Treating pulmonary conditions

Abstract

Compositions, methods, and kits useful for treating pulmonary conditions are provided herein. Such compositions can contain synergizing amounts of a non-specific phosphodiesterase inhibitor, such as a methylxanthine, in combination with leucine and/or a leucine metabolite, and resveratrol.

What is claimed is: 
     
         1 . A composition comprising:
 (a) leucine and/or one or more leucine metabolites selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and
 hydroxymethylbutyrate (HMB); and 
   (b) a methylxanthine;
 wherein the composition comprises at least about 250 mg of leucine and/or at least about 10 mg of the one or more leucine metabolites. 
   
     
     
         2 . The composition of  claim 1 , further comprising resveratrol. 
     
     
         3 . The composition of  claim 1 , wherein the composition comprises at least about 500 mg of leucine. 
     
     
         4 . The composition of  claim 1 , wherein the composition comprises between about 250-1500 mg of leucine. 
     
     
         5 . The composition of  claim 1 , wherein the composition comprises at least about 200 mg of leucine metabolites. 
     
     
         6 . The composition of  claim 1 , wherein the composition comprises between about 10-750 mg of leucine metabolites. 
     
     
         7 . The composition of  claim 1 , wherein the methylxanthine is selected from the group consisting of theophylline and theobromine. 
     
     
         8 . The composition of  claim 7 , wherein the composition comprises at least about 5 mg of theophylline. 
     
     
         9 . The composition of  claim 7 , wherein the composition comprises between about 1-100 or 5-50 mg of theophylline. 
     
     
         10 . The composition of  claim 1 , wherein the composition comprises a sub-therapeutic amount of the methylxanthine. 
     
     
         11 . The composition of  claim 7 , wherein the composition comprises a sub-therapeutic amount of theophylline. 
     
     
         12 . The composition of  claim 2 , wherein the composition comprises at least about 35 mg of resveratrol. 
     
     
         13 . The composition of  claim 2 , wherein the composition comprises between about 5-500 or 30-250 mg of resveratrol. 
     
     
         14 . The composition of  claim 1 , wherein the composition is substantially free of non-branched amino acids. 
     
     
         15 . The composition of  claim 1 , wherein the amino acids in the composition are substantially free of non-branched amino acids. 
     
     
         16 . The composition of  claim 1 , wherein the percent of non-branched amino acids relative to total amino acids in the composition is less than about 0.1, 1, or 10%. 
     
     
         17 . The composition of  claim 1 , wherein the composition is a unit dosage. 
     
     
         18 . The composition of  claim 1 , wherein the composition is formulated for oral dosing, inhalation or intravenous delivery. 
     
     
         19 . The composition of  claim 1 , wherein the composition is formulated for sustained release to effect a circulating level of greater than a desired circulating level over a time period of at least about 4, 6, 12, 24, 36, or 48 hours. 
     
     
         20 . The composition of  claim 19 , wherein the sustained release formulation effects a circulating level of methylxanthine in a subject that is greater than about 1 μM for the time period. 
     
     
         21 . A composition comprising:
 (a) leucine and/or one or more leucine metabolites selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and
 hydroxymethylbutyrate (HMB); and 
   (b) a methylxanthine;   wherein the mass ratio of (a) to (b) is at least about 15, 25, 50, 75, or 100, and   wherein the composition comprises at least about 5 mg of the methylxanthine.   
     
     
         22 . The composition of  claim 20 , further comprising at least about 10 mg of resveratrol. 
     
     
         23 . The composition of  claim 20 , wherein the methylxanthine is theophylline or theobromine. 
     
     
         24 . A composition comprising:
 (a) leucine and/or one or more leucine metabolites selected from the group consisting of keto-isocaproic acid (KIC), alpha-hydroxy-isocaproic acid, and
 hydroxymethylbutyrate (HMB); and 
   (b) a methylxanthine;   wherein the molar ratio of (a) to (b) is at least about 400, 500, 750, or 1000, and   wherein the composition comprises at least about 0.05 μg of the methylxanthine.   
     
     
         25 . The composition of  claim 24 , further comprising at least about 0.01 μg of resveratrol. 
     
     
         26 . The composition of  claim 24 , wherein the methylxanthine is theophylline or theobromine. 
     
     
         27 . The composition of  claim 24 , wherein the composition is formulated as a unit dosage for inhalation. 
     
     
         28 . The composition of  claim 27 , wherein the composition is packaged in an inhaler. 
     
     
         29 . The composition of  claim 28 , wherein the inhaler can comprise at least about 20, 50, 200, or 1000 unit dosages of the composition. 
     
     
         30 . A composition comprising:
 (a) leucine; and   (b) a methylxanthine,   wherein component (a) and (b) are present in an amount effective to achieve a circulating level of about 0.3-2 mM leucine and about 0.5-10 μM methylxanthine in a subject.   
     
     
         31 . The composition of  claim 24 , wherein the amounts of (a) and (b) are selected to induce a circulating level of about 0.7-2 mM leucine and about 0.7-3 μM methylxanthine in a subject. 
     
     
         32 . The composition of  claim 24 , wherein the subject is a human, a domesticated animal, or a farm animal. 
     
     
         33 . A composition comprising:
 (a) leucine; and   (b) a methylxanthine,   wherein component (a) and (b) are present in an amount that is effective in increasing expression level or secretion of one or more inflammatory markers in a lung endothelial cell selected from the group consisting of NFκB, eotaxin, IL1-β, and IL6, or reducing expression level or secretion of one or more anti-inflammatory markers in a lung endothelial cell selected from the group consisting of adiponectin receptor 1 and adiponectin receptor 2.   
     
     
         34 . The composition of  claim 33 , wherein (b) is present in an amount less than the amount required to achieve a circulating level of about 40 μM. 
     
     
         35 . A method of treating pulmonary conditions in a subject in need of treatment comprising administering to the subject a composition of any one of the preceding claims. 
     
     
         36 . A method of increasing expression level or secretion of an inflammatory marker selected from the group consisting of NFκB, eotaxin, IL1-β, and IL6, or reducing expression level or secretion of an anti-inflammatory marker selected from the group consisting of adiponectin receptor 1 and adiponectin receptor 2, the method comprising contacting a lung endothelial cell with a composition of any one of the preceding claims to effect said reduction and/or increase in expression level or secretion of said inflammatory or said anti-inflammatory marker. 
     
     
         37 . The method of  claim 36 , wherein the subject is a human, a domesticated animal, or a farm animal. 
     
     
         38 . The composition of  claims 20 ,  24 , or  33 , wherein the composition is formulated as a unit dosage. 
     
     
         39 . A kit comprising a multi-day supply of unit dosages of the composition of  claims 1 ,  20 ,  24 , or  33 , and instructions directing the administration of said multi-day supply over a period of multiple days.