Methods and compositions for reduction of side effects of therapeutic treatments

Abstract

The invention provides compositions and methods utilizing a nicotinic receptor modulator, e.g., to reduce or eliminate a side effect associated with dopaminergic agent treatment. In some embodiments, the invention provides compositions and methods utilizing a combination of a dopaminergic agent and a nicotinic receptor modulator that reduces or eliminates a side effect associated with dopaminergic agent treatment.

1 . A pharmaceutical composition comprising an effective amount of a dopaminergic agent, an effective amount of a nicotinic receptor agonist and a pharmaceutically acceptable carrier, wherein the amount of agonist is sufficient to reduce a side effect of the dopaminergic agent in a subject. 
   
   
       2 . The composition of  claim 1  wherein the amount of agonist is sufficient to reduce the side effect by at least 30%. 
   
   
       3 . The composition of  claim 1  wherein said side effect is a dyskinesia. 
   
   
       4 . The composition of  claim 1  wherein said dopaminergic agent is a dopamine precursor or a dopamine receptor agonist. 
   
   
       5 . The composition of  claim 1  wherein said dopaminergic agent is levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinorole, apomorphine or a combination thereof. 
   
   
       6 . The composition of  claim 5  wherein said dopaminergic agent is levodopa. 
   
   
       7 . The composition of  claim 1  wherein said nicotinic receptor agonist is selected from the group consisting of a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, an antibody fragment, a vitamin derivative, a carbohydrate and a toxin. 
   
   
       8 . The composition of  claim 1  wherein said agonist is selected from the group consisting of nicotine, conotoxinMII, epibatidine, A-85380, cytisine, lobeline, anabasine, SIB-1508Y, SIB-1553A, ABT-418, ABT-594, ABT-894, TC-2403, TC-2559, RJR-2403, SSR180711, GTS-21 and varenicline. 
   
   
       9 . The composition of  claim 1  wherein said nicotinic receptor agonist is capable of modulating a nicotinic receptor in a brain. 
   
   
       10 . The composition of  claim 9  wherein said nicotinic receptor agonist is capable of modulating a nicotinic receptor in a nigrostriatal system. 
   
   
       11 . The composition of  claim 10  wherein said nicotinic receptor agonist is capable of modulating a nicotinic receptor in a striatum or substantia niagra. 
   
   
       12 . The composition of  claim 1  further comprising a therapeutic amount of a third agent. 
   
   
       13 . The composition of  claim 12  wherein said third therapeutic agent is used to achieve a therapeutic effect in combination with the dopaminergic agent or to treat a side effect of the dopaminergic agent. 
   
   
       14 . The composition of  claim 13  wherein said nicotinic receptor agonist and said third agent are capable of treating said side effect. 
   
   
       15 . The composition of  claim 12  wherein said nicotinic receptor agonist and said third agent are capable of treating a different side effect. 
   
   
       16 . The composition of  claim 12  wherein said third agent is selected from the group consisting of amantadine, carbidopa and entacapone. 
   
   
       17 . The composition of  claim 1  wherein said nicotinic receptor agonist is capable of modulating a nicotinic receptor comprising at least one α subunit or a nicotinic receptor comprising at least one α subunit and at least one β subunit. 
   
   
       18 . The composition of  claim 17  wherein said α subunit is selected from the group consisting of α2, α3, α4, α5, α6, α7, α8, α9, and α10 and wherein said β subunit is selected from the group consisting of β2, β3 and β4. 
   
   
       19 . The composition of  claim 17  wherein said α subunit is selected from the group consisting of a α3, α4 and α6. 
   
   
       20 . The composition of  claim 1  wherein said nicotinic receptor agonist is capable of modulating a nicotinic receptor comprising subunits selected from the group consisting of α4β2, α6β2, α4α6β2, α4α5β2, α4α6β2α3, α6β2β3 and α4α2β2. 
   
   
       21 . The composition of  claim 1  wherein said nicotinic receptor agonist is capable of modulating a nicotinic receptor comprising subunits selected from the group consisting of α4 and α7. 
   
   
       22 . The composition of  claim 1  wherein said dopaminergic agent is levodopa and said nicotinic receptor agonist is nicotine. 
   
   
       23 . The composition of  claim 22  wherein levodopa and nicotine are present in a relative molar ratio of about 0.001:1 to about 10:1. 
   
   
       24 . The composition of  claim 22  wherein levodopa is present at about 0.1 to about 1000 mg and nicotine is present at about 0.1-2000 mg. 
   
   
       25 . The composition of  claim 24  wherein said levodopa is present at about 40 to about 500 mg and nicotine is present at about 1 to about 100 mg. 
   
   
       26 . The composition of  claim 25  wherein levodopa is present at about 50 to about 150 mg and nicotine is present at about 1 to about 50 mg. 
   
   
       27 . The composition of  claim 1  wherein a therapeutic effect of dopaminergic agent is increased in said subject at least about 5%. 
   
   
       28 . A pharmaceutical composition comprising an effective amount of levodopa, an effective amount of carbidopa, an effective amount of nicotine capable of reducing levodopa-induced dyskinesias and a pharmaceutically acceptable carrier. 
   
   
       29 . A kit comprising the composition of  claim 1  and instructions for use of the composition. 
   
   
       30 . A pharmaceutical composition comprising an effective amount of a dopaminergic agent, and an effective amount of nicotine capable of reducing a side effect of said dopaminergic agent and a pharmaceutically acceptable carrier. 
   
   
       31 . The composition of  claim 30  wherein said side effect is a dyskinesia. 
   
   
       32 . The composition of  claim 30  wherein said dopaminergic agent and nicotine are present in a relative molar ratio of about 0.001:1 to about 10:1. 
   
   
       33 . The composition of  claim 30  wherein nicotine is present at about 0.1 to about 100 mg. 
   
   
       34 . The composition of  claim 33  wherein nicotine is present at about 0.1 to about 10 mg. 
   
   
       35 . The composition of  claim 34  wherein nicotine is present at about 0.5 mg. 
   
   
       36 . The composition of  claim 30  wherein said composition is capable of reducing said side effect at least about 30% when the composition is administered to a subject. 
   
   
       37 . The composition of  claim 30  wherein said composition is capable of being administered to an individual when a therapeutic effect is desired in said individual from said dopaminergic agent. 
   
   
       38 . The composition of  claim 30  wherein said composition is capable of being administered to the upper gastrointestinal tract. 
   
   
       39 . The composition of  claim 30  wherein said composition is capable of being administered so that nicotine achieves a plasma level of about 1 to about 500 ng/ml. 
   
   
       40 . The composition of  claim 39  wherein said plasma level is capable of being achieved in less than about 60 minutes before the side effect reaches a peak. 
   
   
       41 . The composition of  claim 39  wherein said plasma is capable of being achieved in less than about 60 minutes before the dopaminergic agent reaches the bloodstream or the tissue where the side effect is generated. 
   
   
       42 . The composition of  claim 39  wherein said plasma level is capable of remaining constant throughout treatment. 
   
   
       43 . The composition of  claim 30  wherein said composition is capable to being administered so that one or more metabolites of nicotine achieve a plasma level of about 1 to about 500 ng/ml. 
   
   
       44 . The composition of  claim 43  wherein said plasma level is capable of being achieved in less than about 60 minutes before the side effect reaches a peak. 
   
   
       45 . The composition of  claim 43  wherein said plasma level is capable of being achieved in less than about 60 minutes before the dopaminergic agent reaches the bloodstream or the tissue where the side effect is generated. 
   
   
       46 . The composition of  claim 43  wherein said plasma level is capable of remaining constant throughout treatment. 
   
   
       47 . A pharmaceutical composition comprising an effective amount of a dopaminergic agent, nicotine and a pharmaceutically acceptable carrier, wherein nicotine is present at about 0.01 to about 10 mg. 
   
   
       48 . The composition of  claim 47  wherein nicotine is capable of reducing a side effect induced by said dopaminergic agent. 
   
   
       49 . The method of  claim 48  wherein said side effect is dyskinesias. 
   
   
       50 . The composition of  claim 48  wherein the composition is capable of decreasing a side effect at least about 30% when the composition is administered to an animal. 
   
   
       51 . The composition of  claim 47  wherein said composition is capable of being administered to an individual when a therapeutic effect from said dopaminergic agent is desired in said individual. 
   
   
       52 . The composition of  claim 48  wherein the release of nicotine from said pharmaceutical composition is capable of reducing a side effect of the dopaminergic agent. 
   
   
       53 - 143 . (canceled) 
   
   
       144 . A multilayer tablet comprising an immediate release layer and a sustained release layer, wherein said immediate release layer comprises one or more therapeutic agents independently selected from the group consisting of nicotinic receptor agonist and dopaminergic agent, and said sustained release layer comprises one or more therapeutic agents independently selected from the group consisting of nicotinic receptor agonist and dopaminergic agents. 
   
   
       145 . The multilayer tablet of  claim 144  wherein said dopaminergic agent comprises a dopamine precursor or a dopamine receptor agonist. 
   
   
       146 . The multilayer tablet of  claim 144  wherein said dopaminergic agent comprises levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinorole, apomorphine or a combination thereof. 
   
   
       147 . The multilayer tablet of  claim 146  wherein said dopaminergic agent is levodopa. 
   
   
       148 . The multilayer tablet of  claim 144  wherein said agonist is selected from the group consisting of a simple or complex organic or inorganic molecule, a peptide, a protein, an oligonucleotide, an antibody, an antibody derivative, an antibody fragment, a vitamin derivative, a carbohydrate and a toxin. 
   
   
       149 . The multilayer tablet of  claim 144  wherein said agonist is selected from the group consisting of nicotine, conotoxinMII, epibatidine, A-85380, cytisine, lobeline, anabasine, SIB-1508Y, SIB-1553A, ABT-418, ABT-594, ABT-894, TC-2403, TC-2559, RJR-2403, SSR180711, GTS-21 and varenicline. 
   
   
       150 . The multilayer tablet of  claim 149  wherein said agonist is nicotine. 
   
   
       151 . The multilayer tablet of  claim 144  where said immediate release layer or said sustained release agent further comprises a third agent. 
   
   
       152 . The multilayer tablet of  claim 151  wherein said third agent is used to achieve a therapeutic effect in combination with the dopaminergic agent or to treat a side effect of the dopaminergic agent.