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 - 57 . (canceled) 
   
   
       58 . A method of decreasing a side effect of treatment with a dopaminergic agent comprising administering to a human in need of a treatment with a dopaminergic agent an effective amount of a nicotinic receptor agonist in combination with said dopaminergic agent, wherein the amount of nicotinic receptor agonist is sufficient to reduce a side effect of said dopaminergic agent. 
   
   
       59 . The method of  claim 58  wherein the amount of nicotinic receptor agonist is sufficient to reduce said side effect at least about 30%. 
   
   
       60 . The method of  claim 58  wherein said side effect is a dyskinesia. 
   
   
       61 . The method of  claim 58  wherein said nicotinic receptor agonist modulates a nicotinic receptor comprising at least one α subunit or a nicotinic receptor containing at least one α subunit and at least one β subunit. 
   
   
       62 . The method of  claim 61  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. 
   
   
       63 . The method of  claim 62  wherein said α subunit is selected from the group consisting of a α3, α4 and α6. 
   
   
       64 . The method of  claim 58  wherein said nicotinic receptor agonist modulates a nicotinic receptor comprising subunits selected from the group consisting of α4β2, α6β2, α4α6β2, α4α5β2, α4α6β2β3, α6β2β3 and α4α2β2. 
   
   
       65 . The method of  claim 58  wherein said nicotinic receptor agonist modulates a nicotinic receptor comprising subunits selected from the group consisting of α4 and α7. 
   
   
       66 . The method of  claim 58  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. 
   
   
       67 . The method of  claim 58  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. 
   
   
       68 . The method of  claim 67  wherein said agonist is nicotine. 
   
   
       69 . The method of  claim 58  wherein said dopaminergic agent comprises a dopamine precursor or a dopamine receptor agonist. 
   
   
       70 . The method of  claim 58  wherein said dopaminergic agent comprises levodopa, bromocriptine, pergolide, pramipexole, cabergoline, ropinorole, apomorphine or a combination thereof. 
   
   
       71 . The method of  claim 70  wherein said dopaminergic agent is levodopa. 
   
   
       72 . The method of  claim 58  wherein said human suffers from a condition selected from the group consisting of Parkinson and Alzheimer's disease. 
   
   
       73 . The method of  claim 72  wherein said condition is Parkinson's disease. 
   
   
       74 . The method of  claim 73  wherein further comprising a third agent. 
   
   
       75 . The method of  claim 74  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. 
   
   
       76 . The method of  claim 58  wherein said administration comprises a single dose of said dopaminergic agent and single or multiple doses of said nicotinic receptor agonist. 
   
   
       77 . The method of  claim 58  wherein said administration comprises multiple doses of said dopaminergic agent and single or multiple doses of said nicotinic receptor agonist. 
   
   
       78 . The method of  claim 58  wherein said administration comprises simultaneous administration of said dopaminergic agent and said nicotinic receptor agonist in the same dosage form or simultaneous administration in separate dosage forms. 
   
   
       79 . The method of  claim 58  wherein said administration comprises separate administration of said dopaminergic agent and said nicotinic receptor agonist. 
   
   
       80 . The method of  claim 58  wherein said administration comprises simultaneous administration of said dopaminergic agent and said nicotinic receptor agonist in the same dosage form. 
   
   
       81 . The method of  claim 58  wherein the relative molar ratio of the amount of the dopaminergic agent administered and the amount of nicotinic receptor agonist administered is about 0.001:1 to about 10:1. 
   
   
       82 . The method of  claim 58  wherein the nicotinic receptor agonist is present in an amount sufficient to increase the therapeutic effect of said dopaminergic agent by an average of at least about 5%. 
   
   
       83 . The method of  claim 58  wherein said nicotinic receptor agonist is co-administered with said dopaminergic agent every time said dopaminergic agent is administered to said human. 
   
   
       84 . A method of decreasing a side effect of treatment with a dopaminergic agent comprising administering to a human in need of a treatment with a dopaminergic agent an effective amount of nicotine in combination with said dopaminergic agent, wherein said dopaminergic agent and nicotine are administered simultaneously to said human in an oral composition. 
   
   
       85 . The method of  claim 84  wherein said side effect is a dyskinesia. 
   
   
       86 . The method of  claim 84  wherein said human suffers from a condition selected from the group consisting of Parkinson and Alzheimer's disease. 
   
   
       87 . The method of  claim 86  wherein said condition is Parkinson's disease. 
   
   
       88 . The method of  claim 84  further comprising a third agent. 
   
   
       89 . The method of  claim 88  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. 
   
   
       90 . The method of  claim 84  wherein said administration comprises simultaneous administration of said dopaminergic agent and nicotine in separate dosage forms. 
   
   
       91 . The method of  claim 84  wherein said administration comprises simultaneous administration of said dopaminergic agent and nicotine in the same dosage form. 
   
   
       92 . The method of  claim 84  wherein the nicotinic receptor agonist is present in an amount sufficient to decrease the side effect of said dopaminergic agent by an average of at least about 30%. 
   
   
       93 . The method of  claim 92  wherein nicotinic receptor agonist is present in an amount sufficient to increase the therapeutic effect of said dopaminergic agent by an average of at least about 5%. 
   
   
       94 . A method of decreasing a side effect of treatment with a dopaminergic agent comprising administering to a human in need of a treatment with a dopaminergic agent an effective amount of nicotine in combination with said dopaminergic agent, wherein nicotine reduces a side effect of the dopaminergic agent. 
   
   
       95 . The method of  claim 94  wherein said side effect is a dyskinesia. 
   
   
       96 . The method of  claim 94  wherein said human suffers from a condition selected from the group consisting of Parkinson and Alzheimer's disease. 
   
   
       97 . The method of  claim 96  wherein said condition is Parkinson's disease. 
   
   
       98 . The method of  claim 94  further comprising a third agent. 
   
   
       99 . The method of  claim 98  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. 
   
   
       100 . The method of  claim 94  wherein said administration comprises a single dose of said dopaminergic agent and single or multiple doses of nicotine. 
   
   
       101 . The method of  claim 94  wherein said administration comprises multiple doses of said dopaminergic agent and single or multiple doses of nicotine. 
   
   
       102 . The method of  claim 94  wherein said administration comprises simultaneous administration of said dopaminergic agent and nicotine in the same dosage form or simultaneous administration in separate dosage forms. 
   
   
       103 . The method of  claim 94  wherein said administration comprises separate administration of said dopaminergic agent and nicotine. 
   
   
       104 . The method of  claim 94  wherein said administration comprises simultaneous administration of said dopaminergic agent and nicotine in the same dosage form. 
   
   
       105 . The method of  claim 94  wherein the nicotinic receptor agonist is present in an amount sufficient to decrease the side effect of said dopaminergic agent by an average of at least about 30%. 
   
   
       106 . The method of  claim 105  wherein nicotine is present in an amount sufficient to increase the therapeutic effect of said dopaminergic agent by an average of at least about 5. 
   
   
       107 . The method of  claim 94  wherein the effective amount of said dopaminergic agent is the same as the effective amount when said dopaminergic agent is administered alone. 
   
   
       108 . The method of  claim 107  wherein said effective amount of said dopaminergic agent is a dyskinesia inducing amount. 
   
   
       109 . The method of  claim 94  wherein the effective amount of said dopaminergic agent is 100% to about 75% of the effective amount when said dopaminergic agent is administered alone. 
   
   
       110 . The method of  claim 94  wherein the effective amount of nicotine is less than 93 mg per day. 
   
   
       111 . The method of  claim 94  wherein an effect on said side effect is observed within one hour after administration of said dopaminergic agent. 
   
   
       112 . The method of  claim 94  wherein said effective amount of nicotine is administered to an individual when a therapeutic effect is desired in said individual from said dopaminergic agent. 
   
   
       113 . The method of  claim 94  wherein said effective amount of nicotine is administered to the upper gastrointestinal tract. 
   
   
       114 . The method of  claim 94  wherein said effective amount of nicotine is administered so that nicotine achieves a plasma level of about 1 to about 500 ng/ml. 
   
   
       115 . The method of  claim 114  wherein said plasma level is achieved in less than about 60 minutes before the side effect reaches a peak. 
   
   
       116 . The method of  claim 114  wherein said plasma level is achieved in less than about 60 minutes before the dopaminergic agent reaches the bloodstream or the tissue where the side effect is generated. 
   
   
       117 . The method of  claim 114  wherein said plasma level remains constant throughout treatment. 
   
   
       118 . The method of  claim 94  wherein said composition is administered so that one or more metabolites of nicotine achieve a plasma level of about 1 to about 500 ng/ml. 
   
   
       119 . The method of  claim 118  wherein said plasma level is achieved in less than about 60 minutes before the side effect reaches a peak. 
   
   
       120 . The method of  claim 118  wherein said plasma level is achieved in less than about 60 minutes before the dopaminergic agent reaches the bloodstream or the tissue where the side effect is generated. 
   
   
       121 . The method of  claim 118  wherein said plasma level remains constant throughout treatment. 
   
   
       122 - 140 . (canceled) 
   
   
       141 . A method of decreasing levodopa-induced dyskinesias comprising administering to a human in need of treatment an effective amount of a nicotine in combination with an effective amount of levodopa and an effective amount of carbidopa, wherein the amount of nicotine is sufficient to reduce said dyskinesias and wherein levodopa and nicotine are administered orally simultaneously to said human. 
   
   
       142 . The method of  claim 141  wherein the amount of nicotine is sufficient to reduce said dyskinesias by at least 30%. 
   
   
       143 . The method of  claim 141  further comprising administering an effective amount of amantadine. 
   
   
       144 - 152 . (canceled)