Use of beta-adrenergic inverse agonists for smoking cessation

Abstract

The chronic use of β-adrenergic inverse agonists such as nadolol, carvedilol, and ICI-118,551 provides an improved method for the treatment of mucus hypersecretion in subjects with such mucus hypersecretion or at risk of developing mucus hypersecretion, especially in subjects attempting smoking cessation. One aspect of a method according to the present invention is a method of preventing or controlling mucus hypersecretion in the respiratory tract comprising administering a therapeutically effective quantity of a β-adrenergic inverse agonist to a subject with mucus hypersecretion or at risk of mucus hypersecretion. Another aspect of a method according to the present invention is a method of treating or preventing a disease or condition characterized by mucus hypersecretion comprising administering a therapeutically effective quantity of a β-adrenergic inverse agonist to a subject with such a disease or condition or at risk of contracting such a disease or condition. The inverse agonist can be used together with a therapeutically effective quantity of an additional compound to treat mucus hypersecretion, or, in the case of the use of the β-adrenergic inverse agonist in subjects attempting smoking cessation, a therapeutically effective quantity of an additional compound to promote smoking cessation. The invention further encompasses pharmaceutical compositions comprising the β-adrenergic inverse agonist and the additional compound.

We claim: 
     
         1 . A method of preventing or controlling mucus hypersecretion in the respiratory tract comprising administering to a subject with mucus hypersecretion or at risk of mucus hypersecretion, wherein the mucus hypersecretion is associated with smoking cessation and the subject is attempting smoking cessation or is about to cease smoking:
 (a) a therapeutically effective quantity of a β-adrenergic inverse agonist;   (b) a therapeutically effective quantity of an additional compound to treat mucus hypersecretion; and   (c) a therapeutically effective quantity of an additional compound to promote smoking cessation.   
     
     
         2 . The method of  claim 1  wherein the β-adrenergic inverse agonist is selected from the group consisting of β 2 -selective inverse agonists, and non-selective inverse agonists having inverse agonist activity against both β 1 - and β 2 -adrenergic receptors. 
     
     
         3 . The method of  claim 2  wherein the β-adrenergic inverse agonist is a β 2 -selective inverse agonist. 
     
     
         4 . The method of  claim 1  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol, bupranolol, butoxamine, carazolol, carvedilol, IC-118,551, levobunolol, metoprolol, propranolol, sotalol, and timolol, and the salts and prodrugs thereof. 
     
     
         5 . The method of  claim 1  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and m and n are 1 to 3, with the proviso that where R 1  and R 2  are both hydrogen and m is 1, n is other than 1. 
     
     
         6 . The method of  claim 5  wherein the β-adrenergic inverse agonist is nadolol. 
     
     
         7 . The method of  claim 1  wherein the β-adrenergic inverse agonist is selected from the group consisting of carvedilol and analogues of carvedilol of formula (II) wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and R 3  is hydrogen or lower alkyl, with the proviso that all of R 1 , R 2 , and R 3  are not all hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         8 . The method of  claim 7  wherein the β-adrenergic inverse agonist is carvedilol. 
     
     
         9 . The method of  claim 1  wherein the β-adrenergic inverse agonist is selected from the group consisting of timolol and analogues of timolol of formula (III) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         10 . The method of  claim 9  wherein the β-adrenergic inverse agonist is timolol. 
     
     
         11 . The method of  claim 1  wherein the β-adrenergic inverse agonist is selected from the group consisting of metoprolol and analogues of metoprolol of formula (IV) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         12 . The method of  claim 11  wherein the β-adrenergic inverse agonist is metoprolol. 
     
     
         13 . The method of  claim 1  wherein the β-adrenergic inverse agonist is selected from the group consisting of IC-118,551 and analogues of IC-118,551 of formula (V) wherein R 1  is lower alkyl, R 2  is hydrogen or lower alkyl, R 3  is hydrogen or lower alkyl, R 4  is hydrogen or lower alkyl, R 5  is lower alkyl, and R 6  is lower alkyl, with the proviso that all of R 1 , R 3 , R 5 , and R 6  are not methyl and all of R 2  and R 4  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         14 . The method of  claim 13  wherein the β-adrenergic inverse agonist is ICI-118,551. 
     
     
         15 . The method of  claim 1  wherein the additional compound to promote smoking cessation is selected from the group consisting of buproprion, varenicline, clonidine, and nortriptyline, and the salts and prodrugs thereof. 
     
     
         16 . The method of  claim 1  wherein the additional compound to treat mucus hypersecretion is selected from the group consisting of: an antibiotic; a DNase; a bronchodilator; a corticosteroid; an epidermal growth factor antagonist; an expectorant; (2R,3R,4S,5R)-2-[6 amino-2-(1 S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydrofuran-3,4-diol; 4-hydroxy-7-[2-[[2-[[3-(2-phenylethyoxy)propyl]sulfonyl]ethyl]amino]ethyl-2-(3H)-benzothiazolone; cis-20,4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid; and a PDE4 inhibitor. 
     
     
         17 . A pharmaceutical composition comprising:
 (a) a therapeutically effective quantity of a β-adrenergic inverse agonist; and   (b) at least one pharmaceutically acceptable carrier;   
       wherein the pharmaceutical composition is formulated to treat mucus hypersecretion. 
     
     
         18 . The pharmaceutical composition of  claim 17  wherein the pharmaceutical composition is formulated to treat mucus hypersecretion associated with nicotine withdrawal. 
     
     
         19 . The pharmaceutical composition of  claim 17  wherein the β-adrenergic inverse agonist is selected from the group consisting of β 2 -selective inverse agonists, and non-selective inverse agonists having inverse agonist activity against both β 1 - and β 2 -adrenergic receptors. 
     
     
         20 . The pharmaceutical composition of  claim 19  wherein the β-adrenergic inverse agonist is a β 2 -selective inverse agonist. 
     
     
         21 . The pharmaceutical composition of  claim 17  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol, bupranolol, butoxamine, carazolol, carvedilol, IC-118,551, levobunolol, metoprolol, propranolol, sotalol, and timolol, and the salts and prodrugs thereof. 
     
     
         22 . The pharmaceutical composition of  claim 17  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and m and n are 1 to 3, with the proviso that where R 1  and R 2  are both hydrogen and m is 1, n is other than 1. 
     
     
         23 . The pharmaceutical composition of  claim 22  wherein the β-adrenergic inverse agonist is nadolol. 
     
     
         24 . The pharmaceutical composition of  claim 17  wherein the β-adrenergic inverse agonist is selected from the group consisting of carvedilol and analogues of carvedilol of formula (II) wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and R 3  is hydrogen or lower alkyl, with the proviso that all of R 1 , R 2 , and R 3  are not all hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         25 . The pharmaceutical composition of  claim 24  wherein the β-adrenergic inverse agonist is carvedilol. 
     
     
         26 . The pharmaceutical composition of  claim 17  wherein the β-adrenergic inverse agonist is selected from the group consisting of timolol and analogues of timolol of formula (III) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         27 . The pharmaceutical composition of  claim 26  wherein the β-adrenergic inverse agonist is timolol. 
     
     
         28 . The pharmaceutical composition of  claim 17  wherein the β-adrenergic inverse agonist is selected from the group consisting of metoprolol and analogues of metoprolol of formula (IV) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         29 . The pharmaceutical composition of  claim 28  wherein the β-adrenergic inverse agonist is metoprolol. 
     
     
         30 . The pharmaceutical composition of  claim 17  wherein the β-adrenergic inverse agonist is selected from the group consisting of IC-118,551 and analogues of IC-118,551 of formula (V) wherein R 1  is lower alkyl, R 2  is hydrogen or lower alkyl, R 3  is hydrogen or lower alkyl, R 4  is hydrogen or lower alkyl, R 5  is lower alkyl, and R 6  is lower alkyl, with the proviso that all of R 1 , R 3 , R 5 , and R 6  are not methyl and all of R 2  and R 4  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         31 . The pharmaceutical composition of  claim 30   
       wherein the β-adrenergic inverse agonist is ICI-118,551. 
     
     
         32 . The pharmaceutical composition of  claim 17  wherein the pharmaceutical composition is formulated for administration via a transdermal patch. 
     
     
         33 . The pharmaceutical composition of  claim 17  wherein the pharmaceutical composition is formulated for administration as chewing gum. 
     
     
         34 . A pharmaceutical composition comprising:
 (a) a therapeutically effective quantity of a β-adrenergic inverse agonist;   (b) a therapeutically effective quantity of an additional compound to treat mucus hypersecretion; and   (c) at least one pharmaceutically acceptable carrier;   
       wherein the pharmaceutical composition is formulated to treat mucus hypersecretion. 
     
     
         35 . The pharmaceutical composition of  claim 34  wherein the pharmaceutical composition is formulated to treat mucus hypersecretion associated with nicotine withdrawal. 
     
     
         36 . The pharmaceutical composition of  claim 34  wherein the β-adrenergic inverse agonist is selected from the group consisting of β 2 -selective inverse agonists, and non-selective inverse agonists having inverse agonist activity against both β 1 - and β 2 -adrenergic receptors. 
     
     
         37 . The pharmaceutical composition of  claim 36  wherein the β-adrenergic inverse agonist is a β 2 -selective inverse agonist. 
     
     
         38 . The pharmaceutical composition of  claim 34  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol, bupranolol, butoxamine, carazolol, carvedilol, IC-118,551, levobunolol, metoprolol, propranolol, sotalol, and timolol, and the salts and prodrugs thereof. 
     
     
         39 . The pharmaceutical composition of  claim 34  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and m and n are 1 to 3, with the proviso that where R 1  and R 2  are both hydrogen and m is 1, n is other than 1. 
     
     
         40 . The pharmaceutical composition of  claim 39  wherein the β-adrenergic inverse agonist is nadolol. 
     
     
         41 . The pharmaceutical composition of  claim 34  wherein the β-adrenergic inverse agonist is selected from the group consisting of carvedilol and analogues of carvedilol of formula (II) wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and R 3  is hydrogen or lower alkyl, with the proviso that all of R 1 , R 2 , and R 3  are not all hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         42 . The pharmaceutical composition of  claim 41  wherein the β-adrenergic inverse agonist is carvedilol. 
     
     
         43 . The pharmaceutical composition of  claim 34  wherein the β-adrenergic inverse agonist is selected from the group consisting of timolol and analogues of timolol of formula (III) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         44 . The pharmaceutical composition of  claim 43  wherein the β-adrenergic inverse agonist is timolol. 
     
     
         45 . The pharmaceutical composition of  claim 34  wherein the β-adrenergic inverse agonist is selected from the group consisting of metoprolol and analogues of metoprolol of formula (IV) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         46 . The pharmaceutical composition of  claim 45  wherein the β-adrenergic inverse agonist is metoprolol. 
     
     
         47 . The pharmaceutical composition of  claim 34  wherein the β-adrenergic inverse agonist is selected from the group consisting of ICI-118,551 and analogues of IC-118,551 of formula (V) wherein R 1  is lower alkyl, R 2  is hydrogen or lower alkyl, R 3  is hydrogen or lower alkyl, R 4  is hydrogen or lower alkyl, R 5  is lower alkyl, and R 6  is lower alkyl, with the proviso that all of R 1 , R 3 , R 5 , and R 6  are not methyl and all of R 2  and R 4  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         48 . The pharmaceutical composition of  claim 47  wherein the β-adrenergic inverse agonist is ICI-118,551. 
     
     
         49 . The pharmaceutical composition of  claim 34  wherein the additional compound to treat mucus hypersecretion is selected from the group consisting of: an antibiotic; a DNase; a bronchodilator; a corticosteroid; an epidermal growth factor antagonist; an expectorant; (2R,3R,4S,5R)-2-[6 amino-2-(1 S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydrofuran-3,4-diol; 4-hydroxy-7-[2-[[2-[[3-(2-phenylethyoxy)propyl]sulfonyl]ethyl]amino]ethyl-2-(3H)-benzothiazolone; cis-20,4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid; and a PDE4 inhibitor. 
     
     
         50 . The pharmaceutical composition of  claim 34  wherein the pharmaceutical composition is formulated for administration via a transdermal patch. 
     
     
         51 . The pharmaceutical composition of  claim 34  wherein the pharmaceutical composition is formulated for administration as chewing gum. 
     
     
         52 . A pharmaceutical composition comprising:
 (a) a therapeutically effective quantity of a β-adrenergic inverse agonist;   (b) a therapeutically effective quantity of an additional compound to promote smoking cessation; and   (c) at least one pharmaceutically acceptable carrier;   
       wherein the pharmaceutical composition is formulated to treat mucus hypersecretion associated with nicotine withdrawal. 
     
     
         53 . The pharmaceutical composition of  claim 52  wherein the β-adrenergic inverse agonist is selected from the group consisting of β 2 -selective inverse agonists, and non-selective inverse agonists having inverse agonist activity against both β 1 - and β 2 -adrenergic receptors. 
     
     
         54 . The pharmaceutical composition of  claim 53  wherein the β-adrenergic inverse agonist is a β 2 -selective inverse agonist. 
     
     
         55 . The pharmaceutical composition of  claim 52  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol, bupranolol, butoxamine, carazolol, carvedilol, IC-118,551, levobunolol, metoprolol, propranolol, sotalol, and timolol, and the salts and prodrugs thereof. 
     
     
         56 . The pharmaceutical composition of  claim 52  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and m and n are 1 to 3, with the proviso that where R 1  and R 2  are both hydrogen and m is 1, n is other than 1. 
     
     
         57 . The pharmaceutical composition of  claim 56  wherein the β-adrenergic inverse agonist is nadolol. 
     
     
         58 . The pharmaceutical composition of  claim 52  wherein the β-adrenergic inverse agonist is selected from the group consisting of carvedilol and analogues of carvedilol of formula (II) wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and R 3  is hydrogen or lower alkyl, with the proviso that all of R 1 , R 2 , and R 3  are not all hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         59 . The pharmaceutical composition of  claim 58  wherein the β-adrenergic inverse agonist is carvedilol. 
     
     
         60 . The pharmaceutical composition of  claim 52  wherein the β-adrenergic inverse agonist is selected from the group consisting of timolol and analogues of timolol of formula (III) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         61 . The pharmaceutical composition of  claim 60  wherein the β-adrenergic inverse agonist is timolol. 
     
     
         62 . The pharmaceutical composition of  claim 52  wherein the β-adrenergic inverse agonist is selected from the group consisting of metoprolol and analogues of metoprolol of formula (IV) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         63 . The pharmaceutical composition of  claim 62  wherein the β-adrenergic inverse agonist is metoprolol. 
     
     
         64 . The pharmaceutical composition of  claim 52  wherein the β-adrenergic inverse agonist is selected from the group consisting of ICI-118,551 and analogues of IC-118,551 of formula (V) wherein R 1  is lower alkyl, R 2  is hydrogen or lower alkyl, R 3  is hydrogen or lower alkyl, R 4  is hydrogen or lower alkyl, R 5  is lower alkyl, and R 6  is lower alkyl, with the proviso that all of R 1 , R 3 , R 5 , and R 6  are not methyl and all of R 2  and R 4  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         65 . The pharmaceutical composition of  claim 64  wherein the β-adrenergic inverse agonist is ICI-118,551. 
     
     
         66 . The pharmaceutical composition of  claim 52  wherein the additional compound to promote smoking cessation is selected from the group consisting of buproprion, varenicline, clonidine, and nortriptyline, and the salts and prodrugs thereof. 
     
     
         67 . The pharmaceutical composition of  claim 52  wherein the pharmaceutical composition is formulated for administration via a transdermal patch. 
     
     
         68 . The pharmaceutical composition of  claim 52  wherein the pharmaceutical composition is formulated for administration as chewing gum. 
     
     
         69 . A pharmaceutical composition comprising:
 (a) a therapeutically effective quantity of a β-adrenergic inverse agonist;   (b) a therapeutically effective quantity of an additional compound to treat mucus hypersecretion;   (c) a therapeutically effective quantity of an additional compound to promote smoking cessation; and   (d) at least one pharmaceutically acceptable carrier;   
       wherein the pharmaceutical composition is formulated to treat mucus hypersecretion associated with nicotine withdrawal. 
     
     
         70 . The pharmaceutical composition of  claim 69  wherein the β-adrenergic inverse agonist is selected from the group consisting of β 2 -selective inverse agonists, and non-selective inverse agonists having inverse agonist activity against both β 1 - and β 2 -adrenergic receptors. 
     
     
         71 . The pharmaceutical composition of  claim 70  wherein the β-adrenergic inverse agonist is a β 2 -selective inverse agonist. 
     
     
         72 . The pharmaceutical composition of  claim 69  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol, bupranolol, butoxamine, carazolol, carvedilol, IC-118,551, levobunolol, metoprolol, propranolol, sotalol, and timolol, and the salts and prodrugs thereof. 
     
     
         73 . The pharmaceutical composition of  claim 69  wherein the β-adrenergic inverse agonist is selected from the group consisting of nadolol and a compound of formula (I) 
       
         
           
           
               
               
           
         
       
       wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and m and n are 1 to 3, with the proviso that where R 1  and R 2  are both hydrogen and m is 1, n is other than 1. 
     
     
         74 . The pharmaceutical composition of  claim 73  wherein the β-adrenergic inverse agonist is nadolol. 
     
     
         75 . The pharmaceutical composition of  claim 69  wherein the β-adrenergic inverse agonist is selected from the group consisting of carvedilol and analogues of carvedilol of formula (II) wherein R 1  is hydrogen or lower alkyl, R 2  is hydrogen or lower alkyl, and R 3  is hydrogen or lower alkyl, with the proviso that all of R 1 , R 2 , and R 3  are not all hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         76 . The pharmaceutical composition of  claim 75  wherein the β-adrenergic inverse agonist is carvedilol. 
     
     
         77 . The pharmaceutical composition of  claim 69  wherein the β-adrenergic inverse agonist is selected from the group consisting of timolol and analogues of timolol of formula (III) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         78 . The pharmaceutical composition of  claim 77  wherein the β-adrenergic inverse agonist is timolol. 
     
     
         79 . The pharmaceutical composition of  claim 69  wherein the β-adrenergic inverse agonist is selected from the group consisting of metoprolol and analogues of metoprolol of formula (IV) wherein R 1  is hydrogen or lower alkyl and R 2  is hydrogen or lower alkyl, with the proviso that both R 1  and R 2  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         80 . The pharmaceutical composition of  claim 79  wherein the β-adrenergic inverse agonist is metoprolol. 
     
     
         81 . The pharmaceutical composition of  claim 69  wherein the β-adrenergic inverse agonist is selected from the group consisting of ICI-118,551 and analogues of IC-118,551 of formula (V) wherein R 1  is lower alkyl, R 2  is hydrogen or lower alkyl, R 3  is hydrogen or lower alkyl, R 4  is hydrogen or lower alkyl, R 5  is lower alkyl, and R 6  is lower alkyl, with the proviso that all of R 1 , R 3 , R 5 , and R 6  are not methyl and all of R 2  and R 4  are not hydrogen. 
       
         
           
           
               
               
           
         
       
     
     
         82 . The pharmaceutical composition of  claim 81  wherein the β-adrenergic inverse agonist is ICI-118,551. 
     
     
         83 . The pharmaceutical composition of  claim 69  wherein the additional compound to treat mucus hypersecretion is selected from the group consisting of: an antibiotic; a DNase; a bronchodilator; a corticosteroid; an epidermal growth factor antagonist; an expectorant; (2R,3R,4S,5R)-2-[6 amino-2-(1 S-hydroxymethyl-2-phenyl-ethylamino)-purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydrofuran-3,4-diol; 4-hydroxy-7-[2-[[2-[[3-(2-phenylethyoxy)propyl]sulfonyl]ethyl]amino]ethyl-2-(3H)-benzothiazolone; cis-20,4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexanecarboxylic acid; and a PDE4 inhibitor. 
     
     
         84 . The pharmaceutical composition of  claim 69  wherein the additional compound to promote smoking cessation is selected from the group consisting of buproprion, varenicline, clonidine, and nortriptyline, and the salts, solvates, analogues, congeners, mimetics, bioisosteres, stereoisomers, hydrolysis products, metabolites, precursors, and prodrugs thereof. 
     
     
         85 . The pharmaceutical composition of  claim 69  wherein the pharmaceutical composition is formulated for administration via a transdermal patch. 
     
     
         86 . The pharmaceutical composition of  claim 69  wherein the pharmaceutical composition is formulated for administration as chewing gum.