HK1145978B - Methods and compositions for reduction of side effects of therapeutic treatments - Google Patents

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.

Description

Methods and compositions for reducing side effects of treatment

Benefits of government

Certain embodiments of the present invention were made with the funding of the national institute of health under NIH NS34886 and NS 42091, to which the national institute of health may have certain rights.

Cross-referencing

The present application claims the benefits of a provisional application No. 60/909,637 entitled "methods and compositions for reducing side effects of treatment" filed on day 4/2 2007, No. 60/956,296 entitled "methods and compositions for reducing side effects of treatment" filed on day 8/16 2007, and No. 60/956,657 entitled "methods and compositions for reducing side effects of treatment" filed on day 8/17 2007.

Background

Many of the primary treatments for disease result in undesirable side effects. For example, levodopa, the standard treatment for parkinson's disease, is associated with debilitating abnormal involuntary movements or dyskinesias. These motor abnormalities can appear after only a few months of treatment and can affect most patients within 5-10 years. They may be quite incapacitating and are a major complication in the treatment of parkinson's disease. Currently, there are only limited treatment options for dyskinesias.

Parkinson's disease is very common among those over 65 years of age, and in north america, the proportion of this age group is expected to rise from 12% to 24% in the next 30 years. The overall incidence of parkinson's disease in these populations is at the level of 1.5-2% and increases with age. Therefore, additional treatments are needed for this disability complication of levodopa therapy.

Disclosure of Invention

The present invention provides methods, compositions and kits for using nicotinic receptor modulators. For example, the methods, compositions, and kits described herein are useful for reducing or eliminating side effects. In certain embodiments, the methods, compositions, and kits described herein are used to reduce or eliminate the side effects of dopaminergic agents.

In one aspect, the invention provides compositions comprising nicotinic receptor modulators. In certain embodiments of this aspect, the invention provides pharmaceutical compositions comprising a nicotinic receptor modulator. In certain embodiments, the invention encompasses pharmaceutical compositions wherein the nicotinic receptor modulator is present in an amount sufficient to reduce the side effects of the dopaminergic agent when the composition is administered to an animal. In certain embodiments, the invention includes pharmaceutical compositions wherein the nicotinic receptor modulator is present in an amount sufficient to reduce or eliminate the side effects of the 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 comprising nicotinic receptor modulators are administered by a variety of different delivery routes as further described herein. In certain embodiments, the pharmaceutical composition comprising a nicotinic receptor modulator is administered orally to an animal. In certain embodiments, the present invention provides solid pharmaceutical compositions for oral administration comprising an effective amount of a nicotinic receptor modulator and a pharmaceutically acceptable excipient suitable for oral administration. In certain embodiments, the present invention provides liquid pharmaceutical compositions for oral administration comprising an effective amount of a nicotinic receptor modulator and a pharmaceutically acceptable excipient suitable for oral administration.

In certain embodiments of this aspect, the invention provides a pharmaceutical composition comprising a dopaminergic agent and a nicotinic receptor modulator. In certain embodiments, the invention encompasses pharmaceutical compositions wherein the nicotinic receptor modulator is present in an amount sufficient to reduce the side effects of the dopaminergic agent when the composition is administered to an animal.

In certain embodiments of this aspect, the nicotinic receptor modulator modulates a nicotinic receptor in the brain. In certain embodiments, the nicotinic receptor modulator modulates a nicotinic receptor in the striatum or substantia nigra (substanta niagara). In certain embodiments, the nicotinic receptor modulator modulates a nicotinic receptor comprising at least one alpha subunit or a nicotinic receptor comprising at least one alpha subunit and at least one beta subunit. In certain embodiments, the alpha subunit is selected from 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 beta 2, beta 3, and beta 4. In certain embodiments, the nicotinic receptor modulator modulates a nicotinic receptor comprising a subunit selected from the group consisting of α 4 β 2, α 6 β 2, α 4 α 5 β 2, α 4 α 6 β 2 β 3, and α 4 α 2 β 2.

In certain embodiments of the composition, the nicotinic receptor modulator in the composition comprises a nicotinic receptor agonist. In certain embodiments, the nicotinic receptor agonist in the composition is selected from the group consisting of simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, and toxins. Examples of nicotinic receptor agonists include, but are not limited to, nicotine, conotoxin (contoxin) MII, epibatidine, A-85380, cytisine, lobeline, quinaline, SIB-1508Y, SIB-1553A, ABT-418, ABT-594, ABT-894, TC-2403, TC-2559, RJR-2403, SSR180711, GTS-21, and varenicline (varenicline). In certain embodiments, the agonist is nicotine.

In certain embodiments of the composition, the dopaminergic agent is a dopamine precursor or a dopamine receptor agonist. Examples of dopaminergic drugs include, but are not limited to, levodopa, bromocriptine, pergolide (pergolide), pramipexole (pramipexole), cabergoline (cabergoline), ropinirole (ropinolone), apomorphine, or combinations thereof. In certain embodiments, the dopaminergic agent is levodopa.

In certain embodiments of the compositions of the present invention, the side effects to be treated include tremors, headache, changes in motor function, changes in mental state, changes in sensory function, seizures, insomnia, paresthesia, dizziness, coma and dyskinesia. In certain embodiments, the side effect is dyskinesia. In certain embodiments of the compositions of the present invention, the side effects are reduced by at least 30% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments of the invention, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 5% when the composition is administered to an animal as compared to the therapeutic effect in the absence of the nicotinic receptor modulator.

In certain embodiments of the compositions of the present invention, the side effects can be reduced by administering the nicotinic receptor modulator to an animal suffering from or about to suffer from the side effects caused by dopaminergic agents such that an optimal concentration of the nicotinic receptor modulator or metabolite in the blood, plasma and/or target tissue of the animal is achieved. In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal prior to the dopaminergic agent. In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal after the dopaminergic agent but before the onset of the side effect caused by the dopaminergic agent. In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal following the dopaminergic agent and following presentation of the initial signs of a dopaminergic agent-induced side effect by the animal. In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal following the dopaminergic agent and following exposure of the animal to a side effect caused by the dopaminergic agent.

In certain embodiments, the nicotinic receptor modulator is administered by pulsed delivery. In certain embodiments, the nicotinic receptor modulator is administered in a sustained or controlled release dosage form. In certain embodiments, the nicotinic receptor modulator and/or the dopaminergic agent is administered in a multilayer tablet form.

In certain embodiments of the compositions of the present invention, the pharmaceutical composition comprises a composition of the present invention and a pharmaceutically acceptable excipient. In certain embodiments of the compositions, the molar ratio of the dopaminergic agent and nicotinic receptor modulator is from about 0.001: 1 to about 10: 1. In certain embodiments of the composition, the dopaminergic agent is present in an amount from about 0.1 to about 1000mg, and the nicotinic receptor modulator is present in an amount from about 0.1 to about 2000 mg. In certain embodiments, the nicotinic receptor modulator is nicotine. In certain embodiments, nicotine is present in an amount of about 0.1 to about 100 mg. In certain embodiments, nicotine is present in an amount of about 0.1 to about 10 mg. In certain embodiments, nicotine is present in an amount of about 0.5 mg. In certain embodiments of the compositions of the present invention, the pharmaceutical composition comprises an effective amount of levodopa and nicotine in an amount sufficient to reduce levodopa-induced dyskinesia, and a pharmaceutically acceptable carrier.

In certain embodiments, the pharmaceutical composition comprises a third agent that is also useful for treating a side effect of a dopaminergic agent. In certain embodiments, the side effect of the nicotinic receptor modulator and the third drug treatment is the same side effect. In certain embodiments, the side effects of the nicotinic receptor modulator and the third drug treatment are different side effects. In certain embodiments, the third drug is amantadine. In certain embodiments, the pharmaceutical compositions of the present invention comprise one or more drugs used in the art in combination with a dopamine drug to achieve a therapeutic effect. For example, in certain embodiments, the pharmaceutical compositions of the present invention comprise an agent, such as carbidopa, which is capable of blocking the conversion of levodopa to dopamine in the blood. In certain embodiments, the pharmaceutical compositions of the present invention comprise COMT inhibitors such as entacapone (entacapone). In certain embodiments, the pharmaceutical compositions of the present invention comprise a type B monoamine oxidase (MAO-B) inhibitor, such as selegiline.

In certain embodiments of the compositions of the present invention, the pharmaceutical composition comprises an effective amount of levodopa, an effective amount of carbidopa, an effective amount of nicotine capable of reducing levodopa-induced dyskinesia, and a pharmaceutically acceptable carrier.

In certain embodiments of the compositions of the present invention, the pharmaceutical composition comprises an effective amount of a dopaminergic agent, an effective amount of nicotine, and a pharmaceutically acceptable carrier, wherein nicotine is present in an amount from about 0.01 to about 10 mg.

In certain embodiments of the compositions of the present invention, a solid pharmaceutical composition for oral administration comprises nicotine and a pharmaceutically acceptable carrier, wherein nicotine is present in an amount of about 0.01mg to about 2.8 mg. In certain embodiments of the compositions of the present invention, nicotine is present in an amount of less than 3 mg.

In certain embodiments of the compositions of the present invention, the multilayer tablet comprises an immediate release layer and a sustained release layer, wherein the immediate release layer comprises one or more therapeutic agents independently selected from the group consisting of a nicotinic receptor agonist and a dopaminergic agent, and the sustained release layer comprises one or more therapeutic agents independently selected from the group consisting of a nicotinic receptor agonist and a dopaminergic agent. In certain embodiments, the immediate release layer or the sustained release layer further comprises a third drug. In certain embodiments, the third agent is used in combination with the dopaminergic agent to achieve a therapeutic effect or for treating a side effect of the dopaminergic agent.

In certain embodiments of the invention, a kit comprises a composition of the invention and instructions for using the composition.

In another aspect, the invention provides methods of using nicotinic receptor agonists. In certain embodiments of this aspect, the invention provides a method of treating an animal by administering to the animal an effective amount of a nicotinic receptor agonist sufficient to reduce or eliminate a side effect of a dopaminergic agent. In certain embodiments of this aspect, the invention provides a method of treating an animal by administering to the animal a nicotinic receptor agonist in an amount effective to reduce or eliminate the side effects of a dopaminergic agent and to prevent or reduce the likelihood of addiction to a nicotinic receptor modulator, when the composition is administered to the animal. In certain embodiments, the nicotinic receptor modulators are administered by a variety of different delivery routes as further described herein. In one embodiment, the nicotinic receptor modulator is administered orally to the animal.

In certain embodiments of this aspect, the invention provides a method of treating a condition by administering to an animal having 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 certain embodiments, the agonist reduces or eliminates multiple side effects of the dopaminergic agent. In certain embodiments, the dopaminergic agent and the nicotinic receptor agonist are administered in a single composition. In certain embodiments, the dopaminergic agent and nicotinic receptor agonist are mixed in a composition.

In certain embodiments of this aspect, the invention provides a method of reducing the side effects of dopaminergic drug therapy by administering an effective amount of nicotine to a human in need of dopaminergic drug therapy in combination with a dopaminergic drug, wherein the dopaminergic drug and nicotine are administered to the human simultaneously in the form of an oral composition. In certain embodiments, the dopaminergic agent and nicotine are administered in a single composition. In certain embodiments, the dopaminergic agent and nicotine are administered in different compositions. In certain embodiments, the dopaminergic agent and nicotine are mixed in a composition.

In certain embodiments of this aspect, the invention provides a method of reducing movement disorders caused by levodopa by administering an effective amount of nicotine to a person in need of treatment in combination with an effective amount of levodopa and an effective amount of carbidopa, wherein the amount of nicotine is sufficient to reduce said movement disorders, and wherein the levodopa and nicotine are administered to said person simultaneously by oral administration.

In certain 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 reduce an average of at least about 30% of the side effects of the dopaminergic agent as compared to the effect in the absence of the nicotinic receptor agonist. In certain embodiments, the administration is oral administration. In certain embodiments, the administering is transdermal.

In certain embodiments of the methods of the present invention, the nicotinic receptor modulator is administered to an animal suffering from or about to suffer from a side effect caused by a dopaminergic agent, such that the nicotinic receptor modulator, or a metabolite of the nicotinic receptor modulator, reaches an effective concentration in the blood, plasma, and/or target tissue, thereby reducing or eliminating the side effect associated with the dopaminergic agent, wherein the effective concentration is the concentration necessary to reduce or eliminate the side effect. In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal prior to the dopaminergic agent. In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal after the dopaminergic agent but before the onset of the side effect caused by the dopaminergic agent.

In various embodiments, the presence of the dopaminergic agent and the nicotinic receptor modulator, or a metabolite thereof, in the blood can be modulated temporally and/or spatially. For example, the individual drugs may be administered at different times in time (one before the other). In addition, both drugs may be administered at the same time, but in a dosage form that has the function of modulating the release of one drug relative to the other over a period of time (e.g., a bilayer tablet dosage form).

In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal following the dopaminergic agent and following presentation of the initial signs of a dopaminergic agent-induced side effect by the animal. In certain embodiments, the nicotinic receptor modulator or metabolite is present in the bloodstream of the animal subsequent to the dopaminergic agent and subsequent to the animal exhibiting dopaminergic agent-induced side effects.

In certain embodiments, the nicotinic receptor modulator is administered by pulsed delivery. In certain embodiments, the nicotinic receptor modulator is administered in the form of a sustained or controlled release formulation. In certain embodiments, the nicotinic receptor modulator and the dopaminergic agent are administered in the form of a multilayer tablet.

In certain embodiments of the methods of the invention, the nicotinic receptor agonist in the composition is selected from the group consisting of simple or complex organic or inorganic molecules, peptides, proteins, oligonucleotides, antibodies, antibody derivatives, antibody fragments, vitamin derivatives, carbohydrates, and toxins. Examples of nicotinic receptor agonists include, but are not limited to, nicotine, conotoxin MII, epibatidine, A-85380, cytisine, lobeline, quinaline, SIB-1508Y, SIB-1553A, ABT-418, ABT-594, ABT-894, TC-2403, TC-2559, RJR-2403, SSR180711, GTS-21, and valencene. In certain embodiments, the agonist is nicotine. In certain embodiments of the invention, the dopaminergic agent is a dopamine precursor or a dopamine receptor agonist. Examples of dopaminergic drugs include, but are not limited to, levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, or combinations thereof. In certain embodiments, the dopaminergic agent is levodopa.

In certain embodiments, the methods described herein include a third agent that is also useful for treating a side effect of a dopaminergic agent. In certain embodiments, the side effect of the nicotinic receptor modulator and the third drug treatment is the same side effect. In certain embodiments, the side effects of the nicotinic receptor modulator and the third drug treatment are different side effects. In certain embodiments, the third drug is amantadine. In certain embodiments, the methods described herein comprise one or more drugs used in the art in combination with dopamine drug therapy to achieve a therapeutic effect. For example, in certain embodiments, the methods described herein include drugs such as carbidopa that block the conversion of levodopa to dopamine in the blood. In certain embodiments, the methods described herein comprise COMT inhibitors such as entacapone. In certain embodiments, the methods described herein comprise a type B monoamine oxidase (MAO-B) inhibitor such as selegiline.

In certain embodiments of the methods of the invention, the subject has a condition comprising parkinson's disease, alzheimer's disease, dopa-responsive dystonia, cerebral palsy, post-ischemic contractile dysfunction, severe ovarian hyperstimulation syndrome, pediatric dyskinesia, and non-oliguric renal failure.

In another aspect, the invention provides methods for treating dyskinesia by administering to an animal in need of such treatment a nicotinic receptor agonist in an amount sufficient to reduce or eliminate dyskinesia.

In another aspect, the invention provides methods of treating parkinson's disease by administering to an animal in need of treatment thereof an amount of a nicotinic receptor agonist sufficient to reduce or eliminate parkinson's disease. In certain embodiments, the invention provides methods of treating parkinson's disease by administering to an animal in need of treatment for parkinson's disease a nicotinic receptor agonist in an amount sufficient to reduce or eliminate the physiological symptoms associated with parkinson's disease, although the patient may still be afflicted with parkinson's disease.

The invention also includes the use of a nicotine or nicotinic receptor agonist in the manufacture of a medicament for alleviating dyskinesia in the treatment of parkinson's disease in a human.

The invention also includes the use of nicotine or nicotinic receptor agonists for alleviating dyskinesia in the treatment of parkinson's disease in humans without the need to reduce the effective amount of a dopaminergic agent.

The invention also includes a combined preparation of an effective amount of a dopaminergic agent and a nicotine or nicotinic receptor agonist for simultaneous, separate or sequential use in alleviating dyskinesia in the treatment of Parkinson's disease in a human.

The invention also includes a combined preparation of a dopaminergic agent and a nicotine or nicotinic receptor agonist for reduced dyskinesia, for simultaneous, separate or sequential use in the alleviation of dyskinesia in the treatment of Parkinson's disease in a human.

The invention also includes a combined preparation of an effective, but dyskinetic inducing amount of a dopaminergic agent and a nicotine or nicotinic receptor agonist for simultaneous, separate or sequential use in alleviating dyskinesia in the treatment of Parkinson's disease in a human.

The invention also includes a combined preparation of an effective, but dyskinetic causing amount of a dopaminergic agent and a nicotine or nicotinic receptor agonist for simultaneous, separate or sequential administration in a human for treating parkinson's disease.

The invention also includes a pharmaceutical composition for oral administration comprising both a dopaminergic agent and a nicotine or nicotinic receptor agonist.

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.

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.

Drawings

The novel features believed characteristic 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:

fig. 1 depicts a medication schedule and behavioral testing period.

Figure 2 depicts the time course of nicotine-induced reduction of levodopa-induced dyskinesia.

Figure 3 shows that nicotine treatment reduced overall dyskinesia.

Figure 4 depicts a graph showing that nicotine treatment reduces the peak dyskinesia.

Figure 5 depicts a graph showing that nicotine administration reduces total levodopa-induced dyskinesia in levodopa-pretreated (prime) monkeys.

Figure 6 depicts a graph showing that nicotine removal exacerbates levodopa-induced dyskinesia in levodopa-pretreated monkeys.

Figure 7 depicts a graph showing that nicotine administration does not affect parkinson's disease with or without levodopa treatment.

Figure 8 depicts a schedule of treatment paradigms and behavioral testing in rats.

FIG. 9 depicts a time course showing nicotine treatment of total L-dopa-induced AIM in 6-hydroxydopamine-injured rats.

Figure 10 depicts a graph showing that nicotine treatment differentially reduces the components of L-dopa-induced AIM.

Figure 11 depicts a graph showing that intermittent nicotine treatment reduces L dopa-induced Abnormal Involuntary Movement (AIM) in rats.

Figure 12 depicts a graph showing that intermittent nicotine treatment after L-dopa treatment reduces individual AIM components in rats.

FIG. 13 shows a cross-study depicting the effect of watered intermittent nicotine treatment on L-dopa-induced AIM in rats.

Figure 14 shows that continuous nicotine exposure via a micropump reduces L-dopa-induced AIM.

Figure 15 shows that constant nicotine exposure via the minipump reduces the individual AIM components after treatment with L-dopa.

Fig. 16 shows a cross-study depicting the effect of constant nicotine exposure via a micropump on L-dopa-induced AIM.

Detailed Description

A particularly preferred embodiment of the present invention will now be described in detail. Examples of preferred embodiments are illustrated in the examples section below.

Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference.

The present invention provides compositions and methods. In certain embodiments, the present invention provides compositions and methods for utilizing nicotinic receptor modulators, e.g., to reduce or eliminate side effects of dopaminergic drug treatment. In certain embodiments, the present invention provides compositions and methods utilizing a combination of a dopaminergic agent and a nicotinic receptor modulator. In certain embodiments, the nicotinic receptor modulators reduce or eliminate the side effects associated with dopaminergic drug therapy. In certain embodiments, the nicotinic receptor modulator is an agonist. Dopaminergic agents include dopamine precursors and dopamine receptor agonists. Examples of dopaminergic agents include levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, or combinations thereof.

Nicotine-like receptor systems

A. Nicotinic cholinergic system of the striatum

Localization of cholinergic neurons in the striatum.Cholinergic neurons in the striatum are large interneurons, accounting for approximately 2% of the neuronal population. Although limited in number, these interneurons have a large axonal tree (axonal arbor) that provides very dense local innervation both in the tail and in the core. Indeed, high levels of acetylcholine, the enzyme acetylcholine synthesis-acetylcholine transferase and the enzyme acetylcholine degrading-acetylcholinesterase are expressed in the striatum. These cholinergic markers overlap with dopaminergic trees (arbors) that contain dopamine, dopamine synthase-tyrosine hydroxylase, and other dopaminergic markers, also expressed at relatively high densities. Without being bound to any theory, the overlapping distribution of cholinergic and dopaminergic systems provides the structural basis for functional interactions between these two neurotransmitters.

Nicotinic acetylcholine receptors in the striatum. Cholinergic interneurons of the striatum stimulate activation through the eventual release of acetylcholine, which is regulated by a number of striatal systems, including glutamatergic, dopaminergic, gabaergic, 5-hydroxytryptamine-ergic systems, and other factors. The released acetylcholine interacts with nachrs present on dopaminergic and other striatal neurons. These receptors are pentameric ligand-gated ion channels consisting of only alpha subunits (homomeric), or of alpha and beta subunits (heteromeric receptors).To date, six different alpha subunits (α 2, α 13, α 4, α 5, α 6, α 7) and three different α 0 subunits (α 22, β 3, β 4) have been identified in the nigrostriatal pathway. These subunits combine to form nachrs, with the major subtype in the striatum consisting of α 4 β 2^*And α 3/α 6 β 2^*Subunit composition and also a small group of homopolymeric α 7 nachrs. (^*Asterisks indicate the presence of other subunits, there are some that have not yet been identified and may be species dependent). Alpha 4 beta 2^*Receptors are localized on dopaminergic endings and the striatum and other neurons throughout the CNS. However, they are not present in the peripheral nervous system or skeletal muscle. Interestingly, α 3/α 6 β 2^*Receptor subtypes are selectively located in the dopaminergic nigrostriatal pathway and in only limited other brain regions, suggesting that they may be particularly relevant to the function of the nigrostriatal. These latter receptors (. alpha.3/. alpha.6. beta.2)^*) It is thought that the α 3 and/or α 6 subunits are expressed because they are present in the striatum of monkeys and α -conotoxin MII (the ligand used to identify these receptors) interacts with both the α 3 and α 6nAChR subtypes. Without being bound to any theory, the presence of different receptor groups on dopaminergic neurons creates the possibility to select subtypes that may be more directly related to the development of dyskinesias and the anti-dyskinesia properties of nicotine. These knowledge will enable the development of nAChR agonists that more specifically target the improvement of dyskinesias.

Nicotinic receptor activation of the striatum causes dopamine release.Endogenously released acetylcholine or exogenously applied drugs (e.g., nicotine and nicotinic agonists) are known to stimulate nachrs on dopaminergic neurons and to increase dopamine release in the striatum, both in vitro and in vivo environments. Agonist-triggered dopamine release in the striatum in response to α 4 β 2^*And α 3/α 6 β 2^*Stimulation of the nAChR subtype of subunit composition occurs. Without being bound by any theory, the anti-dyskinetic effects of nicotine described herein may be related to α 4 β 2^*And/or alpha 3/alpha 6 beta 2^*Changes in dopamine release following nAChR stimulation.

B. Dopaminergic system of the striatum and its use in reducing the side effects of dopaminergic drug therapy

One of the neurotransmitter systems responsible for the occurrence of dopaminergic drug therapy side effects (e.g. dyskinesias) in parkinson's disease animals or individuals suffering from parkinson's disease is the dopaminergic system itself. For example, D1, D2, and D3 receptor agonists all cause dyskinesias, suggesting that multiple receptor subtypes are involved. This shows an imbalance in the activity of the two striatal export pathways for dyskinesias, which may be through activation of the D1 receptor and inhibition of the D2 receptor on the direct and indirect pathways, respectively, and the D3 receptor may exert a modulatory effect. Although it is clear that dopamine receptor stimulation is required, the D1, D2 and D3 receptors themselves do not have consistent changes in dyskinesia. Without being bound to any theory, this finding most likely suggests that: the changes caused by levodopa may not occur at the receptor level but involve downstream signaling events. Recent data show that: the D1 receptor (possibly through increased G-protein coupling) plays a role in dopaminergic drug-induced dyskinesia, while the D2 receptor may be more involved in mediating the anti-parkinsonian effects of dopaminergic drugs. G-proteins are membrane-associated molecules that couple ligand-activated neurotransmitter receptors to intracellular second messenger systems. Enhanced striatal G-protein coupling stimulated by the D1 dopamine receptor in striatal tissues of monkeys with dopaminergic drug-induced dyskinesia, as compared to controls. In addition, the latest data shows: there is also an enhancement of μ -opioid receptor coupling for dopaminergic drug-induced dyskinesia, another measure associated with activation of the D1 direct dopaminergic pathway. Increases were also confirmed in cyclin-dependent kinase 5(Cdk5) and dopamine cAMP regulated phosphoprotein (DARPP-32), an important site for signaling integration in the striatum. Downregulation of the striatal D1 receptor/NMDA receptor complex has also been observed for the development of dyskinesias. Without being bound to any theory, the ability of nicotine to reduce dopaminergic drug-induced dyskinesia may be associated with the normalization of dysregulations between striatal output pathways and the regulation of signaling mechanisms.

In addition to changes in molecular markers associated with the activation of the D1 direct dopaminergic pathway, the development of dopaminergic drug-induced dyskinesia is also associated with altered cellular function. Electrophysiological studies in vivo and in vitro have been used to investigate the function of the basal ganglia in animals under normal conditions and with nigrostriatal lesions. This method offers the advantages of: it enables changes in synaptic function and neuronal excitability to be measured, which are not easily detectable using biochemical techniques. One in vitro formulation that has proven particularly useful for studying the cellular mechanisms of dopaminergic drug-induced dyskinesia changes is a cortico-striatal slice from rat brain. Brain slices at the level of the pallidous have been widely used because they integrate many of the structures present in the basal ganglia motor circuit. This involves corticotlutamatergic inputs that densely stimulate striatal mediator spiny gabaergic neurons and are a determinant of neuronal activity of striatal projection neurons. Synaptic plasticity (defined as a persistent change in synaptic transmission potency) has been identified in long-term potentiation (LTP), long-term inhibition (LTD), and de-potentiation in cortical striatal slices in vitro. High Frequency Stimulation (HFS) of glutamatergic cortical striatal afferent fibers in sections from non-injured rats can cause LTD and LTP in striatal media spiny neurons, most likely due to release of striatal glutamate which triggers dopamine release. Stimulation of the D1 and D2 receptors is required for induction of LTD, and these two receptor subtypes play opposite roles in LTP. This plasticity of the corticobasal synapses is sensitive to dopamine exposure and nigrostriatal damage with damage resulting in loss of plasticity. Furthermore, it has been shown that: the plasticity of the chronic L-dopa is regulated. It has been found that: l-dopa treatment can restore LTP in rats with or without dyskinesia, but the response (de-potentiation) caused by Low Frequency Stimulation (LFS) is definitively lost in dyskinetic rats. Furthermore, it has been found that: exogenous dopamine causes mild LTP in the corticospinal sections from L-dopa treated dyskinetic animals, but LTD in sections from non-dyskinetic animals. Without being bound by any theory, these data suggest: dopamine-mediated activity-dependent synaptic enhancement may be altered in dyskinetic animals as compared to non-dyskinetic animals. Thus, the accumulated evidence suggests that: abnormal plasticity of cortical striatal synapses may be involved in the development of dopaminergic drug-induced dyskinesia.

Interestingly, these inventors have recently discovered that: nicotine treatment modulates synaptic plasticity in corticobasal sections from non-human primates. In particular, it restores long-term inhibition (LTD) that was lost as a result of nigrostriatal damage. Without being bound to any theory, it is likely that nicotine modulates synaptic plasticity and also promotes functional recovery in animals with dopaminergic drug-induced dyskinesia, and that this mechanism underlies its anti-dyskinesia effects.

Nicotine-like receptor modulators

In one aspect, the invention provides compositions and methods for utilizing nicotinic receptor modulators, e.g., to reduce or eliminate side effects associated with dopaminergic drug treatment. The modulator may be any suitable modulator.

In certain embodiments, the nicotinic receptor modulator modulates a nicotinic receptor in the brain. In certain embodiments, the nicotinic receptor modulator modulates a nicotinic receptor in the striatum or substantia nigra. In certain embodiments, the nicotinic receptor modulator modulates a nicotinic receptor comprising at least one alpha subunit or a nicotinic receptor comprising at least one alpha subunit and at least one beta subunit. In certain embodiments, the alpha subunit is selected from 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 beta 2, beta 3, and beta 4. In certain embodiments, the nicotinic receptor modulator modulates a nicotinic receptor comprising a subunit selected from the group consisting of α 4 β 2, α 6 β 2, α 4 α 5 β 2, α 4 α 6 β 2 β 3, and α 4 α 2 β 2. In certain 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.

In certain embodiments, modulators useful in the present invention are nicotinic receptor antagonists. The term "antagonist" as used herein refers to a molecule that has the ability to inhibit a biological function of a polypeptide of interest. Thus, the term "antagonist" is defined in the context of the biological effect of the polypeptide of interest. Although the preferred antagonists herein specifically interact with (e.g., bind to) the target, molecules that inhibit the biological activity of the target polypeptide by interacting with other members of the signaling pathway in which the target polypeptide is a member are also specifically included in this definition. Antagonists as defined herein include, but are not limited to, antibodies, antibody derivatives, antibody fragments and immunoglobulin variants, peptides, peptidomimetics, simple or complex organic or inorganic molecules, antisense molecules, decoy oligonucleotides, proteins, oligonucleotides, vitamin derivatives, carbohydrates and toxins.

In certain embodiments, modulators useful in the present invention are nicotinic receptor agonists. The term "agonist" as used herein refers to a molecule that has the ability to elicit or enhance a biological function of a polypeptide of interest. Thus, the term "agonist" is defined in the context of the biological effect of the polypeptide of interest. Although preferred agonists herein specifically interact with (e.g., bind to) a target, molecules that enhance the biological activity of a target polypeptide by interacting with other members of a signaling pathway in which the target polypeptide is a member are also specifically included in this definition. Agonists as defined herein include, but are not limited to, antibodies, antibody derivatives, antibody fragments and immunoglobulin variants, peptides, peptidomimetics, simple or complex organic or inorganic molecules, antisense molecules, decoy oligonucleotides, proteins, oligonucleotides, vitamin derivatives, carbohydrates and toxins.

The nicotinic receptor agonists of the present invention may be any ligand that binds to and activates a nicotinic receptor, thereby eliciting a biological response. The ability of a given substance to act as a nicotinic receptor agonist can be determined using standard in vitro binding assays and/or standard in vivo functional tests.

Nicotinic receptor agonists for use in the present invention include those described in, for example, WO 92/21339(Abbott), WO 94/08992(Abbott), WO 96/40682(Abbott), WO97/46554(Abbott), WO 99/03859(AstraZeneca), WO 96/15123(SalkInstitute), WO 97/19059(Sibia), WO 00/10997(Ortho-McNeil), WO00/44755(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), WO 8211056/11073 (Nevos 8653), Nevos 868427 (Nevos 8653), and Novos 8653 (Novos 8653), Those described in WO 98/54152 (neoseal), WO 98/54189 (neoseal), WO 99/21834 (neoseal), WO 99/24422 (neoseal), WO 00/32600 (neoseal), WO PCT/DK00/00211 (neoseal), WO PCT/DK00/00202 (neoseal), or their exotic equivalents.

Examples of nicotinic receptor agonists according to the invention include nicotine, ethylnicotine, 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-azatbutylmethoxy ] -2-chloro-pyridine (ABT-594), 3-PMP or 3- (1-pyrrolidinyl-methyl) pyridine (rjreynolds), (3E) -N-methyl-4- (3-pyridyl) -3-buten-1-amine (RJR-2403), quinuclidine or 3, 4,5, 6-tetrahydro-2, 3' -bipyridine (rjreynolds), 5-fluoronicotine or (S) -5-fluoro-3- (1-methyl-2-pyrrolidinyl) pyridine (rjreynolds), MCC or 2- (dimethylamino) ethylmethylcarbamate (Lundbeck), ethylamphetazone (arecoline) or 1- (1, 2, 5, 6-tetrahydro-1-methyl-3-pyridinyl) -1-propanone (Lilly) or isoarecoline (isoarecoline) or 1- (1, 2, 3, 6-tetrahydro-1-methyl-4-pyridinyl) ethanone (Lilly), AR-R17779 (AstraZeneca), epibatidine, GTS-21, 1- (6-chloro-3-pyridinyl) -homopiperazine, 1- (3-pyridinyl) 15-homopiperazine, 1- (5-ethynyl-3-pyridinyl-homopiperazine, conotoxin MII, epibatidine, A-85380, cytisine, belulin or salts thereof, Free base, racemate or enantiomer.

Other nicotinic receptor agonists include cholinesterase inhibitors (e.g., increasing local concentrations of acetylcholine), specific binding to nicotinic receptor type neurons (reduced binding to muscarinic receptors), and epibatidine derivatives with reduced adverse side effects (e.g., epidoxine, ABT-154, ABT418, ABT-594; abbott Laboratories (Damaj et al (1998) J. Pharmacol exp. Ther.284: 105865, describes several analogs of epibatidine that have the same potency as epibatidine but are highly specific for nicotinic receptor type neurons.) additional nicotinic receptor agonists of interest include, but are not necessarily limited to, N-methylcarbamoyl esters of choline and N-methylthiocarbamoyl (methythi-O-carbamyl) esters (e.g., trimethylaminoethanol) (Abood et al (1988) Pharmacol. biochem. Behav.30: 4038), acetylcholine (an endogenous ligand for nicotinic receptor), and the like.

In certain embodiments, the nicotinic receptor agonist is nicotine (which is understood to include nicotine derivatives and similar compounds). The chemical name of nicotine is S-3- (1-methyl-2-pyrrolidinyl) pyridine. It has a chemical composition formula of C₁₀H₁₄N₂And its structural formula is:

nicotine can be isolated and purified from nature or synthetically prepared in any manner. The term "nicotine" is also intended to include 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 (saccharate), benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, camphorate (camphorate), and pamoate. Nicotine is a colorless to yellowish white, strongly basic, oily, volatile, hygroscopic liquid with a molecular weight of 162.23.

Unless otherwise specifically stated, the term "nicotine" further includes any pharmacologically acceptable nicotine derivative or metabolite that exhibits similar drug therapeutic properties as nicotine. These derivatives, metabolites, and derivatives of metabolites are known in the art and include, but are not necessarily limited to cotinine (cotinine), norcotinine, nornicotine, nicotine N-oxide, cotinine N-oxide, 3-hydroxyccotinine, and 5-hydroxyccotinine, or pharmaceutically acceptable salts thereof. Many useful derivatives of nicotine are disclosed in the Physician's desk reference (latest edition) and Harrison's Principles of Internal Medicine. Methods for preparing nicotine derivatives and analogs are well known in the art. See, for example, U.S. patent nos. 4,590,278, 4,321,387, 4,452,984, 4,442,292, and 4,332,945.

The compounds of the present invention may contain asymmetric carbon atoms. All isomers, including stereoisomeric mixtures such as racemic mixtures and pure enantiomers, are considered part of the present invention.

Without being bound to any one theory, one mechanism of action may be: after prolonged exposure to nicotinic receptor agonists, the nicotinic receptor becomes desensitized and the nicotinic receptor agonist begins to act like a nicotinic receptor antagonist. In certain embodiments, the nicotinic receptor agonist acts as an antagonist to reduce or eliminate side effects caused by the majority of the aminergic drugs.

In certain embodiments, the present invention provides compositions for administering nicotine to an animal. In certain embodiments, the present invention provides compositions for administering nicotine to an animal (e.g., for oral administration of nicotine) to reduce the side effects of dopaminergic agents, comprising 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 certain embodiments, the present invention provides a composition for oral administration of nicotine comprising 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 certain embodiments, the present invention provides compositions comprising from about 1% to about 100% nicotine, or from about 10% to about 100% nicotine, or from about 20% to about 100% nicotine, or from about 50% to about 100% nicotine, or from about 80% to about 100% nicotine, or from about 90% to about 100% nicotine, or from about 95% to about 100% nicotine, or from about 99% to about 100% nicotine. In certain embodiments, the present invention provides compositions comprising from about 1% to about 90% nicotine, or from about 10% to about 90% nicotine, or from about 20% to about 90% nicotine, or from about 50% to about 90% nicotine, or from about 80% to about 90% nicotine. In certain embodiments, the present invention provides compositions comprising from about 1% to about 75% nicotine, or from about 10% to about 75% nicotine, or from about 20% to about 75% nicotine, or from about 50% to about 75% nicotine. In certain embodiments, the present invention provides compositions comprising from about 1% to about 50% nicotine, or from about 10% to about 50% nicotine, or from about 20% to about 50% nicotine, or from about 30% to about 50% nicotine, or from about 40% to about 50% nicotine. In certain embodiments, the present invention provides compositions comprising from about 1% to about 40% nicotine, or from about 10% to about 40% nicotine, or from about 20% to about 40% nicotine, or from about 30% to about 40% nicotine. In certain embodiments, the present invention provides compositions comprising from about 1% to about 30% nicotine, or from about 10% to about 30% nicotine, or from about 20% to about 30% nicotine. In certain embodiments, the present invention provides compositions comprising from about 1% to about 20% nicotine, or from about 10% to about 20% nicotine. In certain embodiments, the present invention provides compositions comprising about 1-10% nicotine. In certain embodiments, the present invention provides compositions comprising about 1, 2, 5, 10, 20, 30, 40, 50, 60, 70, 80, 90, 95, 96, 97, 98, or 99% nicotine.

In certain of these embodiments, a pharmaceutically acceptable excipient is also included.

Dopaminergic medicine

In one aspect, the present invention provides compositions and methods for reducing or eliminating the effects of dopaminergic agents. In certain embodiments, the compositions and methods maintain or enhance a desired effect of the dopaminergic agent, e.g., an anti-parkinsonian effect. The methods and compositions of the present invention are applicable to any dopaminergic agent for which it is desirable to reduce one or more side effects. In certain embodiments, the compositions and methods of the present invention utilize a dopamine precursor. In certain embodiments, the compositions and methods of the invention utilize dopamine agonists. In certain embodiments, the dopaminergic agent is levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, or a combination thereof. In certain embodiments, the dopaminergic agent is levodopa. In certain embodiments, the compositions and methods of the present invention utilize one or more agents used in the art in combination with dopamine drug therapy to achieve a therapeutic effect. For example, in one exemplary embodiment, the compositions and methods of the present invention utilize levodopa in combination with a drug that blocks the conversion of levodopa to dopamine in the blood (e.g., carbidopa). In another exemplary embodiment, the compositions and methods of the present invention utilize levodopa in combination with a COMT inhibitor (e.g., entacapone). In another exemplary embodiment, the compositions and methods of the present invention utilize levodopa in combination with a type B monoamine oxidase (MAO-B) inhibitor (e.g., selegiline). In yet another exemplary embodiment, the compositions and methods of the present invention utilize levodopa in combination with amantadine.

Levodopa

Levodopa (aromatic amino acid) is a white, crystalline compound, slightly soluble in water, with a molecular weight of 197.2. The chemical name is (-) -L-a-amino-b- (3, 4-dihydroxy benzene) propionic acid. It has a chemical composition formula of C₉H₁₁NO₄And its structural formula is:

levodopa is used for treating Parkinson disease. Parkinson's disease is a progressive neurodegenerative disease of the extrapyramidal nervous system that affects the movement and control of the skeletal muscular system. Its characteristic features include resting tremor (rest tremor), rigidity and slowness of movement.

Current evidence suggests that: symptoms of parkinson's disease are associated with depletion of dopamine in the striatum. Dopamine administration is clearly ineffective in the treatment of parkinson's disease because it cannot cross the blood brain barrier. However, levodopa (a metabolic precursor of dopamine) does cross the blood brain barrier and is likely to be converted to dopamine in the brain. This is believed to be the mechanism by which levodopa reduces the symptoms of parkinson's disease.

However, although initially very effective, long-term treatment with levodopa causes a number of complications. Levodopa treatment can cause nausea, vomiting, involuntary movements (e.g., dyskinesias), psychotic disorders, depression, syncope, and hallucinations. The exact pathophysiological mechanism of the side effects of levodopa is still a mystery, but is thought to be due to an increase in dopamine in the brain following levodopa administration.

Previous work has shown that: levodopa-induced dyskinesia (LID) arises due to the enhancement of intermittent stimulation by D1, D2 and/or other dopamine receptor subtypes. This causes an imbalance in the activity of the two major striatal export pathways, possibly through activation of the D1 receptor and inhibition of the D2 receptor on the direct and indirect dopaminergic pathways, respectively, although there is some overlap between striatal efferents. Recent data suggest: the D1 receptor (through increased G-protein coupling) may play a more prominent role in functional hypersensitivity associated with levodopa-induced dyskinesia, while D2 receptor activation may be more closely linked to the anti-parkinsonian effects of dopaminergic drugs.

Side effects

Major side effects of dopaminergic drugs include headache, diarrhea, hypertension, nausea, vomiting, involuntary movements (e.g., dyskinesias), psychiatric disorders, depression, syncope, hallucinations, and renal dysfunction.

The present invention provides compositions and methods utilizing nicotinic receptor modulators that reduce or eliminate side effects of dopaminergic agent therapy. In certain embodiments, the present invention provides compositions and methods utilizing nicotinic receptor modulators that reduce or eliminate movement disorders associated with dopaminergic drug therapy. Without being limited to any theory, one possibility is: nicotinic receptor modulators exert their effects by acting on nicotinic acetylcholine receptors expressed in the striatum. There is a dense cholinergic innervation in the striatum that is highly coincident with dopaminergic neurons. Under physiological conditions, these cholinergic interneurons stimulate the release of acetylcholine, which stimulates nicotinic receptors on dopaminergic nerve endings to release dopamine. Similarly, exogenously applied drugs such as nicotine cause the release of dopamine at the striatal ends.

In certain embodiments, the present invention provides compositions and methods utilizing a dopaminergic agent in combination with a nicotinic receptor modulator that reduces or eliminates side effects associated with dopaminergic agent treatment. Typically, the nicotinic receptor modulator is an agonist. In certain embodiments, the nicotinic receptor agonist modulates a nicotinic receptor comprising at least one alpha subunit or a nicotinic receptor comprising at least one alpha subunit and at least one beta subunit. In certain embodiments, the alpha subunit is selected from 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 beta 2, beta 3, and beta 4. In certain embodiments, the nicotinic receptor agonist modulates a nicotinic receptor composed of subunits selected from the group consisting of α 4 β 2, α 6 β 2, α 4 α 5 β 2, α 4 α 6 β 2 β 3, and α 4 α 2 β 2. In certain 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.

In certain embodiments, the dopaminergic agent comprises a dopamine precursor and a dopamine receptor agonist. Examples of dopaminergic drugs include, but are not limited to, levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, or combinations thereof.

The nicotinic receptor modulator which causes a reduction in side effects of dopaminergic agents may be an agonist or an antagonist of a protein. The modulating effect may be dose-dependent, e.g., certain modulators act as agonists in one dose range and as antagonists in another dose range. In certain embodiments, the modulator of a nicotinic receptor is used at a dosage where it acts primarily as an agonist.

Typically, use of the nicotinic receptor modulator (e.g., agonist) results in a reduction in one or more side effects of the dopaminergic agent. The efficacy of dopaminergic agents may be reduced, maintained or enhanced; however, in a preferred embodiment, if the therapeutic effect is reduced, it is not reduced to the same extent as the side effects. It can be understood that: a given dopaminergic agent may have more than one therapeutic effect and/or one or more side effects, and may be: the treatment ratio (in this case, the ratio of the change in the desired effect to the change in the undesired effect) may be different depending on the measured effect. However, at least one therapeutic effect of the dopaminergic agent is reduced to a lesser extent than at least one side effect of the dopaminergic agent.

Furthermore, in certain embodiments, by using a nicotinic receptor modulator in combination, one or more of the therapeutic effects of the dopaminergic agent is enhanced, while one or more side effects of the dopaminergic agent is reduced or substantially eliminated. For example, in certain embodiments, the anti-parkinsonian effect of a dopaminergic agent is increased while one or more side effects of the dopaminergic agent are reduced or substantially eliminated.

Thus, in certain embodiments, the present invention provides a composition comprising a dopaminergic agent and a nicotinic receptor modulator, wherein, when the composition is administered to an animal, 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 a side effect of the dopaminergic agent as compared to a side effect in the absence of the nicotinic receptor modulator.

In certain embodiments, the compositions of the present invention comprise one or more dopaminergic agents and one or more nicotinic receptor modulators. One or more dopaminergic agents may have one or more side effects that it is desirable to reduce. In certain embodiments, the compositions of the present invention comprise one or more drugs, one or more dopaminergic drugs, and one or more nicotinic receptor modulators. The one or more drugs are those used in the art in combination with dopaminergic drug therapy to achieve a therapeutic effect and/or to reduce side effects. In certain embodiments, the compositions of the present invention include a drug, such as carbidopa, that blocks the conversion of levodopa to dopamine in the blood. In certain embodiments, the compositions of the present invention comprise a COMT inhibitor, such as entacapone. In certain embodiments, the compositions of the present invention comprise a type B monoamine oxidase (MAO-B) inhibitor, such as selegiline. In certain embodiments, the compositions of the present invention comprise amantadine.

The compositions of the present invention may be prepared in any suitable form for administration to an animal. In certain embodiments, the present invention provides pharmaceutical compositions.

In certain embodiments, the present invention provides compositions suitable for oral administration. In certain embodiments, the composition is suitable for transdermal administration. In certain embodiments, the composition is suitable for injection by any standard injection route (e.g., intravenous, subcutaneous, intramuscular, or intraperitoneal). Compositions suitable for other routes of administration (e.g., inhalation), as described herein, are also encompassed by the present invention.

In certain embodiments, the invention provides methods of reducing the side effects of a dopaminergic agent in an animal (e.g., a human) that has received an amount of a dopaminergic agent that produces side effects by administering to the animal (e.g., a human) a nicotinic receptor modulator in an amount sufficient to reduce or eliminate the side effects of the dopaminergic agent.

The side effects may be acute or chronic. The effect may be biochemical, cellular, tissue-level, organ-level, multi-organ-level, or whole biological level. The effect may be displayed in one or more objective or subjective ways, any of which may be used to measure the effect. If the effect (e.g., movement disorder, etc.) is measured objectively or subjectively, any suitable method of evaluating the subjective or objective effect may be used. Examples include visual and numerical ratings for evaluation by individuals. Further examples include standard tests for measuring sleep latency for drowsiness, or for measuring attention, mental state, memory, etc. These and other methods of objectively and subjectively evaluating side effects by objective observers, individuals, or both are well known in the art.

The term "therapeutic effect" as used herein includes therapeutic benefit and/or prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying disease requiring treatment. Likewise, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, whereby an improvement in the patient is observed, although the patient may still suffer from the underlying disease. With respect to prophylactic benefits, the compositions can be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though diagnosis of the disease may not have been completed. A prophylactic effect includes delaying or eliminating the appearance of a disease or disorder, delaying or eliminating the onset of symptoms of a disease or disorder, slowing, halting, or reversing the progression of a disease or disorder, or any combination thereof.

Composition comprising a metal oxide and a metal oxide

In one aspect, the invention provides compositions comprising nicotinic receptor modulators that, for example, reduce or eliminate the side effects of one or more dopaminergic agents. In certain embodiments, the dopaminergic agent is co-administered with the nicotinic receptor modulator. As used herein, "co-administration," "combined administration," or grammatical equivalents thereof includes administration of two or more drugs to an animal such that the drugs 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 drugs are present.

In certain embodiments, the present invention provides compositions comprising nicotinic receptor modulators. In a further embodiment, the present invention provides a pharmaceutical composition further comprising a pharmaceutically acceptable excipient.

In certain embodiments, the invention encompasses pharmaceutical compositions wherein the nicotinic receptor modulator is present in an amount sufficient to reduce the side effects of the dopaminergic agent when the composition is administered to an animal. In certain embodiments, the invention includes a pharmaceutical composition wherein the nicotinic receptor modulator is present in an amount sufficient to reduce the side effects of the dopaminergic agent and prevent addiction to the nicotinic receptor modulator when the composition is administered to an animal. For example, the pharmaceutical compositions comprising nicotinic receptor modulators are administered by a variety of different delivery routes as further described herein.

In one embodiment, the pharmaceutical composition comprising a nicotinic receptor modulator is administered orally to an animal. In various embodiments, the present invention provides solid pharmaceutical compositions for oral administration comprising an effective amount of a nicotinic receptor modulator and a pharmaceutically acceptable excipient suitable for oral administration; or a liquid pharmaceutical composition for oral administration comprising an effective amount of a nicotinic receptor modulator and a pharmaceutically acceptable excipient suitable for oral administration.

In certain embodiments, the pharmaceutical composition is suitable for transdermal administration.

In certain embodiments, the present invention provides a composition comprising a nicotinic receptor modulator, wherein the nicotinic receptor modulator is present in an amount sufficient to reduce the side effect of the dopaminergic agent in a measurable amount, when the composition is administered to an animal, as compared to the side effect in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced 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 95% or more as compared to side effects in the absence of a nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 5% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 10% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 15% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 20% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 30% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects are substantially eliminated as compared to the side effects in the absence of the nicotinic receptor modulator. As used herein, "substantially eliminates" when a nicotinic receptor modulator is administered includes non-measurable or non-statistically significant side effects (one or more side effects) of the dopaminergic agent.

In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine), wherein the nicotinic receptor agonist (e.g., nicotine) is present in an amount sufficient to reduce the side effects of the dopaminergic agent in a measurable amount when the composition is administered to an animal as compared to the side effects in the absence of the nicotinic receptor agonist (e.g., nicotine). The measurable amount may be on average at least about 5%, 10%, 15%, 20%, 30%, or 30% or more as described herein. The side effect may be any side effect described herein. In certain embodiments, the side effect is dyskinesia.

In exemplary embodiments, the present invention provides compositions comprising nicotine in an amount effective to reduce the side effects of dopaminergic agents in a measurable amount (e.g., on average at least about 5, 10, 15, 20, 30, or 30% or more as described herein). In certain exemplary embodiments, the present invention provides compositions comprising nicotine wherein the nicotine is present in an amount effective to reduce the side effects of the dopaminergic agent in a measurable amount (e.g., an average of at least about 5, 10, 15, 20, or 20% or more as described herein) and to increase the efficacy of the dopaminergic agent in a measurable amount (e.g., an average of at least about 5, 10, 15, 20, 30, or 30% or more as described herein). In certain embodiments, the present invention provides compositions comprising nicotine wherein the nicotine is present in an amount effective to reduce dopaminergic drug side effects in measurable amounts (e.g., on average at least about 5, 10, 15, 20, 30, or 30% or more as described herein) and prevent nicotine addiction. In certain exemplary embodiments, the present invention provides compositions comprising nicotine wherein the nicotine is present in an amount effective to reduce dopaminergic agent side effects in a measurable amount (e.g., an average of at least about 5, 10, 15, 20, 30, or 30% or more as described herein) and to increase dopaminergic agent efficacy in a measurable amount (e.g., an average of at least about 5, 10, 15, 20, 30, or 30% or more as described herein) and to prevent nicotine addiction. The side effect may be any side effect described herein. In certain embodiments, the side effect is dyskinesia.

In certain embodiments, the present invention provides compositions comprising a combination of a dopaminergic agent and a nicotinic receptor modulator that reduces or eliminates a side effect of the dopaminergic agent. In certain embodiments, the present invention provides compositions comprising a combination of a dopaminergic agent and a nicotinic receptor modulator that reduces or eliminates a side effect of the dopaminergic agent, wherein the nicotinic receptor modulator is present in an amount that prevents addiction to the nicotinic receptor modulator. In certain embodiments, the present invention provides a pharmaceutical composition further comprising a pharmaceutically acceptable excipient. In certain embodiments, the pharmaceutical composition is suitable for oral administration. In certain embodiments, the pharmaceutical composition is suitable for transdermal administration. In certain embodiments, the pharmaceutical composition is suitable for injection. Other forms of administration are also compatible with embodiments of the pharmaceutical compositions of the present invention, as described herein.

In certain embodiments, the nicotinic receptor modulator comprises an agonist or an antagonist, as described herein. In certain embodiments, upon prolonged exposure to an agonist, the nicotinic receptor becomes desensitized and the nicotinic receptor agonists described herein function as antagonists.

In certain embodiments, the reduced dopaminergic drug side effects are selected from involuntary movements (e.g., movement disorders), mental disorders, depression, syncope, or hallucinations or combinations thereof. In certain embodiments, the reduced dopaminergic drug side effect is dyskinesia.

In certain embodiments, the dopaminergic agent is a dopamine precursor or a dopamine receptor agonist. Examples of dopaminergic drugs include, but are not limited to, levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinirole, apomorphine, or combinations thereof.

In certain embodiments, the compositions of the present invention comprise one or more drugs, one or more dopaminergic drugs, and one or more nicotinic receptor modulators. The one or more agents are agents used in the art for achieving therapeutic efficacy and/or reducing side effects in combination with dopaminergic agent therapy. In certain embodiments, the compositions of the invention comprise a drug, such as carbidopa, that blocks the conversion of levodopa to dopamine in the blood. In certain embodiments, the compositions of the present invention comprise a COMT inhibitor, such as entacapone. In certain embodiments, the compositions of the present invention comprise a type B monoamine oxidase (MAO-B) inhibitor, such as selegiline. In certain embodiments, the compositions of the present invention comprise amantadine.

In certain embodiments, the present invention provides a composition comprising a dopaminergic agent and a nicotinic receptor modulator, wherein the dopaminergic agent is present in an amount sufficient to exert a therapeutic effect when the composition is administered to an animal, and the nicotinic receptor modulator is present in an amount sufficient to reduce a side effect of the dopaminergic agent in a measurable amount as compared to a side effect in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced 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 95% or more as compared to side effects in the absence of a nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 5% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 10% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 15% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 20% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects of the dopaminergic agent are reduced by an average of at least about 30% as compared to side effects in the absence of the nicotinic receptor modulator. In certain embodiments, the side effects are substantially eliminated as compared to the side effects in the absence of the nicotinic receptor modulator. As used herein, "substantially eliminates" includes non-measurable or statistically insignificant side effects (one or more side effects) of a dopaminergic agent when administered with a nicotinic receptor modulator.

Thus, in certain embodiments, the present invention provides a composition comprising a nicotinic receptor agonist (e.g., nicotine) and a dopaminergic agent, wherein, when the composition is administered to an animal, the dopaminergic agent is present in an amount sufficient to exert a therapeutic effect and the nicotinic receptor agonist (e.g., nicotine) is present in an amount sufficient to reduce a side effect of the dopaminergic agent in a measurable amount as compared to a side effect in the absence of the nicotinic receptor agonist (e.g., nicotine). The measurable amount may be on average at least about 5%, 10%, 15%, 20%, 30%, or 30% or more as described herein. The side effect may be any side effect described herein. In certain embodiments, the side effect is dyskinesia.

In certain embodiments, the invention provides a composition comprising a nicotinic receptor agonist (which is nicotine) and a dopaminergic agent (which is levodopa), wherein when the composition is administered to an animal, the levodopa is present in an amount sufficient to exert a therapeutic effect and the nicotine is present in an amount sufficient to reduce a side effect of the levodopa in a measurable amount as compared to a side effect in the absence of nicotine. The measurable amount may be on average at least about 5%, 10%, 15%, 20%, 30%, or 30% or more as described herein. The side effect may be any side effect described herein. In certain embodiments, the side effect is dyskinesia.

In certain embodiments, the nicotinic receptor modulator is present in an amount sufficient to reduce the side effects of the dopaminergic agent in a measurable amount and increase the efficacy of the dopaminergic agent in a measurable amount, when the composition is administered to an animal, as compared to the side effects and the efficacy in the absence of the nicotinic receptor modulator. In certain embodiments, the 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 95% or more as compared to the therapeutic effect in the absence of the nicotinic receptor modulator. In certain embodiments, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 5% as compared to the therapeutic effect in the absence of a nicotinic receptor modulator. In certain embodiments, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 10% as compared to the therapeutic effect in the absence of a nicotinic receptor modulator. In certain embodiments, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 15% as compared to the therapeutic effect in the absence of the nicotinic receptor modulator. In certain embodiments, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 20% as compared to the therapeutic effect in the absence of the nicotinic receptor modulator. In certain embodiments, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 30% as compared to the therapeutic effect in the absence of the nicotinic receptor modulator. In certain embodiments, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 40% as compared to the therapeutic effect in the absence of the nicotinic receptor modulator. In certain embodiments, the therapeutic effect of the dopaminergic agent is increased by an average of at least about 50% as compared to the therapeutic effect in the absence of the nicotinic receptor modulator.

Thus, in certain embodiments, the present invention provides compositions comprising a nicotinic receptor modulator, which when administered to an animal in combination with a dopaminergic agent, is present in an amount sufficient to reduce an average of at least about 5% of the side effects of the dopaminergic agent and increase an average of at least about 5% of the therapeutic effects of the dopaminergic agent as compared to the side effects and the therapeutic effects in the absence of the nicotinic receptor modulator. In certain embodiments, the present invention provides compositions comprising a nicotinic receptor modulator present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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 as compared to the side effects and efficacy in the absence of the nicotinic receptor modulator. In certain embodiments, the present invention provides compositions comprising a nicotinic receptor modulator present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 20% and increase the efficacy 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, as compared to the side effects and efficacy when the nicotinic receptor modulator is not used. In certain embodiments, the present invention provides compositions comprising a nicotinic receptor modulator present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy when the nicotinic receptor modulator is not used. In certain embodiments, the present invention provides compositions comprising a nicotinic receptor modulator present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy when the nicotinic receptor modulator is not used. In certain embodiments, the present invention provides compositions comprising a nicotinic receptor modulator present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy when the nicotinic receptor modulator is not used. In certain embodiments, the present invention provides compositions comprising a nicotinic receptor modulator present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy when the nicotinic receptor modulator is not used.

In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine) present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 5% and increase the efficacy 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 as compared to the side effects and efficacy in the absence of the nicotinic receptor agonist (e.g., nicotine). In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine) present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy of the dopaminergic agent when administered in the absence of the nicotinic receptor agonist (e.g., nicotine). In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine) present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 20% and increase the efficacy 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, as compared to the side effects and efficacy of the dopaminergic agent when administered in the absence of the nicotinic receptor agonist (e.g., nicotine). In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine) present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy of the dopaminergic agent when administered in the absence of the nicotinic receptor agonist (e.g., nicotine). In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine) present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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 as compared to the side effects and efficacy of the dopaminergic agent when administered in the absence of the nicotinic receptor agonist (e.g., nicotine). In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine) present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy of the dopaminergic agent when administered in the absence of the nicotinic receptor agonist (e.g., nicotine). In certain embodiments, the present invention provides compositions comprising a nicotinic receptor agonist (e.g., nicotine) present in an amount sufficient to reduce the side effects of a dopaminergic agent by an average of at least about 10% and increase the efficacy 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, as compared to the side effects and efficacy of the dopaminergic agent when administered in the absence of the nicotinic receptor agonist (e.g., nicotine).

In an exemplary embodiment, the invention provides a composition comprising nicotine and a dopaminergic agent (e.g., levodopa or a dopamine agonist), wherein the dopaminergic agent is present in an amount sufficient to exert a therapeutic effect and the nicotine is present in an amount effective to reduce a measurable amount of a side effect of the dopaminergic agent (e.g., an average of at least about 5, 10, 15, 20, 30, or 30% or more as described herein) and to increase a measurable amount of a therapeutic effect of the dopaminergic agent (e.g., an average of at least about 5, 10, 15, 20, 30, or 30% or more as described herein). The side effect may be any side effect described herein. In certain embodiments, the side effect is dyskinesia.

As used herein, "average" is preferably calculated over a group of normal human subjects, which group is 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.

In certain embodiments, the present invention provides compositions comprising a dopaminergic agent and a nicotinic receptor modulator (e.g., an agonist, such as nicotine). In certain embodiments, the concentration of one or more dopaminergic agents and/or nicotinic receptor modulators (e.g., agonists, such as 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%, 0.0003%, 0.0002.0003%, 0.0001% w/v/w%.

In certain embodiments, the concentration of one or more dopaminergic agents and/or nicotinic receptor modulators (e.g., agonists, such as nicotine) is greater than 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%, 19.75%, 19.50%, 19.25%, 19%, 18.75%, 18.50%, 18%, 17.75%, 17.50%, 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%, 7.25%, 7.5%, 7.75%, 6.5%, 6.75%, 5%, 6.75%, 7.25%, 6.25%, 7.25%, 6.25%, 6%, 7.25, 4.25%, 4%, 3.75%, 3.50%, 3.25%, 3%, 2.75%, 2.50%, 2.25%, 2%, 1.75%, 1.50%, 1.25%, 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.

In certain embodiments, the concentration of one or more dopaminergic agents and/or nicotinic receptor modulators (e.g., agonists, such as nicotine) is from about 0.0001% to about 50%, from about 0.001% to about 40%, from about 0.01% to about 30%, from about 0.02% to about 29%, from about 0.03% to about 28%, from about 0.04% to about 27%, from about 0.05% to about 26%, from about 0.06% to about 25%, from about 0.07% to about 24%, from about 0.08% to about 23%, from about 0.09% to about 22%, from about 0.1% to about 21%, from about 0.2% to about 20%, from about 0.3% to about 19%, from about 0.4% to about 18%, from about 0.5% to about 17%, from about 0.6% to about 16%, from about 0.7% to about 15%, from about 0.8% to about 14%, from about 0.9% to about 12%, from about 1% to about 10% w/w, w/v, or v/v.

In certain embodiments, the concentration of one or more dopaminergic agents and/or nicotinic receptor modulators (e.g., agonists, such as nicotine) is from about 0.001% to about 10%, from about 0.01% to about 5%, from about 0.02% to about 4.5%, from about 0.03% to about 4%, from about 0.04% to about 3.5%, from about 0.05% to about 3%, from about 0.06% to about 2.5%, from about 0.07% to about 2%, from about 0.08% to about 1.5%, from about 0.09% to about 1%, from about 0.1% to about 0.9% w/w, w/v, or v/v.

In certain embodiments, the amount of one or more dopaminergic agents and/or nicotinic receptor modulators (e.g., agonists, such as nicotine) is equal to or less than 10g, 9.5g, 9.0g, 8.5g, 8.0g, 7.5g, 7.0g, 6.5g, 6.0g, 5.5g, 5.0g, 4.5g, 4.0g, 3.5g, 3.0g, 2.5g, 2.0g, 1.5g, 1.0g, 0.95g, 0.9g, 0.85g, 0.8g, 0.75g, 0.7g, 0.65g, 0.6g, 0.55g, 0.5g, 0.45g, 0.4g, 0.35g, 0.3g, 0.25g, 0.2g, 0.15g, 0.008g, 0.04g, 0.06g, 0.0.0.0.7 g, 0.7g, 0.6g, 0.8g, 0.06g, 0.3g, 0.06g, 0.3g, 0.7g, 0.06g, 0.7g, 0.06.

In certain embodiments, the amount of one or more dopaminergic agents and/or nicotinic receptor modulators (e.g., agonist, such as nicotine) exceeds 0.0001g, 0.0002g, 0.0003g, 0.0004g, 0.0005g, 0.0006g, 0.0007g, 0.0008g, 0.0009g, 0.001g, 0.0015g, 0.002g, 0.0025g, 0.003g, 0.0035g, 0.004g, 0.0045g, 0.005g, 0.0055g, 0.006g, 0.0065g, 0.007g, 0.0075g, 0.008g, 0.0085g, 0.009g, 0.0095g, 0.01g, 0.02g, 0.025g, 0.03g, 0.065g, 0.04g, 0.005g, 0.85g, 0.009g, 0.95g, 0.05g, 0.15g, 0.05g, 0.7g, 0.06g, 0.7g, 0.06g, 0.6g, 0.7g, 0.6g, 0.7g, 0.06g, 0.7g, 5g, 5.5g, 6g, 6.5g, 7g, 7.5g, 8g, 8.5g, 9g, 9.5g, or 10 g.

In certain embodiments, the amount of one or more dopaminergic agents and/or nicotinic receptor modulators (e.g., agonists, such as nicotine) is 0.0001 to 10g, 0.0005 to 9g, 0.001 to 8g, 0.005 to 7g, 0.01 to 6g, 0.05 to 5g, 0.1 to 4g, 0.5 to 4g, or 1 to 3 g.

In exemplary embodiments, the compositions of the present invention comprise nicotine, wherein nicotine is present in an amount of 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 0.01mg, or about 0.1mg, or about 0.5mg, or about 1mg, or about 10mg, or about 25mg, or about 50mg, or about 100mg, or about 200mg, or about 250mg, or about 300mg, or about 400mg, or about 500mg, or about 600mg, or about 700mg, or about 800mg, or about 900mg, or about 1000 mg. In certain embodiments, the compositions of the present invention comprise nicotine, wherein nicotine is present in an amount of about 0.1-10 mg. In certain embodiments, the compositions of the present invention comprise nicotine, wherein nicotine is present in an amount of about 0.1 to about 5 mg. In certain embodiments, the compositions of the present invention comprise nicotine, wherein nicotine is present in an amount of about 0.1 to about 2.8 mg. In certain embodiments, the compositions of the present invention comprise nicotine, wherein nicotine is present in an amount of less than 3 mg. In certain embodiments, the compositions of the present invention comprise nicotine, wherein nicotine is present in an amount of about 0.5 mg.

In exemplary embodiments, the compositions of the invention comprise nicotine and levodopa, wherein nicotine is present in an amount of 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 1mg, or about 10mg, or about 25mg, or about 50mg, or about 100mg, or about 200mg, or about 250mg, or about 300mg, or about 400mg, or about 500mg, or about 600mg, or about 700mg, or about 800mg, or about 900mg, or about 1000 mg; and levodopa is present in an amount of 0.01 to 1000mg, or about 0.1 to 800mg, or about 0.1, 0.5, 1, 5, 10, 20, 50, 80, 100, 150, 200, 300, 400, or 500 mg.

In certain embodiments, nicotine/levodopa is present in an amount of about 0.1/50mg (nicotine/levodopa). In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 150 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 300 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 1000 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 150 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 300 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 1000 mg. In certain embodiments, nicotine is present in an amount of about 5mg and levodopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 5mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 5mg and levodopa is present in an amount of about 150 mg. In certain embodiments, nicotine is present in an amount of about 5mg and levodopa is present in an amount of about 500 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 50 mg.

In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 150 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg and levodopa is present in an amount of about 500 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 150 mg. In certain embodiments, nicotine is present in an amount of about 1mg and levodopa is present in an amount of about 500 mg. In certain embodiments, nicotine is present in an amount of about 7mg and levodopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 7mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 7mg and levodopa is present in an amount of about 150 mg. In certain embodiments, nicotine is present in an amount of about 7mg and levodopa is present in an amount of about 500 mg. In certain embodiments, nicotine is present in an amount of about 10mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 10mg and levodopa is present in an amount of about 200 mg. In certain embodiments, nicotine is present in an amount of about 10mg and levodopa is present in an amount of about 300 mg. In certain embodiments, nicotine is present in an amount of about 10mg and levodopa is present in an amount of about 1000 mg. In certain embodiments, nicotine is present in an amount of about 14mg and levodopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 14mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 14mg and levodopa is present in an amount of about 150 mg. In certain embodiments nicotine is present in an amount of about 14mg and levodopa is present in an amount of about 500 mg. In certain embodiments, nicotine is present in an amount of about 21mg and levodopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 21mg and levodopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 21mg and levodopa is present in an amount of about 150 mg. In certain embodiments nicotine is present in an amount of about 21mg and levodopa is present in an amount of about 500 mg. In certain embodiments, levodopa is present in an amount of 100% to about 75% of the effective amount of levodopa when administered alone.

In another exemplary embodiment, the composition of the invention comprises nicotine, levodopa, and carbidopa. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 25mg, and carbidopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 25mg, and carbidopa is present in an amount of about 250 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 12.5mg, and carbidopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 6.5mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 12.5mg, and carbidopa is present in an amount of about 125 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 6.25mg, and carbidopa is present in an amount of about 62.5 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 12.5mg, and carbidopa is present in an amount of about 125 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 100mg, and carbidopa is present in an amount of about 10 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 100mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 0.5mg, levodopa is present in an amount of about 250mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 25mg, and carbidopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 25mg, and carbidopa is present in an amount of about 250 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 12.5mg, and carbidopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 6.5mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 12.5mg, and carbidopa is present in an amount of about 125 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 6.25mg, and carbidopa is present in an amount of about 62.5 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 100mg, and carbidopa is present in an amount of about 10 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 100mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 1mg, levodopa is present in an amount of about 250mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 4mg, levodopa is present in an amount of about 25mg, and carbidopa is present in an amount of about 100 mg. In certain embodiments, nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 25mg, and carbidopa is present in an amount of about 250 mg. In certain embodiments, nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 12.5mg, and carbidopa is present in an amount of about 50 mg. In certain embodiments, nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 6.5mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 12.5mg, and carbidopa is present in an amount of about 125 mg. In certain embodiments, nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 6.25mg, and carbidopa is present in an amount of about 62.5 mg. In certain embodiments, nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 100mg, and carbidopa is present in an amount of about 10 mg. In certain embodiments nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 100mg, and carbidopa is present in an amount of about 25 mg. In certain embodiments, nicotine is present in an amount of about 7mg, levodopa is present in an amount of about 250mg, and carbidopa is present in an amount of about 25 mg.

In a liquid formulation, levodopa may be present in an amount of about 1-1000 mg/ml, or 1-500 mg/ml, or 1-200 mg/ml, or about 1, 5, 10, 20, 50, or 100mg/ml, and nicotine may be present in an amount of about 0.001-1000 mg/ml, or about 0.010-1000 mg/ml, or about 0.050-1000 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 0.001mg/ml, or about 0.025mg/ml, or about 0.050mg/ml, or about 0.1mg/ml, or about 0.2mg/ml, or about 0.25mg/ml, or about 3mg/ml, Or about 0.4mg/ml, or about 0.5mg/ml, or about 0.6mg/ml, or about 0.7mg/ml, or about 0.8mg/ml, or about 0.9mg/ml, or about 1 mg/ml. At higher concentrations of nicotine, solubility can be increased by adjusting the type of diluent. In certain embodiments, levodopa is present in an amount of 100% to about 75% of the effective amount of levodopa when administered alone.

In certain embodiments, the molar ratio of the one or more dopaminergic agents to the nicotinic receptor modulator (e.g., agonist, such as nicotine) can be from 0.0001: 1 to 1: 1. Without limiting the scope of the invention, the molar ratio of the one or more dopaminergic agents to the nicotinic receptor modulator (e.g., agonist, such as nicotine) can be from about 0.0001: 1 to about 10: 1, or from about 0.001: 1 to about 5: 1, or from about 0.01: 1 to about 5: 1, or from about 0.1: 1 to about 2: 1, or from about 0.2: 1 to about 2: 1, or from about 0.5: 1 to about 2: 1, or from about 0.1: 1 to about 1: 1. In certain embodiments, levodopa is present in an amount of 100% to about 75% of the effective amount of levodopa when administered alone.

Without limiting the scope of the invention, the molar ratio of the one or more dopaminergic agents to the nicotinic receptor agonist may be about 0.03 × 10 to 5: 1, 0.1 × 10 to 5: 1, 0.04 × 10 to 3: 1, 0.03 × 10 to 5: 1, 0.02 × 10 to 5: 1, 0.01 × 10 to 3: 1, 0.1 × 10 to 3: 1, 0.15 × 10 to 3: 1, 0.2 × 10 to 3: 1, 0.3 × 10 to 3: 1, 0.4 × 10 to 3: 1, 0.5 × 10 to 3: 1, 0.15 × 10 to 2: 1, 0.1 × 10 to 2: 1, 0.2 × 10 to 2: 1, 0.3 × 10 to 2: 1, 0.4 × 10 to 2: 1, 0.5 × 10 to 2: 1, 0.6 × 10 to 2: 1, 0.2 × 10 to 2: 1, 0.01 to 1, or 0.1 × 10 to 2: 1. In one embodiment, the dopaminergic agent is levodopa. In one embodiment, the nicotinic receptor agonist is nicotine.

Without limiting the scope of the invention, the molar ratio of the one or more dopaminergic agents to the nicotinic receptor modulator (e.g., 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.

A. Pharmaceutical composition

The nicotinic receptor modulators of the present invention are typically administered in the form of a pharmaceutical composition. The above-mentioned drugs are also administered in the form of pharmaceutical compositions. When a nicotinic receptor modulator and a drug are used in combination, the two components may be mixed into one formulation or the two components may be formulated into separate formulations to be used separately or in combination at the same time.

Accordingly, the present invention provides pharmaceutical compositions comprising a nicotinic receptor modulator or a pharmaceutically acceptable salt and/or coordination complex thereof as the active ingredient, together with one or more pharmaceutically acceptable excipients, carriers (including inert solid diluents and fillers), diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants.

The present invention further provides pharmaceutical compositions comprising as an 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 solutions and various organic solvents), penetration enhancers, solubilizers and adjuvants.

The dopaminergic agents and/or nicotinic receptor modulators can be prepared as pharmaceutical compositions in dosages (see, e.g., compositions) as described herein. These compositions are prepared in a manner well known in the pharmaceutical art.

A pharmaceutical composition for oral administration.In certain embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a nicotinic receptor modulator that reduces or eliminates side effects of a dopaminergic agent and a pharmaceutically acceptable excipient for oral administration. In certain embodiments, the present invention provides pharmaceutical compositions for oral administration comprising a combination of a dopaminergic agent and a nicotinic receptor modulator that reduces or eliminates side effects of the dopaminergic agent, and a pharmaceutically acceptable excipient suitable for oral administration. In certain embodiments, the nicotinic receptor modulator that reduces or eliminates the side effects of a dopaminergic agent is a nicotinic receptor agonist, e.g., nicotine, as described herein or elsewhere. In certain embodiments, the nicotinic receptor modulator is present in an amount that prevents addiction to the nicotinic receptor modulator.

In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) a nicotinic receptor modulator in an amount effective to reduce or eliminate one or more side effects of the dopaminergic agent; and (ii) a pharmaceutically acceptable excipient suitable for oral administration. In certain embodiments, the nicotinic receptor modulator is present in an amount that prevents addiction to the nicotinic receptor modulator.

In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of a dopaminergic agent; (ii) a nicotinic receptor modulator in an amount effective to reduce or eliminate one or more side effects of the dopaminergic agent; and (iii) a pharmaceutically acceptable excipient suitable for oral administration. In certain embodiments, the nicotinic receptor modulator is present in an amount that prevents addiction to the nicotinic receptor modulator.

In certain embodiments, the composition further comprises: (iv) an effective amount of a second dopaminergic agent. In certain embodiments, the composition further comprises: (iv) an effective amount of a drug, such as carbidopa, that blocks the conversion of levodopa to dopamine in the blood. In certain embodiments, the composition further comprises: (iv) an effective amount of a COMT inhibitor, such as entacapone. In certain embodiments, the composition further comprises: (iv) an effective amount of a type B monoamine oxidase (MAO-B) inhibitor, such as selegiline. In certain embodiments, the composition further comprises: (iv) an effective amount of amantadine.

In certain embodiments, the pharmaceutical composition may be a liquid pharmaceutical composition suitable for oral administration.

In certain embodiments, the dopaminergic agent is levodopa. In certain embodiments, the dopaminergic agent is a dopamine agonist. In certain embodiments, the nicotinic receptor modulator capable of reducing or eliminating one or more side effects of a dopaminergic agent is a nicotinic receptor agonist, e.g., nicotine.

In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: a nicotinic receptor agonist in an amount effective for nicotine; and (ii) a pharmaceutically acceptable excipient suitable for oral administration. In certain embodiments, the nicotinic receptor modulator is present in an amount that prevents or reduces addiction to the nicotinic receptor modulator.

In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising: (i) an effective amount of a dopaminergic agent that is a levodopa or dopamine agonist; (ii) a nicotinic receptor agonist in an amount effective for nicotine; and (iii) a pharmaceutically acceptable excipient suitable for oral administration. In certain embodiments, the nicotinic receptor modulator is present in an amount that prevents or reduces addiction to the nicotinic receptor modulator.

In certain embodiments, the composition further comprises: (iv) an effective amount of a second dopaminergic agent. In certain embodiments, the composition further comprises: (iv) an effective amount of a drug, such as carbidopa, that blocks the conversion of levodopa to dopamine in the blood. In certain embodiments, the composition further comprises: (iv) an effective amount of a COMT inhibitor, such as entacapone. In certain embodiments, the composition further comprises: (iv) an effective amount of a type B monoamine oxidase (MAO-B) inhibitor, such as selegiline. In certain embodiments, the composition further comprises: (iv) an effective amount of amantadine.

In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising an effective amount of levodopa, an amount of nicotine effective to reduce or eliminate the side effects of levodopa, and a pharmaceutically acceptable excipient. In certain embodiments, the present invention provides a liquid pharmaceutical composition for oral administration comprising an effective amount of levodopa, an amount of nicotine effective to reduce or eliminate the side effects of levodopa, and a pharmaceutically acceptable excipient. In certain embodiments, nicotine is present in an amount that prevents or reduces addiction to nicotine.

In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising about 40-800 mg of levodopa, about 0.01-200 mg of nicotine, and a pharmaceutically acceptable excipient. In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising about 40-800 mg of levodopa, about 0.01-10 mg of nicotine, and a pharmaceutically acceptable excipient. In certain embodiments, the present invention provides a liquid pharmaceutical composition for oral administration comprising about 0.1-800 mg/ml levodopa, about 0.005-100 mg/ml nicotine, and a pharmaceutically acceptable excipient.

In certain embodiments, the present invention provides a solid pharmaceutical composition for oral administration comprising an effective amount of levodopa, an effective amount of nicotine, and a pharmaceutically acceptable excipient, wherein release of nicotine from the pharmaceutical composition reduces or eliminates the side effects of levodopa. In certain embodiments, the present invention provides a liquid pharmaceutical composition for oral administration comprising an effective amount of levodopa, an effective amount of nicotine, and a pharmaceutically acceptable excipient, wherein release of nicotine from the pharmaceutical composition reduces or eliminates the side effects of levodopa.

Pharmaceutical compositions of the invention suitable for oral administration may be presented in discrete dosage forms, such as capsules, cachets, or tablets, or as liquid or aerosol sprays (each of which contains a predetermined amount of the active ingredient as a powder or granules), as solutions, or as suspensions in aqueous or non-aqueous liquids, as oil-in-water emulsions, or as water-in-oil liquid emulsions. These dosage forms may be prepared by any of the methods of pharmacy, but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired form. For example, tablets may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable device the active ingredient in a free-flowing form, such as a powder or granules, optionally mixed with excipients such as, but not limited to, binders, lubricants, inert diluents, and/or surface active or dispersing agents. Molded tablets may be prepared by molding in a suitable apparatus a mixture of the powdered compound moistened with an inert liquid diluent.

The present invention further includes anhydrous pharmaceutical compositions and dosage forms containing active ingredients because water can facilitate the degradation of certain compounds. For example, water (e.g., 5%) may be added in the pharmaceutical field as a means of simulating long-term storage in order to determine the time-varying properties (e.g., shelf-life) or stability of the formulation. Anhydrous pharmaceutical compositions and dosage forms of the invention can be prepared using anhydrous or low moisture content components and low water or low moisture conditions. The lactose-containing pharmaceutical compositions and dosage forms of the present invention can be prepared anhydrous if substantial exposure to moisture and/or wetting during manufacture, packaging, and/or storage is expected. Anhydrous pharmaceutical compositions can be prepared and stored such that their anhydrous nature is maintained. Thus, anhydrous compositions may be packaged using materials known to prevent exposure to water, such that they may be included in a suitable kit-of-parts. Examples of suitable packaging include, but are not limited to, hermetically sealed foils, plastics and the like, unit dose containers, blister packs and strip packs (strip packs).

The active ingredients may be combined in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques. The carrier may take a wide variety of forms depending on the form of preparation desired for administration. In preparing the compositions in oral dosage form, any of the usual pharmaceutical media may be employed as the carrier, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations (e.g., suspensions, solutions and elixirs) or aerosols; or in the case of oral solid formulations, carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders and disintegrating agents may be employed, in certain embodiments lactose is not employed. For example, suitable carriers for solid oral formulations include powders, capsules and tablets. If desired, the tablets may be coated by standard aqueous or non-aqueous techniques.

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, pregelatinized starch, hydroxypropyl methyl cellulose, microcrystalline cellulose, and mixtures thereof.

Examples of fillers suitable for use in the pharmaceutical compositions and dosage forms described herein include, but are not limited to, talc, calcium carbonate (e.g., granules or powder), microcrystalline cellulose, powdered cellulose, dextrates (dextrates), kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof.

Disintegrants may be used in the compositions of the invention to allow the tablet to disintegrate when exposed to an aqueous environment. Too much disintegrant may result in tablets that may disintegrate in the bottle. Too little disintegrant may be insufficient for disintegration to occur and thus alter the rate and extent of release of the active ingredient from the dosage form. Thus, a sufficient amount of disintegrant that is neither too little nor too much to adversely alter the release of the active ingredient may be used to prepare the dosage forms of the compounds described herein. The amount of disintegrant used may vary based on the type of dosage form and the manner of administration, and can be readily determined by one of ordinary skill in the art. About 0.5 to about 15 weight percent of a disintegrant, or about 1 to about 5 weight percent of a disintegrant, may be used in the pharmaceutical composition. Disintegrants that can be used to form the 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, pregelatinized starch, other starches, clays, other algins, other celluloses, gums, or mixtures thereof.

Lubricants that may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, light mineral oil, glycerol, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oils (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil, and soybean oil), zinc stearate, ethyl oleate, ethyl laurate, agar, or mixtures thereof. Additional lubricants include, for example, syloid silica gel, a condensed aerosol of synthetic silica, or mixtures thereof. Lubricants may optionally be added in an amount of less than about 1% by weight of the pharmaceutical composition.

When aqueous suspensions and/or elixirs are desired for oral administration, the principal 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 diluents such as water, ethanol, propylene glycol, glycerin and various combinations thereof.

The tablets may be uncoated or coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide sustained activity over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed. Formulations for oral use may 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 in the form of soft capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil. The tablet may be a disintegrating tablet for rapid release of the therapeutic agent.

Surfactants that may be used to form the pharmaceutical compositions and dosage forms of the present invention include, but are not limited to, hydrophilic surfactants, lipophilic surfactants, and mixtures thereof. That is, a mixture of hydrophilic surfactants may be used, a mixture of lipophilic surfactants may be used, or a mixture of at least one hydrophilic surfactant and at least one lipophilic surfactant may be used.

Suitable hydrophilic surfactants may generally have an HLB value of at least 10, while suitable lipophilic surfactants may generally have an HLB value equal to or less than about 10. An empirical parameter used to characterize the relative hydrophilicity and hydrophobicity of nonionic amphiphilic compounds is the hydrophilic-lipophilic balance ("HLB" value). Surfactants with lower HLB values are more lipophilic or hydrophobic and have higher solubility in oil; while surfactants with higher HLB values are more hydrophilic and have higher 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 generally not applicable. Similarly, lipophilic (i.e., hydrophobic) surfactants are compounds having an HLB value equal to or less than about 10.

However, the HLB value of a surfactant is only a rough guide for enabling the formulation of industrial, pharmaceutical and cosmetic emulsions.

The hydrophilic surfactant may be ionic or non-ionic. Suitable ionic surfactants include, but are not limited to, alkyl ammonium salts; fusidate salts; fatty acid derivatives of amino acids, oligopeptides, and polypeptides; glyceride derivatives of amino acids, oligopeptides, and polypeptides; lecithin and hydrogenated lecithin; lysolecithin and hydrogenated lysolecithin; phospholipids and derivatives thereof; lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; an alkyl sulfate; a fatty acid salt; docusate sodium; acyl lactylate (acyl lactylate); mono-and diacetylated tartaric acid esters of mono-and diglycerides; succinylated mono and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.

Within the aforementioned group, preferred ionic surfactants include (by way of example only): lecithin, lysolecithin, phospholipids, lysophospholipids and derivatives thereof; carnitine fatty acid ester salts; an alkyl sulfate; a fatty acid salt; docusate sodium; an acyl lactate; mono-and diacetylated tartaric acid esters of mono-and diglycerides; succinylated mono and diglycerides; citric acid esters of mono-and diglycerides; and mixtures thereof.

The ionic surfactant may be an ionized form of: lecithin, lysolecithin, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol, phosphatidic acid, phosphatidylserine, lysophosphatidylcholine, lysophosphatidylethanolamine, lysophosphatidylglycerol, lysophosphatidic acid, lysophosphatidylserine, PEG-phosphatidylethanolamine, PVP-phosphatidylethanolamine, lactate esters of fatty acids, stearoyl-2-lactate, stearoyl-lactate, succinylated monoglyceride, mono/diacetyl tartaric acid esters of mono/diglycerides, citrate esters of mono/diglycerides, cholroylsarcosine, hexanoate, octanoate, decanoate, laurate, myristate, palmitate, oleate, ricinoleate, linoleate, stearate, lauryl sulfate, teracecyl sulfate, docusate, lauroyl carnitine, Palmitoyl carnitine, myristoyl carnitine, and salts and mixtures thereof.

Hydrophilic nonionic surfactants may include, but are not limited to, alkyl glucosides; an alkyl maltoside; an alkyl thioglucoside; dodecyl polyglycidyl esters (macrogolglycerides); polyoxyalkylene alkyl ethers such as polyethylene glycol alkyl ethers; polyoxyalkylene alkylphenols such as polyethylene glycol alkylphenols; polyoxyalkylene alkylphenol fatty acid esters such as polyethylene glycol fatty acid monoesters and polyethylene glycol fatty acid diesters; polyethylene glycol glycerol fatty acid ester; polyglyceryl fatty acid esters; polyoxyalkylene sorbitan fatty acid esters such as polyethylene glycol sorbitan fatty acid esters; hydrophilic transesterification products of a polyhydric alcohol with at least one member selected from the group consisting of glycerides, vegetable oils, hydrogenated vegetable oils, fatty acids, and sterols; polyoxyethylene sterols and derivatives and analogs thereof; polyoxyethylated vitamins and their derivatives; polyoxyethylene-polyoxyethylene block copolymers; and mixtures thereof; hydrogenated transesterification products of polyethylene glycol sorbitan fatty acid esters and polyhydric alcohols with at least one member selected from 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 sugar.

Other hydrophilic nonionic surfactants include, but are not limited to, PEG-10 laurate, PEG-12 laurate, PEG-20 laurate, PEG-32 dilaurate, PEG-12 oleate, PEG-15 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-32 glyceryl laurate, PEG-30 glyceryl laurate, PEG-20 glyceryl stearate, PEG-20 glyceryl oleate, PEG-30 glyceryl oleate, PEG-30 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 corn oil, PEG-6 capric/caprylic glyceride, PEG-8 capric/caprylic glyceride, polyglyceryl-10 laurate, PEG-30 cholesterol, PEG-25 phytosterol, 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-40 lauryl ether, PEG-50 hydrogenated castor oil, PEG-40 hydrogenated castor oil, PEG-60 corn oil, PEG-6 capric/caprylic glyceride, PEG-8 capric/caprylic glyceride, polyglyceryl-, POE-10 oleyl ether, POE-20 stearyl ether, tocopherol PEG-100 succinate, PEG-24 cholesterol, polyglyceryl-10 oleate, Tween 40, Tween 60, sucrose monostearate, sucrose monolaurate, sucrose monopalmitate, PEG 10-100 nonylphenol series, PEG 15-100 octylphenol series, and poloxamer.

Suitable lipophilic surfactants include, by way of example only: a fatty alcohol; glycerin fatty acid ester; acetylated glycerin fatty acid ester; lower alcohol fatty acid esters; a propylene glycol fatty acid ester; 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 diglycerides; a hydrophobic transesterification product of a polyhydric alcohol with at least one member selected from 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 polyols and at least one selected from vegetable oils, hydrogenated vegetable oils, and triglycerides.

In one embodiment, the composition may include a solubilizing agent to ensure good dissolution and/or dissolution of the dopaminergic agent and/or the nicotinic receptor modulator and to minimize precipitation of the dopaminergic agent and/or the nicotinic receptor modulator. This may be particularly important for compositions that are not for oral use (e.g., for injection). Solubilizers may also be added to increase the solubility of the hydrophilic drug and/or other components (e.g., surfactants), or to maintain the composition as a stable or uniform solution or dispersion.

Examples of suitable solubilizing agents include, but are not limited to, the following: alcohols and polyols, such as ethanol, isopropanol, butanol, benzyl alcohol, ethylene glycol, propylene glycol, butylene glycol and isomers thereof, glycerol, pentaerythritol, sorbitol, mannitol, ethylene glycol monoethyl ether (transcutol), dimethyl isosorbide, polyethylene glycol, polypropylene glycol, polyvinyl alcohol, 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-alkylpiperidinone, N-alkylcaprolactam, dimethylacetamide and polyvinylpyrrolidone; esters, such as ethyl propionate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, triethyl citrate, ethyl oleate, ethyl octanoate, ethyl butyrate, triacetin, propylene glycol monoacetate, propylene glycol diacetate, epsilon-caprolactone and its isomers, delta-valerolactone and its isomers, beta-butyrolactone and its isomers; and other solubilizing agents known in the art, such as dimethylacetamide, dimethylisosorbide, N-methylpyrrolidone, monocaprylin, diethylene glycol monoethyl ether, and water.

Mixtures of solubilizers may also be used. Examples include, but are not limited to, triacetin, triethyl citrate, ethyl oleate, ethyl caprylate, dimethylacetamide, N-methylpyrrolidone, N-hydroxyethylpyrrolidone, polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcyclodextrin, ethanol, polyethylene glycol 200-. Particularly preferred solubilizers include sorbitol, glycerol, triacetin, ethanol, PEG-400, glycofurol and propylene glycol.

The amount of the solubilizer that may be contained is not particularly limited. The amount of a given solubilizer may be limited to a biologically acceptable amount, which can be readily determined by one skilled in the art. In some cases, it may be advantageous to include a solubilizing agent in substantial excess of the biologically acceptable amount, e.g., to maximize the concentration of the drug, and to remove excess solubilizing agent using conventional techniques (e.g., distillation or evaporation) prior to administering the composition to a patient. Thus, if present, the solubilizing agent can be 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 solubilizers, e.g., 5%, 2%, 1% or even less, can also be used. Typically, the solubilizing agent is present in an amount of from about 1% to about 100%, more typically from about 5% to about 25%, by weight.

The composition may further comprise one or more pharmaceutically acceptable additives and excipients. Such additives and excipients include, but are not limited to, detackifiers, antifoams, buffers, polymers, antioxidants, preservatives, chelating agents, viscosity modifiers (viscomodulators), tonicity modifiers (tonicifiers), flavoring agents, colorants, fragrances, opacifiers, suspending agents, binders, fillers, plasticizers, lubricants, and mixtures thereof.

In addition, acids or bases may be added to the composition for ease of processing, to improve stability, or for other reasons. Examples of pharmaceutically acceptable bases include amino acids, amino acid esters, ammonium hydroxide, potassium hydroxide, sodium bicarbonate, aluminum hydroxide, calcium carbonate, magnesium hydroxide, magnesium aluminum silicate, synthetic hydrocalcite, magnesium aluminum hydroxide, diisopropylethylamine, ethanolamine, ethylenediamine, triethanolamine, triethylamine, triisopropanolamine, trimethylamine, TRIS (hydroxymethyl) aminomethane (TRIS), and the like. Also suitable are salts of pharmaceutically acceptable acids, for example, 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 (hydroquinosulfonic acid), isoascorbic acid, lactic acid, maleic acid, oxalic acid, p-bromobenzenesulfonic 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 polybasic acids such as sodium phosphate, disodium hydrogen phosphate and sodium dihydrogen phosphate may also be used. When the base is a salt, the cation may be any convenient and pharmaceutically acceptable cation, such as ammonium, alkali metals, alkaline earth metals, and the like. Examples may include, but are not limited to, sodium, potassium, lithium, magnesium, calcium, and ammonium.

Suitable acids are pharmaceutically acceptable organic or inorganic acids. Examples of suitable inorganic acids include hydrochloric acid, hydrobromic acid, hydroiodic 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, p-bromobenzenesulfonic 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.

Drug group for injectionCompound (I)In certain embodiments, the present invention provides pharmaceutical compositions for injection comprising a drug that reduces or eliminates the side effects of dopaminergic drugs. In certain embodiments, the present invention provides a pharmaceutical composition for injection comprising a combination of a dopaminergic agent and an agent that reduces or eliminates side effects of the dopaminergic agent, and a pharmaceutically acceptable excipient suitable for injection. The pharmaceutical components and amounts in the compositions are described herein.

Wherein the novel compositions of the present invention may be incorporated in the form for administration by injection, including aqueous or oily suspensions or emulsions utilizing sesame oil, corn oil, cottonseed oil or peanut oil, as well as elixirs, dextrose, or sterile aqueous solutions, and similar pharmaceutical excipients.

Saline solutions are also commonly used for injection. Ethanol, glycerol, propylene glycol, liquid polyethylene glycols and the like (and suitable mixtures thereof), cyclodextrin derivatives and vegetable oils may also be used. For example, proper fluidity can be maintained, for example, by the use of a coating (e.g., lecithin), by the maintenance of the required particle size in the case of dispersants, and by the use of surfactants. The prevention of microbial activity can be achieved by various antibacterial and antifungal agents, such as parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.

Sterile injectable solutions are prepared by incorporating the nicotinic receptor modulator and/or the dopaminergic agent in the required amount in the appropriate solvent, as required, in combination with various other ingredients enumerated above, as required, and sterile filtering. 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 the above-listed ingredients. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and the freeze-drying technique which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.

Pharmaceutical compositions for topical (e.g., transdermal) deliveryIn certain embodiments, the present invention provides pharmaceutical compositions for transdermal delivery comprising a nicotinic receptor modulator that reduces or eliminates the side effects of dopaminergic agents, and a pharmaceutically acceptable excipient suitable for transdermal delivery. In certain embodiments, the present invention provides pharmaceutical compositions for transdermal delivery comprising a dopaminergic agent in combination with a nicotinic receptor modulator that reduces or eliminates a side effect of the dopaminergic agent, and a pharmaceutically acceptable excipient suitable for transdermal delivery. In certain embodiments, the nicotinic receptor modulator that reduces or eliminates the side effects of a dopaminergic agent is a nicotinic receptor agonist, e.g., nicotine, as further described herein. The components and amounts of nicotinic receptor modulators in the compositions are as described herein.

The compositions of the invention may be formulated for topical or local administration in solid, semi-solid or liquid form, for example as gels, water-soluble gels, creams, lotions, suspensions, foams, powders, ointments, solutions, oils, pastes, suppositories, sprays, emulsions, saline solutions, solutions based on dimethyl sulfoxide (DMSO). Generally, carriers with higher densities are able to provide longer active ingredient contact to the area. In contrast, solution formulations may provide more direct contact of the active ingredient to the selected area.

The pharmaceutical composition may also contain a suitable solid or gel phase carrier or excipient which is a compound that allows for increased penetration of the therapeutic molecule across the stratum corneum permeation barrier of the skin, or facilitates delivery of the therapeutic molecule across the stratum corneum permeation barrier of the skin. There are many permeation enhancing molecules known to those skilled in the art of topical formulations. 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 glycol.

Another formulation for use in the methods of the invention uses a transdermal delivery device (e.g., a drug patch or a micropump). The transdermal devices may be used to infuse a nicotinic receptor modulator with a controlled amount, either continuously or discontinuously, with or without a dopaminergic agent. Thus, in certain embodiments, the present invention provides transdermal devices incorporating nicotinic receptor modulators (e.g., agonists, such as nicotine). In certain embodiments, the present invention provides transdermal devices that incorporate a nicotinic receptor modulator (e.g., an agonist, such as nicotine) in combination with a dopaminergic agent (e.g., levodopa).

The construction and use of transdermal devices for delivering drugs is known in the art. See, for example, U.S. Pat. Nos. 5,023,252, 4,992,445, and 5,001,139. These devices may be configured for continuous, pulsed, or on-demand delivery of drugs.

Pharmaceutical composition for inhalationCompositions for inhalation or insufflation include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. The liquid or solid composition may comprise suitable pharmaceutically acceptable excipients as described above. Preferably, the composition is administered by the oral or nasal respiratory route to obtain a local or systemic effect. Compositions in preferred pharmaceutically acceptable solvents may be nebulized by the use of inert gases. The nebulized solution may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a face mask or intermittent positive pressure ventilator. The solution, suspension or powder composition may be administered from a device that delivers the formulation in a suitable manner, preferably orally or nasally.

Other pharmaceutical compositionsCompositions may also be prepared from a composition described herein and one or more pharmaceutically acceptable excipients suitable for sublingual, buccal, rectal, intraosseous, intraocular, intranasal, epidural, or intraspinal administration. The pharmaceutical compositions are prepared byAs is well known in the art. See, e.g., Anderson, Philip o.; knoben, james e.; troutman, William G eds, Handbook of Clinical Dr μ G Data, 10 th edition, McGraw-Hill, 2002; prat and Taylor editors, Principles of Dr μ g action, third edition, churchilll Livingston, New York, 1990; katzung, Basic and Clinical Pharmacology, ninth edition, McGraw Hill, 20037 ybg; edited by Goodman and Gilman, The Pharmacological Basis of Therapeutics, tenth edition, McGraw Hill, 2001; remingtons Pharmaceutical Sciences, 20 th edition, Lippincott Williams&Wilkins, 2000; martindale, The Extra Pharmaceutical copoeia, 32 nd edition (The Pharmaceutical Press, London, 1999); which is incorporated by reference in its entirety into this application.

B. Reagent kit

The invention also provides kits. The kit includes a nicotinic receptor modulator (in suitable packaging) that reduces or eliminates side effects of a dopaminergic agent, and written material that can include instructions for use, instructions for clinical studies, a list of side effects, and the like. The kit may further comprise a dopaminergic agent having side effects. In certain embodiments, in a kit, the dopaminergic agent and the nicotinic receptor modulator that reduces or eliminates side effects of the dopaminergic agent are provided as separate compositions in separate containers. In certain embodiments, the dopaminergic agent and the nicotinic receptor modulator that reduces or eliminates the side effects of the dopaminergic agent are provided as a single composition in the container of the kit. Suitable packaging and additional items for use (e.g., measuring cups for liquid formulations, foil packaging to minimize air exposure, etc.) are known in the art and may be included in the kit. Method of producing a composite material

In another aspect, the invention provides methods, including methods of treatment and methods of enhancing the therapeutic efficacy of a substance.

The term "animal" or "animal subject" as used herein includes humans and other mammals. The methods generally involve administering one or more drugs for treating one or more diseases. Combinations of drugs can be used to treat a disease or diseases or to modulate side effects of one or more drugs in a combination.

The term "treatment" and its grammatical equivalents as used herein includes achieving a therapeutic benefit and/or a prophylactic benefit. Therapeutic benefit means eradication or amelioration of the underlying disease being treated. In addition, therapeutic benefit is achieved by eradicating or ameliorating one or more physiological symptoms associated with the underlying disease, whereby an improvement is observed in the patient, even though the patient may still suffer from the underlying disease. For prophylactic benefit, the composition may be administered to a patient at risk of developing a particular disease, or to a patient reporting one or more physiological symptoms of a disease, even though diagnosis of the disease may not be complete.

In certain embodiments, the invention provides methods of treating a disease by administering to an animal having the disease an effective amount of a nicotinic receptor modulator sufficient to reduce or eliminate side effects associated with dopaminergic agents. In certain embodiments, the nicotinic receptor modulators reduce or eliminate various side effects associated with dopaminergic agents. In certain embodiments, the animal is a mammal, such as a human.

In certain embodiments, the invention provides methods of treating a disease by administering to an animal having the disease 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 certain embodiments, the modulator reduces or eliminates multiple side effects of dopaminergic agents. In certain embodiments, the animal is a mammal, such as a human.

The dopaminergic agent and nicotinic receptor modulator are co-administered. As used herein, "co-administration," "co-administration," and grammatical synonyms thereof, includes administration of two or more drugs to an animal such that both drugs 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 drugs are present. Thus, in certain embodiments, the nicotinic receptor modulator and the dopaminergic agent are administered in a single composition. In certain embodiments, the dopaminergic agent and the nicotinic receptor modulator are combined in a 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 certain 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, on average, at least about 5, 10, 15, 20, 25, 30, 40, 50, 60, 70, 80, 90, or 90% or more of the side effects of the dopaminergic agent, or to substantially eliminate the side effects, as compared to when the nicotinic receptor modulator is not present. In certain embodiments, the dopaminergic agent and the nicotinic receptor modulator are co-administered to the individual each time a therapeutic effect from the dopaminergic agent is desired in the individual. In certain embodiments, co-administration comprises administering the dopaminergic agent and nicotine simultaneously in the same dosage form or simultaneously in separate dosage forms. In certain embodiments, the dopaminergic agent is present in an amount from 100% to about 75% of an effective amount when the dopaminergic agent is administered alone.

In certain 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.

In certain embodiments, the dopaminergic agent and/or nicotinic receptor modulator is co-administered with an effective amount of an agent, such as carbidopa, which blocks the conversion of levodopa to dopamine in the blood. In certain embodiments, the dopaminergic agent and/or nicotinic receptor modulator is co-administered with an effective amount of a COMT inhibitor (e.g., entacapone). In certain embodiments, the dopaminergic agent and/or nicotinic receptor modulator is co-administered with an effective amount of a type B monoamine oxidase (MAO-B) inhibitor (e.g., selegiline). In certain embodiments, the dopaminergic agent and nicotinic receptor modulator are co-administered with an effective amount of amantadine.

The administration of the dopaminergic agent and the nicotinic receptor modulator that reduces or eliminates at least one side effect of the dopaminergic agent can be by any suitable means. If the drugs are administered in separate compositions, they may be administered by the same route or by different routes. If the drugs are administered as a single composition, they may be administered by any suitable route. In certain embodiments, the medicament is administered in a single composition by the oral route of administration. In certain embodiments, the medicament is administered in a single composition by a transdermal route of administration. In certain embodiments, the medicament is administered by injection in a single composition. In certain embodiments, the dopaminergic agent and the nicotinic receptor modulator are administered to the individual as a single composition each time a therapeutic effect from the dopaminergic agent is desired in the individual. In certain embodiments, the dopaminergic agent is present in an amount from 100% to about 75% of an effective amount when the dopaminergic agent is administered alone. In certain 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.

In certain embodiments, the nicotinic receptor modulator that reduces or eliminates the side effects of dopaminergic agents is a nicotinic receptor agonist, and the nicotinic receptor agonist is as described herein. In certain embodiments, nicotine is used. The dosage is as used for the composition. Typically, the daily dosage of the nicotinic receptor modulator is from about 0.05 to about 100 mg/kg. In certain embodiments, the daily dose of the nicotinic receptor modulator is less than 93 mg/day.

The dopaminergic agent may be any dopaminergic agent described herein. In certain embodiments, the dopaminergic agent is levodopa or a dopamine agonist described herein.

The methods of the invention may be used to treat any suitable disease in which one or more dopaminergic agents having side effects are used. Examples of such diseases include, but are not limited to, parkinson's disease, alzheimer's disease, dopa-responsive dystonia, cerebral palsy, post-ischemic systolic dysfunction, severe ovarian hyperstimulation syndrome, pediatric dyskinesia, and non-oliguric renal failure.

For example, in certain embodiments, the methods of the invention comprise treating a parkinson's disease patient to prevent dyskinesia by administering to an animal in need thereof an effective amount of a dopaminergic agent (e.g., levodopa) and an effective amount of a drug that reduces or eliminates dopaminergic agent-induced dyskinesia.

In other embodiments, the methods of the invention comprise treating post-ischemic contractile dysfunction by administering to an animal in need thereof an effective amount of a dopaminergic agent (e.g., levodopa) and an effective amount of a nicotinic receptor modulator that reduces or eliminates side effects of the dopaminergic agent.

In still other embodiments, the methods of the invention comprise treating severe ovarian hyperstimulation syndrome by administering to an animal in need thereof an effective amount of a dopaminergic agent (e.g., levodopa) and an effective amount of a drug that reduces or eliminates side effects of the dopaminergic agent.

In other embodiments, the methods of the invention comprise treating a pediatric movement disorder by administering to an animal in need of treatment an effective amount of a dopaminergic agent (e.g., levodopa) and an effective amount of a drug that reduces or eliminates side effects of the dopaminergic agent.

In certain embodiments, the methods of the invention comprise treating non-oliguric renal failure by administering to an animal in need of treatment an effective amount of a dopaminergic agent (e.g., levodopa) and an effective amount of a drug that reduces or eliminates a side effect of the dopaminergic agent.

When a dopaminergic agent is used in combination with a nicotinic receptor modulator that reduces or eliminates a side effect of the dopaminergic agent, any suitable ratio of the two agents, such as a molar ratio, a w/w ratio, a w/v ratio, or a v/v ratio, as described herein, can be used. In certain embodiments, the dopaminergic agent is present in an amount from 100% to about 75% of an effective amount when the dopaminergic agent is administered alone.

The invention further provides methods of reversing one or more side effects of a dopaminergic agent by administering a nicotinic receptor modulator to a dopaminergic agent that has received an amount of the dopaminergic agent sufficient to produce the one or more side effects. The method is particularly useful in situations where it is desirable to rapidly reverse one or more side effects of a dopaminergic agent. Any suitable nicotinic receptor modulator described herein may be used.

In certain embodiments, the present invention provides a method of reversing the side effects 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 the side effects of the dopaminergic agent, wherein the human has received an amount of the dopaminergic agent sufficient to produce the side effects. In certain embodiments, the human has received an excess of dopaminergic agents that produce side effects. In certain embodiments, the nicotinic receptor modulator is an agonist, for example, nicotine. Typically, the agonist is administered by oral administration or transdermal delivery at a dose sufficient to partially or completely reverse the side effects of the dopaminergic agent. In certain embodiments, the agonist is delivered by pulsed delivery. In certain 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.

In another aspect, the invention includes a method of reducing dyskinesia comprising administering to an animal suffering from dyskinesia a nicotinic receptor modulator in an amount sufficient to reduce dyskinesia.

In certain embodiments, the nicotinic receptor modulator is an agonist or antagonist described herein. In certain embodiments, the nicotinic receptor agonist modulates a nicotinic receptor comprising at least one alpha subunit or a nicotinic receptor comprising at least one alpha subunit and at least one beta subunit. In certain embodiments, the alpha subunit is selected from 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 beta 2, beta 3, and beta 4. In certain embodiments, the nicotinic receptor agonist modulates a nicotinic receptor composed of subunits selected from the group consisting of α 4 β 2, α 6 β 2, α 4 α 5 β 2, α 4 α 6 β 2 β 3, and α 4 α 2 β 2. In certain 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 of

The present invention relates to the administration of nicotinic receptor modulators that, for example, reduce or eliminate the side effects of dopaminergic agents. In certain embodiments, a dopaminergic agent that produces a side effect is administered in combination with a nicotinic receptor modulator that reduces the effect of the side effect of the dopaminergic agent. In certain embodiments, other drugs, e.g., other dopaminergic drugs or other therapeutic drugs, are also administered. When two or more drugs 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 certain embodiments, the nicotinic receptor modulator and/or the dopaminergic agent is administered to the upper gastrointestinal tract of the subject.

In certain embodiments, the nicotinic receptor modulator that reduces or eliminates the side effects of a dopaminergic agent is administered in a single dose. This may be the case when drugs are introduced into the body of an animal to rapidly reduce the side effects of dopaminergic drugs already present in the body. Typically, such administration is by injection, e.g., intravenously, for rapid introduction of the nicotinic receptor modulator. However, other suitable approaches may be used. When administered with a dopaminergic agent used to treat an acute condition (e.g., a dopaminergic agent that produces side effects), a single dose of the agent that reduces or eliminates the side effects of the dopaminergic agent can also be used.

In certain embodiments, the nicotinic receptor modulator that reduces or eliminates the side effects of a dopaminergic agent is administered in multiple doses. Administration may be about 1, 2, 3, 4,5, 6 or more than 6 times per day. Administration may be about 1 time per month, 1 time every two weeks, 1 time per week, or 1 time every other day. In one embodiment, the dopaminergic agent is levodopa. In another embodiment, the dopaminergic agent and nicotinic receptor modulator are administered together from about 1 time per day to about 6 times per day. In certain embodiments, the nicotinic receptor modulator and the dopaminergic agent are administered to the individual each time a therapeutic effect of the dopaminergic agent is desired in the individual. In another embodiment, the dopaminergic agent and nicotinic receptor modulator are administered for less than about 7 consecutive days. In yet another embodiment, administration is continuous for more than about 6, 10, 14, 28 days, two months, six months, or one year. In some cases, continuous administration is achieved and maintained as long as desired. In certain embodiments, the nicotinic receptor modulator that reduces or eliminates the side effects of the substance and/or dopaminergic agent is administered continuously or in a pulsed manner (e.g., using a micropump, patch, or implanted catheter).

The nicotinic receptor modulators of the present invention may be administered continuously, as long as desired. In certain embodiments, the medicament of the invention is administered for more than 1, 2, 3, 4,5, 6, 7, 14, 28 days or 1 year. In certain embodiments, a medicament of the invention is administered for less than 28, 14, 7, 6, 5, 4,3, 2, or 1 days. In certain embodiments, the agents of the invention are administered chronically on a continuous basis (e.g., for the treatment of chronic effects).

In certain 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 the individual, wherein release of the nicotinic receptor modulator from the composition reduces or eliminates the side effect of the dopaminergic agent. In certain embodiments, the nicotinic receptor modulator or a metabolite of the nicotinic receptor modulator may be present in the bloodstream prior to the dopaminergic agent in order to eliminate or reduce a side effect of the dopaminergic agent. This can be achieved, for example, 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 formulated such that the nicotinic receptor modulator reaches the blood stream before the dopaminergic agent. For example, dosage forms may be used in which one active agent is released directly and the other agent is released slowly/delayed as desired (e.g., a bilayer tablet containing both agents). Examples of multi-drug dosage forms for differential release are known, for example the dosage forms described in us patents 7,011,849, 6,221,394, 5,073,380, 20070104787, 20060204578, 20060057202, 20050276852 and 20050266032.

In certain embodiments, the nicotinic receptor modulator and/or the dopaminergic agent are formulated as a fast-dissolving orally disintegrating tablet. These tablets may be swallowed with or without water. Examples of orally disintegrating tablets are known, such as those described in U.S. patents 7,282,217, 7,229,641, 6,368,625, 6,365,182, 6,221,392, and 6,024,981.

In certain 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 prior to the dopaminergic agent. In other embodiments, the nicotinic receptor modulator or metabolite of the nicotinic receptor modulator is present in the bloodstream 59, 50, 40, 35, 30, 25, 20, 10, 5, 4,3, 2, 1 minute prior to the dopaminergic agent.

In another aspect of the invention, the nicotinic receptor modulator or a metabolite of the nicotinic receptor modulator may be present in the bloodstream subsequent to the dopaminergic agent, in order to eliminate or reduce a side effect of the dopaminergic agent. This can be achieved 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 formulated such that the nicotinic receptor modulator reaches the blood stream after the dopaminergic agent.

In certain 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 certain embodiments, the nicotinic receptor modulator or a metabolite of the nicotinic receptor modulator is present in the bloodstream 59, 50, 40, 35, 30, 25, 20, 10, 5, 4,3, 2, 1 minute after the dopaminergic agent.

In one embodiment, the nicotinic receptor modulator or metabolite has a second plasma half-life that differs from the first plasma half-life by at least about 3 hours, wherein the dosage form is administered to provide a plasma concentration of the dopaminergic agent within the therapeutic range over a period of time that is at least about 70% longer than the period of time for which the nicotinic receptor modulator or metabolite is provided within the therapeutic range by the dosage form. In certain embodiments, the nicotinic receptor modulator or metabolite and the dopaminergic agent have similar half-lives. In certain embodiments, the nicotinic receptor modulator or a metabolite of the nicotinic receptor modulator has a half-life of 48, 36, 24, 12, 10, 8,6, 5, 4,3, 2, 1.5, 1 hour.

In certain embodiments, the dosage form of the present invention comprises a multilayer tablet. In one embodiment, the dosage form of the present invention comprises a bilayer tablet comprising a first layer comprising a nicotinic receptor modulator or metabolite and having a first plasma half-life and a second layer comprising a dopaminergic agent having a second plasma half-life that differs from the first plasma half-life by at least about 3 hours, wherein the bilayer tablet provides a plasma concentration of the dopaminergic agent within a therapeutic range for a time that is at least about 70% longer than a time at which the nicotinic receptor modulator or metabolite provided by the bilayer tablet is at the plasma concentration within the therapeutic range.

In still other embodiments, the second and first plasma half-lives differ by at least 48, 36, 24, 12, 10, 8,6, 5, 4,3, 2, or 1 hour. In certain embodiments, the second and first plasma half-lives are similar.

In certain embodiments, the invention encompasses a multilayer tablet comprising an immediate release layer and a sustained release layer. In certain embodiments, the immediate release layer comprises a nicotinic receptor agonist or metabolite and the sustained release layer comprises a dopaminergic agent. In certain embodiments, the immediate release layer comprises one or more therapeutic agents independently selected from nicotinic receptor agonists and dopaminergic agents, and the sustained release layer comprises one or more therapeutic agents independently selected from nicotinic receptor agonists and dopaminergic agents. In certain embodiments, the immediate release layer comprises a dopaminergic agent and the sustained release layer comprises a nicotinic receptor modulator or a metabolite. In certain embodiments, the immediate release layer or the extended release layer comprises a third therapeutic agent, such as a drug described herein. Examples of drugs include, but are not limited to, amantadine, carbidopa, and entacapone.

An effective amount of a nicotinic receptor modulator and/or an effective amount of a dopaminergic agent may be administered in single or multiple doses by any acceptable mode of administration for administration of a drug having a similar use, including rectal, buccal, intranasal, and transdermal routes, by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, as an inhalant, or by an infused or coated device, such as an implanted catheter.

In certain embodiments, an effective amount of a nicotinic receptor modulator is administered to achieve a critical concentration of the nicotinic receptor modulator in the blood stream, plasma, or tissue in which elimination of side effects is desired, wherein the critical concentration is that necessary to reduce or eliminate the side effects caused by the dopaminergic agent. Examples of different forms of administration include, but are not limited to, administration in a single dose, multiple doses, or by pulsed administration. In certain embodiments, after a nicotinic receptor modulator or a metabolite of a nicotinic receptor modulator has reduced or eliminated a dopaminergic agent-induced side effect, the concentration of the nicotinic receptor modulator or the metabolite of the nicotinic receptor modulator will be reduced at the site of the side effect occurrence (e.g., systemically, such as in the bloodstream; or in the tissue in which the side effect occurs).

In certain embodiments, the nicotinic receptor modulator is administered such that 48, 36, 24, 12, 10, 8,6, 5, 4,3, 2, 1 hour prior to the dopaminergic agent reaching the blood stream or tissue that produces the side effect, or a metabolite of the nicotinic receptor modulator reaches a critical concentration in the blood stream, plasma, or tissue where elimination of the side effect is desired. In certain embodiments, the nicotinic receptor modulator is administered such that 59, 50, 40, 35, 30, 25, 20, 10, 5, 4,3, 2, 1 minute prior to the dopaminergic agent reaching the blood stream or tissue that produces the side effect reaches a critical concentration of the nicotinic receptor modulator or a metabolite of the nicotinic receptor modulator in the blood stream, plasma, or tissue in which elimination of the side effect is desired.

In certain embodiments, the nicotinic receptor modulator is administered such that 48, 36, 24, 12, 10, 8,6, 5, 4,3, 2, 1 hours after the dopaminergic agent reaches the blood stream or tissue that produces the side effect, or the metabolite of the nicotinic receptor modulator reaches a critical concentration in the blood stream, plasma, or tissue where elimination of the side effect is desired. In certain embodiments, the nicotinic receptor modulator is administered such that 59, 50, 40, 35, 30, 25, 20, 10, 5, 4,3, 2, 1 minute after the dopaminergic agent reaches the blood stream, plasma, or tissue that produces the side effect reaches a critical concentration of the nicotinic receptor modulator or a metabolite of the nicotinic receptor modulator in the blood stream, plasma, or tissue where elimination of the side effect is desired.

In certain embodiments, the nicotinic receptor modulator is administered such that the side effect peaks when the nicotinic receptor modulator and/or a metabolite of the nicotinic receptor modulator reaches a critical concentration in the blood stream, plasma, or tissue where elimination of the side effect is desired. In certain embodiments, the nicotinic receptor modulator is administered such that 48, 36, 24, 12, 10, 8,6, 5, 4,3, 2, 1 hour prior to the peak of the side effect in need of elimination, the nicotinic receptor modulator and/or the metabolite of the nicotinic receptor modulator reach a critical concentration in the blood stream, plasma or tissue in need of elimination of the side effect. In certain embodiments, the nicotinic receptor modulator is administered such that 59, 50, 40, 35, 30, 25, 20, 10, 5, 4,3, 2, 1 minute before the side effect in need of elimination peaks, the nicotinic receptor modulator and/or the metabolite of the nicotinic receptor modulator reaches a critical concentration in the blood stream, plasma or tissue in need of elimination of the side effect.

In certain embodiments, the critical concentration of the nicotinic receptor modulator or nicotinic receptor modulator metabolite is about 1pg/ml to about 1 mg/ml. In certain embodiments, the critical concentration of the nicotinic receptor modulator or a metabolite of the nicotinic receptor modulator is from about 1pg/ml to about 1ng/ml, or from about 50pg/ml to about 1ng/ml, or from about 100pg/ml to about 1ng/ml, or from about 500pg/ml to about 1ng/ml, or from about 1ng/ml to about 500ng/ml, or from about 10ng/ml to about 500ng/ml, or from about 100ng/ml to about 500ng/ml, or from about 200ng/ml to about 500ng/ml, or from about 300ng/ml to about 500ng/ml, or from about 400ng/ml to about 500ng/ml, or from about 500ng/ml to about 1 μ g/ml, or from about 600ng/ml to about 1 μ g/ml, or from about 700ng/ml to about 1 μ g/ml, or from about 1 μ g/ml to about 1 μ g/ml, Or from about 800ng/ml to about 1. mu.g/ml, or from about 900ng/ml to about 1. mu.g/ml, or from about 1. mu.g/ml to about 1mg/ml, or from about 10. mu.g/ml to about 1mg/ml, or from about 100. mu.g/ml to about 1mg/ml, or from about 500. mu.g/ml to about 1mg/ml, or from about 600. mu.g/ml to about 1mg/ml, or from about 700. mu.g/ml to about 1mg/ml, or from about 800. mu.g/ml to about 1mg/ml, or from about 900. mu.g/ml to about 1 mg/ml. In certain embodiments, the critical concentration of the nicotinic receptor modulator or nicotinic receptor modulator metabolite is about 200ng/ml to about 420 ng/ml. In certain embodiments, the critical concentration of the nicotinic receptor modulator or nicotinic receptor modulator metabolite is about 1ng/ml to about 20 ng/ml. In certain embodiments, the critical concentration of the nicotinic receptor modulator or nicotinic receptor modulator metabolite is about 1ng/ml to about 5 ng/ml. In certain embodiments, the critical concentration of the nicotinic receptor modulator or nicotinic receptor modulator metabolite is about 20ng/ml to about 100 ng/ml.

In certain embodiments, the nicotinic receptor modulator is administered such that the nicotinic receptor modulator or metabolite reduces or eliminates side effects 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.

The nicotinic receptor modulator and dopaminergic agent may be administered at dosages as described herein (see, e.g., the compositions section). Dosage ranges for dopaminergic agents are known in the art. Also known in the art are: due to the variation of the pharmacokinetics of dopaminergic drugs (e.g., levodopa) between individuals, personalization of the dosing regimen is necessary in order to obtain optimal treatment. The dosage of nicotinic receptor modulator administered can be found by routine experimentation. For nicotinic receptor agonists (e.g., nicotine), typical daily dosages range are, for example, from about 1 to 5000mg, or from about 1 to 3000mg, or from about 1 to 2000mg, or from about 1 to 1000mg, or from about 1 to 500mg, or from about 1 to 100mg, or from about 10 to 5000mg, or from about 10 to 3000mg, or from about 10 to 2000mg, or from about 10 to 1000mg, or from about 10 to 500mg, or from about 10 to 200mg, or from about 10 to 100mg, or from about 20 to 2000mg, or from about 20 to 1500mg, or from about 20 to 1000mg, or from about 20 to 500mg, or from about 20 to 100mg, or from about 50 to 5000mg, or from about 50 to 4000mg, or from about 50 to 3000mg, or from about 50 to 2000mg, or from about 50 to 1000mg, or from about 50 to 500mg, or from about 50 to 100mg, or from about 100 to 5000mg, or from about 100 to 4000mg, or from about 100 to 3000mg, or from about 100 to 2000mg, or from about 100 to 1000 mg. In certain 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 certain embodiments, the daily dose of nicotine is 0.9 mg. In certain embodiments, the daily dose of nicotine is 1.8 mg. In certain embodiments, the daily dose of nicotine is 2.4 mg. In certain embodiments, the daily dose of nicotine is 3 mg. In certain embodiments, the daily dose of nicotine is 6 mg. In certain embodiments, the daily dose of nicotine is 7 mg. In certain embodiments, the daily dose of nicotine is 8 mg. In certain embodiments, the daily dose of nicotine is 9 mg. In certain embodiments, the daily dose of nicotine is 12 mg. In certain embodiments, the daily dose of nicotine is 14 mg. In certain embodiments, the daily dose of nicotine is 18 mg. In certain embodiments, the daily dose of nicotine is 21 mg. In certain embodiments, the daily dose of nicotine is 24 mg. In certain embodiments, the daily dose of nicotine is 32 mg. In certain embodiments, the daily dose of nicotine is 50 mg. In certain embodiments, the daily dose of nicotine is less than 93 mg. The daily dosage range may depend on the form of nicotinic receptor agonist and/or the factors upon which the nicotinic receptor agonist is administered, as described herein.

In certain embodiments, the daily dose of nicotine is such that the plasma level of nicotine or nicotine metabolites is from about 1pg/ml to about 1 mg/ml. In certain embodiments, the daily dose of nicotine is such that the plasma level of nicotine or nicotine metabolites is from about 1pg/ml to about 1ng/ml, or from about 50pg/ml to about 1ng/ml, or from about 100pg/ml to about 1ng/ml, or from about 500pg/ml to about 1ng/ml, or from about 1ng/ml to about 500ng/ml, or from about 10ng/ml to about 500ng/ml, or from about 100ng/ml to about 500ng/ml, or from about 200ng/ml to about 500ng/ml, or from about 300ng/ml to about 500ng/ml, or from about 400ng/ml to about 500ng/ml, or from about 500ng/ml to about 1 μ g/ml, or from about 600ng/ml to about 1 μ g/ml, or from about 700ng/ml to about 1 μ g/ml, or from about 800ng/ml to about 1 μ g/ml, Or from about 900ng/ml to about 1. mu.g/ml, or from about 1. mu.g/ml to about 1mg/ml, or from about 10. mu.g/ml to about 1mg/ml, or from about 100. mu.g/ml to about 1mg/ml, or from about 500. mu.g/ml to about 1mg/ml, or from about 600. mu.g/ml to about 1mg/ml, or from about 700. mu.g/ml to about 1mg/ml, or from about 800. mu.g/ml to about 1mg/ml, or from about 900. mu.g/ml to about 1 mg/ml. In certain embodiments, the daily dose of nicotine is such that the plasma level of nicotine or nicotine metabolites is from about 200ng/ml to about 420 ng/ml. In certain embodiments, the daily dose of nicotine is such that the plasma level of nicotine or nicotine metabolites is from about 1ng/ml to about 20 ng/ml. In certain embodiments, the daily dose of nicotine is such that the plasma level of nicotine or nicotine metabolites is from about 1ng/ml to about 5 ng/ml. In certain embodiments, the daily dose of nicotine is such that the plasma level of nicotine or nicotine metabolites is from about 20ng/ml to about 100 ng/ml.

When a nicotinic receptor modulator (e.g., an agonist, such as nicotine) is administered in a composition comprising one or more dopaminergic agents and the dopaminergic agents have a shorter half-life than the nicotinic receptor modulator, the unit dosage forms of the dopaminergic agents and the nicotinic receptor modulator can be modulated accordingly.

Examples

Example 1: nicotine reduction of levodopa-induced dyskinesia in monkeys with nigrostriatal lesions

Materials and methods

Animals squirrel monkeys (Saimiri sciureus) (n ═ 7) were purchased from World Wide masters (Miami, FL). The weight of the animal is 0.6-0.9 kg, and the animal belongs to the later adult stage in terms of the overall appearance (teeth, fur and the like). Since older animals are available, female monkeys, which may be a better model for parkinson's disease, were used. Animals were quarantined after arrival and maintained in a temperature-controlled room (27 + -3 deg.C), relative humidity > 30%, 13/11 hours of day/night cycling. Monkey food and fruits/vegetables were supplied once a day with no water limitation. Monkeys were housed for clear behavioral assessment. Animals were released from isolation and treatment commenced after 1 month. All procedures were in compliance with the guidelines for laboratory animal care and use of the national institutes of health, and were approved by the laboratory animal care and use committee of the parkinson's disease institute.

1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) administration prior to injury, animals were acclimated to the population and scored for symptoms of Parkinson' S disease as described (Langston et al Ann neurol.2000; 47: S79-89). All values are within the normal range. The monkeys were then injected subcutaneously with 2.0mg/kg MPTP (Sigma, St-Louis, Missouri) dissolved in saline. The symptoms of Parkinson's disease are scored 3-4 weeks after MPTP administration. Disability scores ranged from 0 (normal) to 28 (severe parkinson animals). Animals were evaluated for the following: 1) reduced spatial movement (reduced use of available cage space), 2) bradykinesia (increased slowness of body movement), 3) dexterity in left and 4) dexterity in right, 5) balance, 6) cold stiffness (freezing) and 7) kinetic tremor. If they have no Parkinson disease symptoms, MPTP (1.0-2.0 mg/kg) is repeatedly injected for 2-5 times, and the total dose reaches 3.5-13.5 mg/kg. Despite multiple MPTP administrations, two animals had no stable parkinson's disease symptoms. These two monkeys did not show reliable dyskinesias in response to treatment with levodopa.

Nicotine treatment: all monkeys (n ═ 7) were then given a drinking solution for 3 weeks, containing a commercially available orange flavourTo mask the bitter taste of nicotine (fig. 1). Control group (n-4) was administered only continuouslyIn the Gatorade of the treatment group (n ═ 3), nicotine (free base) was added. Nicotine administration was initiated at 50. mu.g/ml for one week, 150. mu.g/ml for one week, followed by weeks with increasing concentrations in increments of 150g per week up to 650. mu.g/ml (FIG. 1). Since animals are relatively old and teeth are less well-defined, about 25ml of dry food particles is usedOr nicotine-(for the treatment group) softened to ensure adequate nicotine was ingested. Nicotine treatment had no significant effect on body weight or fluid intake, and monkeys showed good health.

Administration of levodopa: administering to monkeys by crushingCR 100/25(DuPont Pharma) tablet and dissolved in water to prepare levodopa/carbidopa (5mg/kg and 1.25mg/kg, respectively). This dose of levodopa is within the dose range prescribed for parkinson's disease patients. Monkeys were gavaged twice daily with 3.5 hour intervals for 8 weeks using a 5 day dosing/2 day withdrawal schedule (Hsu et al, J Pharmacol ExpTher.2004; 311: 770-777). During levodopa treatment, monkey fruits were given in the morning and food particles were given 3.5 hours after levodopa administration in the afternoon to optimize gastrointestinal absorption.

Dyskinesias were scored as described (Hsu et al, J Pharmacol Exp ther. 2004; 311: 770-777) from video. This included a 1 hour baseline period (no drug) from-8: 00-9:00AM, followed by two 3.5 hour levodopa treatment periods starting at-9: 00AM and-12: 30 PM. Dyskinesia scores were assessed by two independent assessors, unknown to treatment, at 30 minute intervals for a2 minute period. They are scored on a score of 0 (no dyskinesia) to 4; score 1 indicates non-sustained weak dyskinesia; score 2 indicates persistent mild dyskinesia; score 3 represents moderate dyskinesia that impairs the ability to remain still; score 4 indicates gross and non-motor severe dyskinesias.

And (3) data analysis: the levodopa treatment regimen used in this study included a 5 day dosing/2 day rest schedule. Scores for parkinson's disease symptoms were made weekly monday and friday, and the scores for these two days were averaged. The dyskinesia score was determined by averaging the weekly wednesday and thursday scores. All values are expressed as mean ± sem of the indicated animal numbers. Results were tested using paired t tests orAnalysis of variance (ANOVA) for comparison, followed by Ponfrontal multiple comparison post hoc test (Bonferroni multiple comparison post test) usingThe program (GraphPad Software, Inc., San Diego, Calif.). A level of 0.05 was considered significant.

Determination of plasma cotinine levels: cotinine (the major (75%) metabolite of nicotine) in plasma is measured as an indicator 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 anesthesia (intramuscular injection of 15-20 mg/kg) at about 3 pm. Blood samples were centrifuged at 1,000 Xg for 12 minutes and plasma was stored at-80 ℃. Plasma cotinine levels were determined using an ELISA kit (oraser Technologies Inc, Bethleham, PA). Plasma cotinine levels were 303+25 (n-7), falling within the range observed in smokers (Hukkanen et al, Pharmacol rev.2005; 57: 79-115 and Matta et al, psychromermacology (berl) 2007; 190: 269-319).

Results

Time course of nicotine in monkeys with nigrostriatal lesions leading to a reduction in dyskinesia caused by levodopa: nicotine treatment (n ═ 3) resulted in a reduction of levodopa-induced dyskinesia over the course of the day compared to non-nicotine treated animals (n ═ 4). This reduction was observed throughout the 8 week study period, with data at weeks 2,4, 6 and 8 as shown in figure 2. In monkeys that did not receive nicotine, the rapidly progressing dyskinesia after levodopa administration reached a maximum after 30-90 minutes and declined within the remaining two hours (figure 2). Nicotine-treated animal dyskinesia was significantly reduced compared to monkeys not receiving nicotine. For example, at 8 weeks, analysis of variance gave a significant major effect of nicotine treatment (F [1, 80] ═ 54.24, p < 0.0001). There is also a significant major effect of time (F15, 80 ═ 8.95, p < 0.0001).

Reduction of overall dyskinesia in monkeys receiving nicotine treatment: the effect of nicotine treatment on overall dyskinesia response was next examined by evaluating the area under the curve over time. A significant decrease was observed at all time points in animals receiving nicotine treatment compared to monkeys not receiving nicotine treatment (figure 3). For example, at week 8, a significant major effect of nicotine was obtained by analysis of variance (F1, 10 ═ 11.41, p ═ 0.007), with no temporal effect.

Nicotine treatment reduces peak dose dyskinesia: peak dyskinesia is defined as the maximum dyskinesia score that occurs during the morning or afternoon. The peak dyskinesia was reduced in nicotine treated animals over the entire 8 weeks of levodopa treatment compared to the control group (fig. 4). At week 8, for example, significant major effects of nicotine were obtained by ANOVA analysis of variance (F [1, 10] ═ 7.90, p ═ 0.0184), with no temporal major effect.

Nicotine shortens the duration of dyskinesia: 3 hours after the second daily levodopa administration, significant dyskinesias remained in non-nicotine treated monkeys, but not in nicotine treated animals (figure 2, table 1). Analysis of variance (F [1, 20] ═ 18.33, p ═ 0.0004) indicated the presence of the major effect of nicotine treatment, but no difference was shown over the 8 week evaluation period (table 1).

TABLE 1 Nicotine administration reduces the duration of levodopa-induced dyskinesia

Each value is the mean ± standard error of dyskinesia assessments 3 hours after levodopa treatment in the afternoon.

^*p < 0.05 was compared to the smokeless base treatment using analysis of variance followed by a Ponfulnery post-hoc test.

Example 2: nicotine reduction of Levodopa-induced monkey dyskinesia

Materials and methods

The materials and methods were the same as in example 1.

Results

Cross-over study: the data depicted in figures 2-4 and table 1 clearly show that nicotine administration attenuates levodopa-induced dyskinesia. A crossover study was then performed in which animals that previously received nicotine were given vehicle (n-3), while vehicle-treated animals now were administered nicotine (n-4). Levodopa treatment was stopped. The nicotine concentration was gradually increased in the drinking solution (see fig. 1) to 650 μ g/ml, at which concentration the animals were maintained for 4 weeks. Monkeys that previously received nicotine were given carrier drinking water for the same period of time. All monkeys were then treated with levodopa (5mg/kg, twice daily, 3.5 hours apart) over the following 8 week period. Since both groups of monkeys had previously received levodopa, they were referred to as levodopa-induced.

Nicotine administration reduced levodopa-induced dyskinesia in levodopa-induced monkeys: for these analyses, the scores of each animal receiving the new treatment were compared to the scores of the same animal during the previous treatment period (i.e., prior to the crossover). Figure 5 results using paired t-tests show that nicotine administration significantly reduced overall dyskinesia at all time points. Analysis of dyskinesia time course also shows the major effect of nicotine throughout levodopa treatment period by analysis of variance (e.g., week 8, F [1, 114] ═ 15.89, p ═ 0.0001). Peak dyskinesia was significantly reduced in the last 4 weeks of levodopa treatment (week 6, p 0.0354; and week 8, p 0.0138, paired t-test). Dyskinesia duration was also reduced by nicotine treatment, with a significant major effect of nicotine shown by differential analysis (F1, 24 ═ 18.00, p ═ 0.0003). Thus, nicotine administration reduces levodopa-induced dyskinesia in animals that previously received levodopa.

Nicotine withdrawal increases levodopa-induced dyskinesia in levodopa-induced monkeys: by control, overall dyskinesia scores were significantly increased at weeks 4, 6 and 8 of levodopa treatment in nicotine deprived animals (figure 6). Analysis of the time course of dyskinesia also showed an increase in dyskinesia in 8 weeks of levodopa treatment, and analysis of variance gave a clear major effect of nicotine (e.g. week 8, F [1, 76] ═ 15.94, p ═ 0.0001). In addition, a significant increase in the duration of dyskinesia assessed 3 hours after levodopa administration in the afternoon, two-factor analysis of variance (F1, 16 ═ 5.33, p ═ 0.0346) gave a clear major effect of nicotine. Thus, nicotine withdrawal enhances levodopa-induced dyskinesia.

Nicotine administration did not affect symptoms of parkinson's disease when treated and untreated with levodopa: levodopa administration reduced the parkinson's disease score, which was determined when its effect was maximal 1.5-2 hours after levodopa administration (fig. 7 and table 2). Nicotine treatment did not affect symptoms of parkinson's disease both when levodopa was treated and when untreated (F1, 16 ═ 0.03, p ═ 0.8718).

TABLE 2 Nicotine administration did not affect symptoms of Parkinson's disease when levodopa was treated and untreated

Figure 7 shows the effect of nicotine administration on parkinson's disease. White bars indicate no nicotine treatment and black bars indicate nicotine treatment. The parkinsonian symptoms were assessed immediately before and 1.5 to 2 hours after levodopa administration in the afternoon, when the greatest anti-parkinsonian effect was expected. Two of the 7 animals in this study did not develop symptoms of parkinson's disease and, therefore, were not included in this analysis. Error bars are mean ± standard error of 5 animals before and after nicotine treatment crossover. Compared with the same group which is not treated by the levodopa, the Mann-Withney test is adopted,^**p is less than 0.01. These results indicate that nicotine treatment affects only dyskinesia behavior and not parkinson's disease symptoms.

The results of examples 1 and 2 are the first to show that nicotine treatment reduces levodopa-induced dyskinesia in non-human primates. Nicotine treatment can significantly reduce peak dyskinesia and duration of dyskinesia response. Importantly, this is not accompanied by worsening of parkinson's disease with or without levodopa treatment. For animals pre-treated with nicotine, i.e. monkeys not treated with levodopa, the dyskinesia caused by levodopa was reduced by about 60%. Furthermore, nicotine treatment reduced dyskinesia by about 35% in monkeys that had previously received levodopa treatment, i.e. those induced by levodopa.

Example 3: effect of continuous nicotine delivery on its anti-dyskinetic effects

Animals: these experiments required two groups of experimental animals (see table 3) to determine the efficacy of the micropump in alleviating dyskinesia in injured monkeys.

Table 3: experimental grouping in example 3

Group of	n	Nicotine	Levodopa treatment (5mg/kg oral)
				(1) Of MPTP Damage	8	Whether or not	Is that
(2) Of MPTP Damage	8	Is that	Is that

MPTP treatment all animals were injured by injection of MPTP (1.5-2.0 mg/kg, subcutaneous injection). Animals were scored for parkinson's disease 3-4 weeks after injury according to the method described in example 1. MPTP was injected repeatedly up to 4 times if one animal had no symptoms of Parkinson's disease. The injury process may take up to 4 months to produce parkinsonian animals. Each group required 8 animals, as our aim was to obtain stable parkinson's disease symptoms. Generally, about 80% of animals produce stable symptoms of parkinson's disease. The animals were then allowed to recover for 1 month from the last MPTP injection to ensure that the animals attained stable parkinson's disease symptoms prior to surgical implantation of the micropump.

Micro-pump delivery: nicotine was delivered by a mini-pump following standard procedures, using a 0.2ml pump (ALZET) to release nicotine over a period of 4 weeks. Nicotine was administered at a dose of 0.5 mg/kg/day (free base). This dose is selected based on data previously known in the art for nonhuman primates. Surgically implanted nicotine-containing micropumps and treatments exhibit good tolerability with no detectable weight loss or adverse effects. The non-nicotine treatment group received the vehicle in the pump. Nicotine and cotinine levels in plasma were measured 1-2 weeks after micropump implantation to ensure a sufficient nicotine dose as described in example 1. The aim was to achieve a concentration similar to that in our current study involving administration of nicotine in drinking water (about 500 ng/ml). The pump was changed every month to ensure that the nicotine supply remained constant. Animals received nicotine for 2 months prior to the initiation of levodopa treatment.

L-dopa: after 2 months of nicotine infusion, both groups of monkeys (vehicle or nicotine) were gavaged with L-dopa/carbidopa (5mg/kg/1.25mg/kg) twice daily at 9:00am and 1:00 pm. Treatment was performed according to a 5 day dosing schedule with 2 day drug withdrawal and for at least 4 weeks. If nicotine treatment reduces dyskinesia, L-dopa treatment is continued (up to 2 months) so that we can determine how long the reduction of dyskinesia can be maintained.

The modified non-human primate parkinson rating scale described in example 1 was used to score parkinson's disease symptoms. Dyskinesia was monitored from video using the scoring system detailed in example 1. Parkinson's disease symptom scores were performed 3 times per week throughout the treatment period (about 9 months). Dyskinesia scores were performed when these animals were treated with L-dopa.

These studies will test the effect of stable nicotine administration which may enhance the anti-dyskinetic effect of nicotine. Without being bound to any theory, continuous nicotine application results in initial receptor activation followed by receptor desensitization or inactivation until nicotine disappears. Receptor desensitization or blockade is then thought to result in compensatory changes in striatal nAChRs, and receptor changes may be more pronounced depending on the period of desensitization. Thus, more permanent desensitization and receptor changes are expected to occur with continuous nicotine therapy.

Example 4: nicotine treatment reduces L-dopa-induced dyskinesia-like locomotion in rats

Materials and methods

Animal model-6-hydroxypolydopamine injury. We used the rat nigrostriatal lesion model of 6-hydroxypolybartamine injury described by Cenci and colleagues (Cenci et al, 1998 Eur JNeurosci 10: 2694-2706; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579). Adult male SD rats were anesthetized with isoflurane (isoflurane) and then placed in Kopf stereotaxic apparatus. 6 μ g of 6-hydroxypolydopamine (2 μ g/. mu.l) was injected intracranially through burr holes, and the ascending dopamine fiber bundle injected to the right was positioned at two independent sites, for a total of 12 μ g of 6-hydroxypolydopamine. The coordinates of the location of these two injury sites relative to the pre-halogen site and the dural surface are as follows: (1) front-to-back, -4.4; lateral, 1.2; ventral, 7.8; gum (tooth bar) -2.4; (2) front-to-back, -4.0; lateral, 0.75; ventral, 8.0; gum +3.4(Cenci et al, 1998 Eur J Neurosci 10: 2694-2706; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579). All procedures were in compliance with NIH laboratory animal use and management guidelines and approved by the laboratory animal care and use committee.

Behavioral assessment of injury. As an indicator of nigrostriatal injury, rats tested for rolling behavior 3-4 weeks after injury. This test was done using an automated behavioral measuring instrument (ROTOMAX, AccuScan Instruments inc. columbus, Ohio, USA) with 4 cylindrical chambers (50cm height x 34cm diameter). Rats were acclimatized by placing them in a cylindrical chamber for 30 minutes and then amphetamine (4mg/kg i.p.) was administered as previously described (Visanji et al, 2006, Neuropharmacology 51: 506-516). Rats were observed for 90 minutes of circling behavior after injection. Rats tested 2 nd after 1 week, and the data from both tests were pooled.

A nicotine treatment regimen. Rats were first given 1% saccharin in a drinking solution for 3-4 days (fig. 8). Then adding nicotine with the concentration of 25 mug/ml, and increasing to 50 mug/ml after 3-4 days. Animals were maintained at this dose for 3 weeks. Treatment of L-dopa was then started as follows with continued administration of nicotine.

L-dopa treatment and behavioral testing of AIM. As described (Cenci et al, 1998 EurJ Neurosci 10: 2694-2706; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579), rats received a single intraperitoneal injection of 8mg/kg L-dopa methyl ester plus 15mg/kg benserazide per day for 3 weeks (FIG. 8). Abnormal Involuntary Movements (AIM) occurring after daily levodopa injection were quantified using the Cenci and colleagues research scale (Cenci et al, 1998 EurJ Neurosci 10: 2694-2706; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579), as previously done in the laboratory (Cox et al, 2007, exp. Neurol.). The rats were placed in the Rotomax test chamber. Then scored on a scale of 0 to 4: 1-occasional; 2 ═ common; 3 ═ persistent but interruptible by sensory distraction (sensory distraction); 4-sustained, severe, uninterrupted by sensory constraints. The scoring categories are (1) axial dystonia, including head and neck twisted postures; (2) orolingual movement disorders with shaped jaw movement and contralateral tongue extension and (3) forelimb movement with tension-disordered movement of the contralateral forelimb. They also evaluated for voluntary dyskinesia (locomotive dyskinesia) or increased locomotion with contralateral excursion. However, since the interpretation of this motor response is unclear (Papa et al, 1994 BrainRes 662; 69-74; Cenci et al, 1998 Eur J Neurosci 10: 2694-2706), these scores were not included in the study.

Autonomic dyskinesia is different from the above-described rotational behavior. After levodopa treatment, rats were observed one by one every 20 minutes for a total of 3 hours. A maximum of 108 scores per session is therefore possible (maximum score 12 per observation; number of observations 9 per session). Rats were evaluated by two evaluators, one of which was blinded.

And (6) analyzing the data. Statistical significance was determined using Student's t test or analysis of variance followed by Pongfulnery post test as needed. Data are presented as mean ± SEM. A p-value level of 0.05 was considered statistically significant.

Results

Nicotine treatment reduced the overall AIM score. The time course of the effect of 50. mu.g/ml nicotine on the total AIM number 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. The test is carried out after the Ponfulnery test is adopted,^*p is less than 0.05. A decrease in AIM score was observed throughout the 3 hour period with a significant primary 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 between the two (F (8, 153) ═ 0.388, p ═ 0.93). The next experiment determined whether a lower nicotine dose also reduced AIM. Thus, the nicotine concentration in the drinking water was reduced from 50 μ g/ml to 25 μ g/ml while continuing to administer L _ dopa (see fig. 8). AIM was tested in rats at 2 and 4 weeks after initiation of low dose nicotine (25. mu.g/ml). Since the results at 2 and 4 weeks were similar, the data were pooled. FIG. 9 (right panel) shows that nicotine-induced AIM reduction is maintained when 25 μ g/ml nicotine is used in drinking water. Two-factor analysis of variance demonstrated significant major effects 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)。

nicotine treatment reduces different AIM components. As already indicated before, AIM consists of several different components: (1) axial dystonia; (2) mouth-tongue dyskinesia; and (3) limb movement disorders. Results are shown for 3 week and 6-8 week time points (FIG. 10). In FIG. 10, the values are expressed as mean + SEM of 9 to 10 rats, using t-test,^*p is less than 0.05 and^**p is less than 0.01. At two time points, both doses of nicotine had a significant reduction in forelimb dyskinesia, and at 6-8 weeks time points, axial dyskinesia was significantly reduced. There is a tendency, but not obvious, for oral dyskinesia to diminish. Thus, nicotine treatment reduces some of the AIM, but not another. These results may suggest that nicotine discrimination affects the molecular mechanisms associated with AIM. To demonstrate this possibility, a correlation analysis between nicotine-mediated reduction of AIM components and molecular mechanisms can be performed.

The effect of nicotine on parkinson's disease-related behavior. Our studies in monkeys show that nicotine treatment reduces levodopa-induced dyskinesia without affecting parkinson's disease symptoms. In a preliminary study in rats, it was found that nicotine treatment did not affect the rolling behaviour, which is an indicator of nigrostriatal damage (Mabandla et al, 2004 Metab Brain Dis 19; 43-50; Howells et al, 2005Behav Brain Res 165: 210-220; Steiner et al, 2006 Exp neuron 199: 291-300). The degree of rotation was quantified using rotomax (accuscan system) and rats receiving saccharin (8.2+3.7, n ═ 10) were not different from rats receiving nicotine (8.4+6.7, n ═ 9). The effect of nicotine on the rotary performance can also be tested. This is another method used to evaluate the effect of drugs on motor performance in Parkinson rats (Lundblad et al, 2003J Neurochem 84: 1398-1410; Dekundy et al, 2007Behav Brain Res 179: 76-89).

Current data indicate that nicotine treatment significantly reduces levodopa-induced AIM in a rat model of 6-hydroxydopamine injury. These data demonstrate that nicotine at 25 and 50 μ g/ml in drinking water reduces AIM. This effect of nicotine persists for at least 2 months of levodopa treatment. These results are important as they further support the concept that nicotine can be used for levodopa-induced dyskinesia in parkinson's disease.

Example 5: effect of nicotinic receptor agonists on Levodopa-induced dyskinetic movement

The effect of nicotinic receptor agonists such as conotoxin MII, epibatidine, A-85380, cytisine, lobeline, quinaline, SIB-1508Y, SIB-1553A, ABT-418, ABT-594, ABT-894, TC-2403, TC-2559, RJR-2403, SSR180711, GTS-21 and warennikelin can be tested using the models described in the preceding examples. The effect of nicotinic receptor agonists in levodopa-induced dyskinesia can be tested using the rodent model described in example 4. In addition, compounds can be tested in non-human primate models that exhibit symptoms of Parkinson's disease and dyskinesias that closely approximate those in Parkinson's disease (the Parkinson's disease models described in examples 1-3). Nicotinic receptors can be tested using both models. Alternatively, testing for nicotinic receptor agonists may employ any of the models described herein as well as any model known in the art.

Rodent model

6-hydroxypolydopamine damage. Rats (30) were first injured with 6-hydroxypolydopamine using the method described in example 4.

Behavioral assessment of injury. The rotational behavior of the rats was tested two (2) weeks after injury as an indicator of nigrostriatal injury. This is done using an automated behavior meter. Baseline activity was monitored for thirty (30) minutes, followed by amphetamine (4mg/kg, i.p.). The animals were diverted to the ipsilateral side because amphetamine caused the uninjured striatum to release more dopamine than the injured striatum. The rotation is monitored for ninety (90) minutes. Rats were retested one (1) week later and the results of the two (2) assay periods were combined. Rats with scores of over 100 rotations were kept on study (20-25 of 30 animals were typically selected).

And (4) processing the levodopa. Rats (20) can be injected intraperitoneally with 8mg/kg L-dopa methyl ester plus 15mg/kg benserazide once a day for three (3) weeks and longer (Cenci et al, 1998 Eur JNeurosci 10: 2694-2706; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579). Three (3) weeks of levodopa treatment resulted in the appearance of AIM in most rats. Levodopa administration was initiated after nicotine agonist treatment.

Evaluation of AIM induced by Levodopa. Levodopa-induced AIM 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 ExpNeurol). This included axial dystonia, orolingual dyskinesia and forelimb movements, rats were scored on a scale of 0 to 4 for each AIM component. Rats were observed one by one every 20 minutes for a total of 3 hours after levodopa treatment. Thus, a maximum of 108 scores are possible for each observation period (maximum score 12 for each observation and 9 for each observation period). Rats were evaluated by two evaluators, one of which was blinded.

A nicotine agonist dosing regimen. The agonist may be administered for 2 to 3 weeks, preferably in drinking water, prior to levodopa treatment. There is a need to determine the optimal dose and route of administration of the agonist prior to the start of the test using the injured animal. If this information is not available, a pilot study can be conducted to determine the optimal dosing regimen.

Evaluation of Parkinson's disease symptoms. As described above, contralateral rotation by amphetamine and levodopa was evaluated to determine the effect on parkinson's disease symptoms.

And (6) processing. All thirty (30) rats were first injured with 6-hydroxypolybartamine over a period of one (1) week. Rats were tested 2-3 weeks later to determine the extent of nigrostriatal damage by evaluating ipsilateral rotation (rotation acceptable for 20-25 rats) in response to amphetamine. It is generally necessary to evaluate the rotational behaviour of an animal for one (1) week; behavioral testing of 20-25 rats typically required two (2) weeks. At week 4, group 1 will be given vehicle only (e.g., saccharin). Group 2 will be given vehicle (probably saccharin) plus agonist. Levodopa plus benserazide was then administered two (2) weeks after the agonist was started. AIM was determined three (3) weeks after the start of levodopa administration. Treatment with levodopa continued throughout.

Non-human primate model

Although rats are an excellent model for screening compounds, non-human primate studies ensure efficacy in a model that more closely resembles human parkinson's disease. Assays can be designed to further optimize understanding of the dosing regimen and mode of administration of the most effective nicotinic receptor agonist. The non-human primate models described in examples 1 and 2 can be used to test the effect of nicotinic receptor agonists on levodopa-induced dyskinesia.

The effect of sustained delivery of nicotinic receptor agonists on levodopa-induced dyskinesia can be tested by micropump as described in example 3.

Example 6: intermittent and continuous nicotine treatment to alleviate levodopa-induced dyskinesia in rat models of Parkinson's disease

Method of producing a composite material

An animal. Male SD rats (initial body weight approximately 250 g) were used for the test, purchased from Charles River Laboratories (Gilroy, Calif.). They were kept in 2 cages in a temperature-controlled room circulating 12-12 hours day-night and were allowed to take food water freely. 3-4 days after the end of the period, rats were unilaterally injured with 6-hydroxypolyamine according to the method described above (Cenci et al, 1998 Eur J Neurosci 10: 2694-2706; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579). Rats were maintained under isoflurane (2%) anesthesia during injury. They were placed in a Kopf stereotaxic instrument and cranial burr holes were drilled at the following coordinates relative to the pre-halo spot and dural surface: (1) front-to-back, -4.4; lateral, 1.2; ventral, 7.8; gum-2.4; (2) front-to-back, -4.0; lateral, 0.75; ventral, 8.0; gum +3.4(Cenci et al, 1998 Eur JNeurosci 10: 2694-2706; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579). 6-Hydroxypolyamine was dissolved in 0.02% ascorbic acid/saline to a concentration of 3. mu.g/. mu.l. 2 μ l were stereotactically injected at each of these sites, for a total of 12mg into the right ascending dopamine fiber bundle. The target area was perfused with 6-hydroxypolybartamine for a period of more than 2 minutes, leaving the catheter at the injection site for an additional 2 minutes. All procedures were in compliance with NIH laboratory animal use and management guidelines and approved by the laboratory animal care and use committee.

And (5) testing the behavior. At 2 and 3 weeks post-injury, rats were tested for rotational behavior using an automated behavior measuring instrument (ROTOMAX, AccuScan Instruments inc. columbus, Ohio, USA). Each rat was placed in a cylindrical glass chamber and acclimated for 30 minutes, followed by amphetamine (4.0mg/kg, i.p.). Behavioral observations were made for an additional 90 minutes, and rats that rotated ipsilaterally at least 100 times were used for further studies.

Nicotine therapy. When the behavioral testing was completed, rats were treated with nicotine by drinking water producing intermittent dosing or by a micro pump providing a constant level of nicotine. For administration through 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 an acclimation period of 2-3 days, nicotine (free base, Sigma Chemical co., st.louis, MO) was added to the saccharin-containing drinking solution (pH 7.0) of the treatment group. Nicotine administration was started at a concentration of 25 μ g/ml for 2 days. Then increased to 50. mu.g/ml and the animals were maintained at this dose for several weeks (FIG. 11). Measurement of fluid intake indicated that the nicotine-containing animals in solution had less water than the vehicle-treated control group, which was consistent with previous studies with mice. Rats appeared healthy, although some minor differences in body weight occurred with continued dosing.

In a separate series of experiments, nicotine was continuously administered to rats by an Alzet micropump (model 2004-200. mu.l) which secreted nicotine for 28 days. The micropump was implanted subcutaneously according to the manufacturer's instructions. The micro-pump was filled with sterile water or nicotine base in water to deliver a dose of 2 mg/kd/d. Rats receiving the vehicle or nicotine containing micropump were similar in body weight (table 4).

TABLE 4 plasma cotinine levels in rats chronically receiving nicotine

Values represent work value. + -. SEM for the animals shown

And (4) processing the levodopa. 3 weeks after the initial 50. mu.g/ml nicotine administration, rats were given a single daily intraperitoneal injection of 8mg/kg levodopa methyl ester plus 15mg/kg benserazide (all 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). Abnormal Involuntary Movements (AIM) were quantified 3 weeks after daily levodopa administration. They include (1) axial dystonia, contralateral contortion of the neck and upper body; (2) orolingual dyskinesia, fixed mandibular movement and contralateral lingual extension and (3) prolimb dyskinesia, repetitive rhythmic tics or contralateral prolimb dystonia posture and/or grasping action on the contralateral paw (Cenci et al, 1998 Eur JNeurosci 10: 2694-2706.; Cenci et al, 2002 Nat Rev Neurosci 3: 574-579; Carta et al, 2006 Neurochem 96: 1718-1727). Rats scored the three AIMs on a scale from 0 to 4 as follows: 1-occasional; 2 ═ common; 3-sustained but interrupted by sensory constraints; 4-persistent, severe, uninterrupted by sensory constraints. Animal performance was assessed every 20 minutes for 3 hours by two assessors after injection, one of which was blinded. This resulted in a total of 9 test sessions per animal. Thus, a maximum of 108 scores per animal are possible (9 for the maximum score per observation period; 12 for the number of 3 hour observation periods).

Plasma cotinine measurements. The nicotine metabolite cotinine was determined as an indirect measure of plasma nicotine levels using an ELISA kit (oracure Technologies, Bethlehem, PA). Blood samples were collected from the femoral vein 1-2 weeks after starting nicotine treatment by drinking water or micro pump. Plasma was prepared and analyzed with < 1 μ l aliquots of plasma according to the manufacturer's instructions. And finishing a standard curve of 5-100 ng/ml cotinine in each measurement.

And (6) analyzing the data. All analyses used GraphPad(GraphPad software, Inc, San Diego, Calif.). Differences in scores between groups were analyzed using a nonparametric test (Mann-Whitney-Mann test or Wilcoxon test of paired data). For the time course study, analysis of variance (ANOVA) was followed by a bangfenney multiple comparison test. A level of 0.05 was considered significant. Results are expressed as mean ± SEM.

Results

Figure 11 shows that intermittent nicotine treatment reduces levodopa-induced Abnormal Involuntary Movements (AIM). The treatment schedule (top panel) describes the timing of nicotine administration (in drinking water), levodopa dosing and behavioral testing. Rats were given drinking water containing 1% saccharin in a vehicle for 1 week. Some rats (n-10) continue to administer this solution, and the remainder of the animals (n-9) have nicotine added to their carrier drinking water. The initial dose of nicotine administration was 25 μ g/ml and then switched to a final maintenance dose of 50 μ g/ml. After 3 weeks, animals were given levodopa (8mg/kg i.p.) 1 time a day for 10 weeks, followed by 12mg/kg l-dopa for another 5 weeks. AIM scores were evaluated by two evaluators throughout the levodopa treatment period, one of which was blinded. AIM was assessed over a 3 hour period in the manner described in methods, including a 30 minute baseline period (no levodopa). Analysis of variance showed that nicotine treatment had a significant effect on the AIM induced by levodopa (P < 0.001). Each symbol is the mean. + -. SEM of 9-10 rats.

Figure 12 shows that intermittent nicotine treatment reduced individual AIM after levodopa treatment. Rats were given nicotine by drinking the solution, followed by levodopa administration. Rats were evaluated for overall, axial, orolingual and forelimb AIM by two evaluators, one of whom was unknown for animal treatment. Each value represents the mean + SEM of 9-10 rats. The Mann-Whitney test was used, and compared to rats receiving saccharin only,^*P＜0.05，^**p < 0.01 and^***P＜0.001。

fig. 13 depicts a cross-study demonstrating the effect of intermittent nicotine treatment through drinking water on l-dopa-induced AIM. The left panel depicts the results for rats that did not initially receive nicotine prior to the first levodopa treatment period, and then were given nicotine in a drinking solution as shown in figure 11. The right panel depicts the results of rats initially receiving nicotine prior to the first levodopa treatment period, and then saccharin was given in the drinking solution. Administration of nicotine reduced the AIM induced by levodopa, although it resulted in an increase in AIM development after withdrawal. Each value represents the mean + SEM of 9-10 rats. Using the Wilcoxon test, compared to the initial treatment,^*p < 0.05 and^***P＜0.001。

figure 14 shows that continuous nicotine exposure through a micropump reduces l-dopa-induced AIM. The treatment schedule (top) describes the timing of nicotine administration (by micropump), levodopa administration and behavioral testing. Half of the rats were implanted with a nicotine (2mg/kg/d) containing micropump 4 weeks after 6-OHDA injury, and the other half with a vehicle containing micropump. After two weeks, all rats were given levodopa (8mg/kg i.p.) 1 time daily for 4 weeks, followed by 12mg/kg of levodopa for a further 3 weeks. AIM was assessed by two evaluators throughout the levodopa treatment period, one of which was blinded. Depicted in the figure is the time course of the effect of nicotine on AIM after levodopa treatment. The AIM evaluation was performed as described in the methods over a 3 hour period, including a 30 minute baseline period (no levodopa). Analysis of variance indicated a significant effect of nicotine treatment on l-dopa-induced AIM (P < 0.001). Each symbol is the mean ± SEM of 12 rats.

Figure 15 shows that constant nicotine exposure through the micropump reduces the individual AIM components after levodopa treatment. Rats were given nicotine (2mg/kg/d) via a minipump, followed by levodopa administration. Rats are evaluated for overall, axial, oral and forelimb AIM by two evaluators, one of whom is unknown to the animal treatment. Each value represents the mean + SEM of 12 rats. Mann-Whitney test and not acceptanceIn comparison with the rats containing nicotine,^*P＜0.05，^**p < 0.01 and^***P＜0.001。

fig. 16 shows a cross-study depicting the effect of constant nicotine exposure through a micropump on l-dopa-induced AIM. The left panel depicts the results for rats that did not initially receive nicotine prior to the first levodopa treatment period, and then were administered nicotine via a micropump as described in figure 14. The right panel depicts the results of rats initially receiving nicotine prior to the first levodopa treatment period and then administered a nicotine-free micropump. Administration of nicotine reduced the AIM induced by levodopa, although it resulted in an increase in AIM development after withdrawal. Each value represents the mean + SEM of 12 rats. Using the Wilcoxon test, compared to the initial treatment,^**p < 0.01 and^***P＜0.001。

example 7: effect of nicotinic receptor agonists on Levodopa-induced dyskinetic movement in humans

Empirical testing can be performed on the effect of nicotine on levodopa-induced dyskinesia. Inclusion criteria included male and female patients with parkinson's disease who were 30 years old or older. The main criteria for grouping are: (i) levodopa-associated peak dose dyskinesia with at least moderate motor disability greater than or equal to 25% of the waking time (UPDRS part IV, items 32 and 33, each greater than or equal to 2); (ii) levodopa-associated dose decay endpoints, recording "rest" times of 2.5 hours or more per day on average based on pre-study patient logs from day 4-29; (iii) stable parkinson's disease medication at least 1 month prior to randomization with a minimum 3 hour interval between levodopa ingestion; (iv) grading the Hoehn-Yahr into 1-4 grades in a rest period; (v) the performance had comprehension and gave informed consent; (vi) the ability to complete a patient diary. The main exclusion criteria included: (i) other clinically significant conditions in addition to those typical symptoms associated with parkinson's disease; (ii) ingestion of drugs that accompany dyskinesia exacerbations or extrapyramidal side effects and tardive dyskinesia or induction of liver enzymes, neuroleptics, drugs for the treatment of cognitive impairment, or specific drugs known to be metabolized essentially by the following cytochrome P450 isoenzymes: 1a2, 2B6, 2C19, 2C9, 2D6 and 2E 1; (iii) hypericum perforatum (st. john's word) or ginkgo were used up to the last treatment day of study drug within 48 hours prior to randomization;

(iv) test drugs were ingested within 30 days prior to initial screening.

The study may be a multicenter, double-blind, placebo-controlled, multi-dose-gradient, safe, tolerant, pharmacokinetic and efficacy study of nicotine administration in parkinson's patients concurrently treated with levodopa or other combination of anti-parkinson's drugs. Patients were randomized into one of 5 treatment groups to receive either fixed or escalated (from 0.3-4 mg per dose) doses of nicotine or placebo. For efficacy evaluation, patients were evaluated with levodopa challenge after overnight withdrawal of the parkinson's drug. Movement disorders caused by levodopa are assessed using standard assessment scales. The time spent in the "off" state or the "on" state in the absence of dyskinesia, with non-difficult dyskinesias and difficult dyskinesias is evaluated with a patient's diary (e.g. electronic medical record). The impairment of daily activity by dyskinesia was quantified using a PDYS-26 questionnaire. To study the positive or negative effects of nicotine on cognitive function, the study included two cognitive tests. Finally, the study included the investigator's assessment of CGI-I scale for dyskinesia, parkinson's disease, and general clinical condition.

Nicotine was mixed into capsules or tablets and supplied to all subjects. The patients were treated as described in the table below.

Table 5: treatment group

Group of	Prescribed intervention
		1. Placebo 1 placebo tablet was administered from day 1 to day 35	Medicine preparation: nicotine in a nicotine oral formulation, administered to a subject (about 3-8 times per day) per levodopa to 35 days
2. Activity control 1-35 days 1 tablet 0.3mg tablet	Medicine preparation: nicotine in a nicotine oral formulation, administered to a subject (about 3-8 times per day) per levodopa to 35 days
		3. 1 tablet of 0.3mg tablet on day 1-7 of activity control, and 1 tablet of 1mg tablet on day 8-35 of activity control	Medicine preparation: nicotine in a nicotine oral formulation, administered to a subject (about 3-8 times per day) per levodopa to 35 days
4. Activity control	Medicine preparation: nicotine

1 tablet of 0.3mg tablet on day 1-7, 1 tablet of 1mg tablet on day 8-14, 1 tablet of 2mg tablet on day 15-21, 1 tablet of 1mg tablet and 1 tablet of 2mg tablet on day 21-35	Orally administered nicotine in a basket, each time levodopa is administered to a subject (about 3-8 times per day) for 35 days
		5. 1 tablet of 0.3mg tablet on day 1-7, 1 tablet of 1mg tablet on day 8-14, 1 tablet of 2mg tablet on day 15-21, and 1 tablet of 1m tablet on day 21-28g tablet, 1 tablet of 2mg tablet, 2 tablets of 2mg tablet on day 28-35.	Medicine preparation: nicotine in a nicotine oral formulation, administered to a subject (about 3-8 times per day) per levodopa to 35 days

Subjects were instructed not to alter the drug combination without the investigator's instructions. The subjects were advised to be exposed daily or every other day to assess the progress of the trial and to increase any side effects associated with nicotine. At the end of the trial, the patient is interviewed. They were asked to assess their own satisfaction with the study drug (-2- +2) and the ability of the study drug to modulate levodopa-induced dyskinesia. If the study used a placebo and was blind, the blind was opened and a statistical comparison of nicotine to placebo was made.

While preferred embodiments of the present invention have been illustrated 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 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.

Claims (5)

1. Use of nicotine for the preparation of a solid pharmaceutical composition for oral administration for reducing side effects caused by a dopaminergic agent, wherein the pharmaceutical composition comprises nicotine and a pharmaceutically acceptable carrier, wherein nicotine is present in an amount of less than 3mg, wherein the nicotine is combined with the pharmaceutically acceptable carrier in the solid pharmaceutical composition.

2. The use of claim 1, wherein nicotine is present in an amount greater than 0.5 mg.

3. The use of claim 1, wherein nicotine is present in an amount greater than 0.5mg and less than 2 mg.

4. Use according to claim 1, wherein nicotine is present in an amount of 2 mg.

5. Use according to claim 1, wherein nicotine is present in an amount of 1 mg.