 mg/kg benserazide once daily for
three (3) weeks and longer (Cenci et al., 1998 Eur J Neurosci
10:2694-2706.; Cenci et al., 2002 Nat Rev Neurosci 3:574-579).
Three (3) weeks of L-dopa treatment results in the development of
AIMs in the majority of rats. L-dopa dosing will be started after
the nicotinic agonist treatment.
[0276] Evaluation of L-dopa-induced AIMs. L-dopa-induced AIMs can
be quantified as described in Example 4 (Cenci et al., 1998 Eur J
Neurosci 10:2694-2706.; Cenci et al., 2002 Nat Rev Neurosci
3:574-579; Cox et al., 2007 Exp Neurol). This includes axial
dystonia, orolingual dyskinesia and forelimb movements with rats
scored on a scale from 0 to 4 for each AIM component. Rats will be
observed individually every twenty (20) minutes for three (3) hours
following L-dopa treatment. The maximum possible score in each
session is thus 108 (maximum score per observation=12; number of
observations per session=9). Two raters, one blinded to treatment,
will evaluate the rats.
[0277] Nicotinic agonist regimen. The agonists can be administered
2-3 weeks prior to L-dopa treatment, preferably in the drinking
water. The optimal dose and route of agonist administration will
need to be determined prior to initiation of the experiments with
lesioned animals. If this information is not available, pilot
studies can be done to determine optimal dosing.
[0278] Evaluation of parkinsonism. Amphetamine and L-dopa-induced
contralateral turning will be evaluated as described above to
determine the effects on parkinsonism.
[0279] Treatment. All thirty (30) rats can be first lesioned with
6-hydroxydopamine over a one (1) week period. They can be tested 2
and 3 weeks later to determine the extent of nigrostriatal damage
by evaluating ipsilateral turning in response to amphetamine (20-25
rats acceptable rotation). One (1) week is usually required to
evaluate turning behavior in the animals; behavioral testing of
20-25 rats usually takes two (2) weeks. At week 4, Group 1 will be
given vehicle (e.g. saccharin) only. Group 2 will be given vehicle
(possibly saccharin) plus agonist. L-dopa plus benserazide will
then be administered two (2) weeks after agonist is started. AIMs
are determined three (3) weeks after the start of L-dopa
administration. L-dopa treatment will be continued throughout.
Non Human Primate Model
[0280] Although rats are an excellent model for screening
compounds, nonhuman primate studies ensure efficacy in a model that
more closely resembles human Parkinson's disease. The experiments
can be designed to further refine the understanding of the dosing
and mode of the nicotinic receptor agonist administration that will
be most effective. The non human primate model described in
Examples 1 and 2 can be used to test the effect of nicotinic
receptor agonist in L-dopa induced dyskinesias.
[0281] The effect of continuous delivery of the nicotinic receptor
agonist on L-dopa induced dyskinesias can be tested via minipump as
described in Example 3.
Example 6
Intermittent and Continuous Nicotine Treatment Reduce
L-Dopa-Induced Dyskinesias in a Rat Model of Parkinson's
Disease
Methods
[0282] Animals. Experiments were performed using male
Sprague-Dawley rats (initial weight .about.250 g) purchased from
Charles River Laboratories (Gilroy, Calif.). They were housed 2 per
cage under a 12-12 h light-dark cycle in a temperature-controlled
room with free access to food and water. Three to four days after
arrival, the rats were unilaterally lesioned with 6-hydroxydopamine
as previously described (Cenci et al., 1998 Eur J Neurosci
10:2694-2706.; Cenci et al., 2002 Nat Rev Neurosci 3:574-579).
During the lesioning procedure the rats were maintained under
isofluorane anesthesia (2%). They were placed in a Kopf stereotaxic
instrument and burr holes drilled through the skull at the
following coordinates relative to the Bregma and dural surface: (1)
anteroposterior, -4.4; lateral, 1.2; ventral, 7.8; tooth bar at
-2.4; (2) anteroposterior, -4.0; lateral, 0.75; ventral, 8.0; tooth
bar at +3.4 (Cenci et al., 1998 Eur J Neurosci 10:2694-2706.; Cenci
et al., 2002 Nat Rev Neurosci 3:574-579). 6-Hydroxydopamine was
dissolved in 0.02% ascorbic acid/saline at a concentration of 3
ug/ul. Two .mu.l was stereotaxically injected at each of these
sites for a total of 12 mg into the right ascending dopamine fiber
bundle. Infusion of 6-hydroxydopamine into the target area was over
a 2-min period, with the cannula maintained at the site of
injection for a further 2 min. All procedures conformed to the NIH
Guide for the Care and Use of Laboratory Animals and were approved
by the Institutional Animal Care and Use Committee.
[0283] Behavioral testing. Two and three weeks after lesioning,
rats were tested for rotational behavior in an automated behavioral
measurement apparatus (ROTOMAX, AccuScan Instruments Inc. Columbus,
Ohio, USA). Each rat was placed in a cylindrical glass chamber for
30 min for acclimatization, after which amphetamine (4.0 mg/kg ip)
was administered. The behavior was monitored for an additional 90
min, with rats making at least 100 ipsilateral turns used for
further study.
[0284] Nicotine treatment. When the behavioral testing was
completed, rats were treated with nicotine via the drinking water
that yields an intermittent dosing regimen or via minipump that
provides a constant level of nicotine. For administration via the
drinking water, rats were first provided with a solution containing
1% saccharin (Sigma Chemical Co., St. Louis, Mo.) to mask the
bitter taste of nicotine. After 2-3 days of acclamation, nicotine
(free base, Sigma Chemical Co., St. Louis, Mo.) was added to the
saccharin-containing drinking solution of the treated group (pH
7.0). Nicotine was initially given at a concentration of 25
.mu.g/ml nicotine for 2 days. This was subsequently increased to 50
.mu.g/ml nicotine, and animals maintained at this dose for several
weeks (FIG. 11). Measurement of fluid intake showed that animals
with nicotine in the solution drank less than their vehicle-treated
counterparts, in agreement with previous studies in mice. The rats
appeared healthy although there was a small difference in body
weight with continued dosing.
[0285] In a separate series of experiments, rats were given
nicotine continuously via Alzet minipumps (model 2004--200 .mu.l),
which secrete nicotine for 28 days. These were subcutaneously
implanted according to the manufacturer's instruction. Pumps were
filled with either sterilized water or nicotine base in water to
deliver 2 mg/kg/d. Body weight was similar in the rats receiving
minipumps containing either vehicle or nicotine (Table 4).
TABLE-US-00004 TABLE 4 Plasma cotinine levels in rats receiving
chronic nicotine Treat- Number [Cotinine] Regimen ment Nicotine of
rats ng/ml Drinking water Saccharin 0 10 0 .+-. 0 Nicotine 50
.mu.g/ml 9 987 .+-. 81 Nicotine 25 .mu.g/ml 9 303 .+-. 23 Minipump
Water 0 12 0 .+-. 0 Nicotine 2 mg/kg/day 12 336 .+-. 49 Values
represent the mean .+-. SEM of the indicated number of animals.
[0286] L-dopa treatment. Three weeks after initiation of the 50
ug/ml nicotine dose, the rats received single daily intraperitoneal
injections of 8 mg/kg L-dopa methyl ester plus 15 mg/kg benserazide
(both from Sigma Chemical Co., St. Louis, Mo.) (Cenci et al., 1998
Eur J Neurosci 10:2694-2706.; Cenci et al., 2002 Nat Rev Neurosci
3:574-579). After 3 weeks of daily L-dopa dosing, abnormal
involuntary movements (AIMs) were quantified. These included (1)
axial dystonia, contralateral twisted posturing of the neck and
upper body; (2) orolingual dyskinesia, stereotyped jaw movements
and contralateral tongue protrusion; and (3) forelimb dyskinesia,
repetitive rhythmic jerks or dystonic posturing of the
contralateral forelimb and/or grabbing movements of the
contralateral paw (Cenci et al., 1998 Eur J Neurosci 10:2694-2706.;
Cenci et al., 2002 Nat Rev Neurosci 3:574-579; Carta et al., 2006
Neurochem 96:1718-1727). Rats were scored on a scale from 0 to 4
for each of these three AIMs as follows: 1=occasional; 2=frequent;
3=continuous but interrupted by sensory distraction; and
4=continuous, severe, not interrupted by sensory distraction.
Animal behavior was evaluated over 20 min sessions by two raters,
one blinded to treatment, for 3 h following injections. This
yielded a total of 9 sessions of testing per animals. The maximum
possible score for each animal was thus 108 (maximum score per
session=9; number of sessions over 3 h=12).
[0287] Plasma cotinine measurement. The nicotine metabolite
cotinine was determined as an indirect measure of plasma nicotine
levels using an ELISA kit (Orasure Technologies, Bethlehem, Pa.).
Blood samples were collected from the femoral vein after 1 to 2 wk
after initiation of nicotine treatment via the drinking water or
minipump. Plasma was prepared and a <1 .mu.l aliquot used for
assay according to the manufacturer's instructions. A standard
curve ranging from 5 to 100 ng/ml cotinine was done with every
assay.
[0288] Data analyses. All analyses were done using GraphPad
Prism.RTM. (GraphPad Software, Inc, San Diego, Calif.). Differences
in rating scores between groups were analyzed using nonparametric
tests (Mann-Whitney-Mann test or Wilcoxon test for paired data).
For the time course studies, analysis of variance (ANOVA) followed
by Bonferroni multiple comparison test was used. A level of 0.05
was considered significant. Results are expressed as
mean.+-.SEM.
Results
[0289] FIG. 11 shows that intermittent nicotine treatment reduces
L-dopa-induced abnormal involuntary movements (AIMs). Treatment
schedule (top panel) depicting the time of administration of
nicotine (in drinking water), L-dopa dosing and behavioral testing.
Rats were provided with vehicle drinking water containing 1%
saccharin for 1 week. Some of the rats (n=10) were continued on
this solution, while nicotine was added to the vehicle drinking
water of the remaining animals (n=9). Nicotine administration was
initiated at a dose of 25 .mu.g/ml, and then switched to a final
maintenance dose of 50 .mu.g/ml. Three weeks later, they were given
L-dopa (8 mg/kg ip) once daily for 10 weeks, and then 12 mg/kg
L-dopa for a further 5 weeks. AIMs were rated throughout the L-dopa
treatment by two raters, one blinded to treatment. AIMs were rated
as described in methods over a 3-hour period, including 30-min of
baseline (no L-dopa). There was a significant effect (P<0.001)
of nicotine treatment on L-dopa-induced AIMS using ANOVA. Each
symbol is the mean.+-.SEM of 9-10 rats.
[0290] FIG. 12 shows that intermittent nicotine treatment reduced
individual AIM components after L-dopa treatment. Rats were given
nicotine in the drinking solution and subsequently administered
L-dopa. The rats were evaluated for total, axial, oral and forelimb
AIMs by two raters, one blinded to treatment status of the animals.
Each value represents the mean+SEM of 9-10 rats. *P<0.05,
**P<0.01 and ***P<0.001 compared to rats receiving only
saccharin using a Mann-Whitney test.
[0291] FIG. 13 shows a crossover study depicting the effect of
intermittent nicotine treatment via the drinking water on
L-dopa-induced AIMs. The left-hand panels depict results from rats
that had initially received no nicotine prior to the first L-dopa
treatment period, and were subsequently given nicotine in the
drinking solution as outlined in FIG. 11. The right-hand panels
depict results from rats that had initially received nicotine prior
to the first L-dopa treatment period, and were subsequently given
saccharin in the drinking solution. Nicotine administration reduced
L-dopa-induced AIMS, while its removal resulted in an increase in
AIMs development. Each value represents the mean.+-.SEM of 9-10
rats. *P<0.05 and ***P<0.001 compared to the initial
treatment using a Wilcoxon test.
[0292] FIG. 14 shows continuous nicotine exposure via minipump
reduces L-dopa-induced AIMs. Treatment schedule (top) depicting the
time of administration of nicotine (via minipump), L-dopa dosing
and behavioral testing. Half of the rats were implanted with
minipumps containing nicotine (2 mg/kg/d) 4 weeks after 6-OHDA
lesioning, and the other half with minipumps containing vehicle.
Two weeks later, all the rats were given L-dopa (8 mg/kg ip) once
daily for 4 weeks, and then 12 mg/kg L-dopa for a further 3 weeks.
AIMs were rated throughout the L-dopa treatment by two raters, one
blinded to treatment. The time course of the effect of nicotine on
AIMs after L-dopa administration is depicted in the graph. AIMs
were rated as described in methods over a 3-hour period, including
30-min of baseline (no L-dopa). There was a significant effect
(P<0.001) of nicotine treatment on L-dopa-induced AIMs using
ANOVA. Each symbol is the mean.+-.SEM of 12 rats.
[0293] FIG. 15 shows that constant nicotine exposure via minipump
reduced individual AIM components after L-dopa treatment. Rats were
given nicotine (2 mg/kg/d) via minipump and subsequently
administered L-dopa. The rats were evaluated for total, axial, oral
and forelimb AIMs by two raters, one blinded to treatment status of
the animals. Each value represents the mean+SEM of 12 rats.
*P<0.05, **P<0.01 and ***P<0.001 compared to rats
receiving no nicotine using a Mann-Whitney test.
[0294] FIG. 16 shows a crossover study depicting the effect of
constant nicotine exposure via minipump on L-dopa-induced AIMs. The
left-hand panels depict results from rats that had initially
received no nicotine prior to the first L-dopa treatment period,
and were subsequently given nicotine via minipump as depicted in
FIG. 14. The right-hand panels depict results from rats that had
initially received nicotine prior to the first L-dopa treatment
period, and were subsequently given minipumps containing no
nicotine. Nicotine administration reduced L-dopa-induced AIMs,
while its removal resulted in an increase in AIMs development. Each
value represents the mean+SEM of 12 rats. **P<0.01 and
***P<0.001 compared to the initial treatment using a Wilcoxon
test.
Example 7
Effects of Nicotinic Receptor Agonist on L-Dopa-Induced Dyskinetic
Movements in Humans
[0295] An empiric trial on the effects of nicotine on
levodopa-induced dyskinesias can be conducted. Inclusion criteria
include patients, both male and female, who suffered from
Parkinson's disease that are 30 years old and older. The main
inclusion criteria are: (i) Levodopa associated peak-dose
dyskinesia which is at least moderately disabling and present for
.gtoreq.25% of the waking day (UPDRS part IV, items 32 and 33, each
.gtoreq.2) (ii) Levodopa associated end of dose deterioration, with
an average `Off` time of 2.5 hours or more per day based on the
pre-study patient diary recordings between Days -4 to 29 (iii)
Stable Parkinson's medication for at least 1 month prior to
randomization, with a minimum of 3 hours between the levodopa
intakes (iv) Hoehn and Yahr Stages 1 to 4 during `Off` period (v)
Demonstrated ability to comprehend and give informed consent (vi)
Ability to complete patient diary. The main exclusion criteria
include: (i) Other clinically significant conditions apart from
those typically associated with Parkinson's disease (ii) Intake of
medication associated with exacerbation of dyskinesia or with
extrapyramidal side effects and tardive dyskinesia or induction of
liver enzymes; neuroleptics; drugs used in treatment of cognitive
impairment; or specified drugs known to be substantially
metabolized through the following cytochrome P450 isoenzymes: 1A2,
2B6, 2C19, 2C9, 2D6, and 2E1 (iii) Use of St. John's Wort or Ginkgo
Biloba within 48 hrs prior to randomization and until the last
treatment day with the study medication (iv) Intake of an
investigational drug within 30 days prior to Initial Screening
[0296] This study can be a multi-center, double-blind,
placebo-controlled, multiple dose escalating, safety, tolerance,
pharmacokinetics, and efficacy study of nicotine administered in
Parkinson's disease patients who are concomitantly being treated
with a combination product of levodopa and possible other
antiparkinson medication. The patients will be randomized into one
of five treatment groups to receive either fixed or ascending doses
of Nicotine (from 0.3 to 4 mg per dose) or placebo. For efficacy
assessments, the patient is assessed with levodopa challenge,
following an overnight withdrawal of Parkinson's medication.
Levodopa-induced dyskinesia is assessed using a standardized rating
scale. Time spent in `Off` state or in `On` state without
dyskinesia, with non-troublesome dyskinesia or with troublesome
dyskinesia, is assessed using patient diaries (e.g. electronic
patient diaries). Impact of dyskinesia on daily activities is
quantified using a PDYS-26 questionnaire. To explore potential
positive or negative impact of nicotine on cognitive functions, the
study includes two cognitive tests. Finally, the study includes
investigator assessments of CGI-I scales for dyskinesia,
Parkinson's disease, and clinical condition in general.
[0297] Nicotine is compounded into capsules or tables and supplied
to all subjects. The patients will be treated as described in Table
below
TABLE-US-00005 TABLE 5 Treatment Groups Group Assigned Intervention
1. Placebo Drug: Nicotine One placebo tablet administered from
Nicotine in oral formulation every time levodopa Day 1 to 35 is
administered to the subjects (~3-8 times per day) for up to 35 days
2. Active Comparator Drug: Nicotine One 0.3 mg tablet from Day 1 to
35 Nicotine in oral formulation every time levodopa is administered
to the subjects (~3-8 times per day) for up to 35 days 3. Active
Comparator Drug: Nicotine One 0.3 mg tablet from Day 1 to 7,
Nicotine in oral formulation every time levodopa One 1 mg tablet
from Day 8 to 35 is administered to the subjects (~3-8 times per
day) for up to 35 days 4. Active Comparator Drug: Nicotine One 0.3
mg tablet from Day 1 to 7, One 1 mg Nicotine in oral formulation
every time levodopa tablet from Day 8 to 14, One 2 mg tablet from
is administered to the subjects (~3-8 times per day) Day 15 to 21,
One 1 mg and One 2 mg tablets for up to 35 days from Day 21 to 35
5. Active Comparator Drug: Nicotine One 0.3 mg tablet from Day 1 to
7, One 1 mg Nicotine in oral formulation every time levodopa tablet
from Day 8 to 14, One 2 mg tablet from is administered to the
subjects (~3-8 times per day) Day 15 to 21, One 1 mg and One 2 mg
tablets for up to 35 days from Day 21 to 28, Two 2 mg tablets from
Day 28 to day 35.
[0298] Subjects are instructed that concomitant medications should
not be altered without speaking with the investigator. Subjects are
advised that they will be contacted every day or every other day to
assess progress in the trial and any side effects associated with
the addition of nicotine. At the end of the trial, patients are
interviewed. They are asked to rate their satisfaction with the
study medication (-2-+2) and its ability to modulate the
levodopa-induced dyskinesias. If the study has used placebo and is
blinded, the blind is broken and statistical comparisons of
nicotine versus placebo are performed.
[0299] While preferred embodiments of the present invention have
been shown and described herein, it will be obvious to those
skilled in the art that such embodiments are provided by way of
example only. Numerous variations, changes, and substitutions will
now occur to those skilled in the art without departing from the
invention. It should be understood that various alternatives to the
embodiments of the invention described herein may be employed in
practicing the invention. It is intended that the following claims
define the scope of the invention and that methods and structures
within the scope of these claims and their equivalents be covered
thereby.
* * * * *