Pharmacological Treatment for Sleep Apnea

Abstract

The present invention relates generally to pharmacological methods for the prevention of amelioration of sleep-related breathing disorders via administration of agents or combinations of agents that possess serotonin-related pharmacological activity.

1 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of at least one serotonin receptor antagonist, in free base or quaternized form, selected from the group consisting of hydrodolasetron, mescaline, homochlorcyclizine, perlapine, loxapine, chlorpromazine, haloperidol, desmethylolanzapine, 2-hydroxymethylolanzapine, and 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime. 
     
     
         2 . The method of  claim 1  wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring. 
     
     
         3 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of at least one serotonin receptor antagonist, in quaternized form, selected from the group consisting of ketanserin, risperidone, cyproheptadine, clozapine, methysergide, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide. 
     
     
         4 . The method of  claim 3  wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring. 
     
     
         5 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of
 (a) at least one of a serotonin receptor antagonist
 (i) in free base or quaternized form selected from the group consisting of hydrodolasetron, mescaline, homochlorcyclizine, perlapine, loxapine, chlorpromazine, haloperidol, desmethylolanzapine, 2-hydroxymethylolanzapine, and 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime; 
 (ii) in quaternized form selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide; and 
 (iii) and mixtures thereof; and 
   (b) a serotonin receptor agonist.   
     
     
         6 . The method of  claim 5  wherein the serotonin receptor antagonist in the quaternized form is methylated, ethylated, or benzylated. 
     
     
         7 . The method of  claim 5  wherein the serotonin receptor agonist is selected from the group consisting of 8-OH-DPAT, sumatriptan, L694247, buspirone, alnitidan, zalospirone, ipsapirone, gepirone, zolmitriptan, risatriptan, 311C90, α-Me-5-HT, BW723C86, and MCPP. 
     
     
         8 . The method of  claim 5  wherein the serotonin receptor agonist is a 5-hydroxytryptamine 1  receptor subtype agonist. 
     
     
         9 . The method of  claim 5  wherein the serotonin receptor agonist is a 5-hydroxytryptamine 2  receptor subtype agonist. 
     
     
         10 . The method of  claim 5  wherein the effects of the serotonin receptor agonist are exerted in the central nervous system. 
     
     
         11 . The method of  claim 5  wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system. 
     
     
         12 . The method of  claim 5  wherein the effects of the serotonin receptor agonist are exerted in the central nervous system and wherein the effects of the serotonin receptor antagonist are exerted in the peripheral nervous system. 
     
     
         13 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of
 (a) at least one of a serotonin receptor antagonist
 (i) in their free base or quaternized form selected from the group consisting of hydrodolasetron, mescaline, homochlorcyclizine, perlapine, loxapine, chlorpromazine, haloperidol, desmethylolanzapine, 2-hydroxymethylolanzapine, 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime; 
 (ii) and in their quaternized form selected from the group consisting of ondansetron, ketanserin, risperidone, cyproheptadine, clozapine, methysergide, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide; and 
 (iii) mixtures thereof; and 
   (b) an effective amount of a selective serotonin reuptake inhibitor selected from the group consisting of fluoxetine, paroxetine, fluvoxamine, sertraline, citalopram, norfluoxetine, r(−) fluoxetine, s(+) fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, milnacipran, sibutramine, nefazodone, R-hydroxynefazodone, (−) venlafaxine, and (+) venlafaxine.   
     
     
         14 . (canceled) 
     
     
         15 . (canceled) 
     
     
         16 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof
 (a) an effective amount of at least one serotonin receptor antagonist selected from the group consisting of hydrodolasetron, mescaline, homochlorcyclizine, perlapine, ketanserin, loxapine, chlorpromazine, haloperidol, desmethylolanzapine, 2-hydroxymethylolanzapine, 1-(2-fluorophenyl)-3-(4-hydroxyaminoethyl)-prop-2-en-1-one-O-(2-dimethylaminoethyl)-oxime, risperidone, cyproheptadine, clozapine, methysergide, granisetron, mianserin, ritanserin, cinanserin, LY-53,857, metergoline, LY-278,584, methiothepin, p-NPPL, NAN-190, piperazine, SB-206553, SDZ-205,557, 3-tropanyl-indole-3-carboxylate, and 3-tropanyl-indole-3-carboxylate methiodide; and   (b) at least one selective serotonin reuptake inhibitor selected from the group consisting of fluvoxamine, sertraline, fluoxetine, paroxetine, citalopram, norfluoxetine, r(−)fluoxetine, s(+)fluoxetine, demethylsertraline, demethylcitalopram, venlafaxine, minacipran, sibutramine, nefazodone, R-hydroxynefazodone, (−) venlafaxine, and (+) venlafaxine.   
     
     
         17 . A method of ameliorating a sleep-related breathing disorder comprising administering to a patient in need thereof an effective amount of at least one serotonin receptor antagonist, in free base or quaternized form, selected from the group consisting of cisapride, norcisapride, (+) cisapride, (−) cisapride, (+) norcisapride, and (−) norcisapride. 
     
     
         18 . The method of  claim 17  wherein the sleep-related breathing disorder is selected from the group consisting of obstructive sleep apnea syndrome, apnea of prematurity, congenital central hypoventilation syndrome, obesity hypoventilation syndrome, central sleep apnea syndrome, Cheyne-Stokes respiration, and snoring. 
     
     
         19 . The method of  claim 17  further comprising administering an effective amount of a selective serotonin reuptake inhibitor selected from the group consisting of fluoxetine, paroxetine, demethylsertraline, demethylcitalopram, venlafaxine, minacipran, sibutramine, nefazodone, R-hydroxynefazodone, (−) venlafaxine, and (+) venlafaxine. 
     
     
         20 . The method of  claim 13  wherein the at least one serotonin receptor antagonist is quaternized ondansetron; and the selective serotonin reuptake inhibitor is fluoxetine. 
     
     
         21 . The method of  claim 13  wherein the sleep-related breathing disorder is obstructive sleep apnea syndrome.