Methods and compositions for treating pulmonary hypertension

Abstract

The present disclosure provides compositions and methods for treating pulmonary hypertension. The compositions and methods are based on administering a NO-releasing compound, such as nitrite, to a subject in need thereof in an amount sufficient to increase the level of circulating nitric oxide (NO), a potent vasodilator, thereby reducing the subject's blood pressure and increasing blood flow.

1 .- 34 . (canceled) 
     
     
         35 . A method for treating pulmonary hypertension in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a phosphodiesterase type-5 inhibitor and a NO-releasing compound, wherein the therapeutically effective amount of the phosphodiesterase type-5 inhibitor improves the half-life of the NO-releasing compound. 
     
     
         36 . The method according to  claim 35 , wherein the phosphodiesterase type-5 inhibitor is vardenafil or a pharmaceutically acceptable salt or ester thereof and the NO-releasing compound is a pharmaceutically acceptable nitrite. 
     
     
         37 . The method according to  claim 35 , wherein said administering to the subject produces an amount of NO in the subject effective to decrease the pulmonary arterial pressure of the subject. 
     
     
         38 . The method according to  claim 37 , wherein the phosphodiesterase type-5 inhibitor and the NO-releasing compound are administered in separate compositions, simultaneously or sequentially. 
     
     
         39 . The method according to  claim 37 , wherein the phosphodiesterase type-5 inhibitor and the NO-releasing compound are co-administered. 
     
     
         40 . The method according to  claim 37 , wherein one or both of the phosphodiesterase type-5 inhibitor and the NO-releasing compound are formulated as a pharmaceutical composition adapted for nebulization into liquid or dry powder medical aerosols for delivery by inhalation to the subject. 
     
     
         41 . The method according to  claim 40 , wherein the pharmaceutical composition is administered to the subject with a metered dose inhaler such as a dry powder inhaler or a soft mist inhaler capable of delivering a fixed amount of the pharmaceutical composition per pulse. 
     
     
         42 . The method according to  claim 37 , wherein the subject is a human. 
     
     
         43 . The method according to  claim 37 , wherein the phosphodiesterase type-5 inhibitor is vardenafil or a pharmaceutically acceptable salt or prodrug thereof. 
     
     
         44 . The method according to  claim 43 , wherein vardenafil is administered in a dosage of about 1 to 500 μg per kilogram body weight, no more than about 200 μg per kilogram body weight, no more than about 100 μg per kilogram body weight, no more than about 50 μg per kilogram body weight, or no more than about 25 μg per kilogram body weight of the subject. 
     
     
         45 . The method according to  claim 37 , wherein the NO-releasing compound is sodium nitrite. 
     
     
         46 . The method according to  claim 45 , wherein the sodium nitrite is administered to achieve a circulating concentration of about 0.5 to 250 μM. 
     
     
         47 . A pharmaceutical composition for treating pulmonary hypertension, comprising a therapeutically effective amount of a phosphodiesterase type-5 inhibitor and a NO-releasing compound, wherein the composition is formulated for delivery by inhalation. 
     
     
         48 . The pharmaceutical composition of  claim 47 , wherein the amount of the phosphodiesterase type-5 inhibitor in the composition is about 200 to 2500 μg/ml. 
     
     
         49 . The pharmaceutical composition of  claim 47 , wherein the amount of the NO-releasing compound is about 200 to 2500 μg/ml. 
     
     
         50 . The pharmaceutical composition of  claim 47 , wherein the phosphodiesterase type-5 inhibitor is vardenafil or a pharmaceutically acceptable salt or ester thereof. 
     
     
         51 . The pharmaceutical composition of  claim 47 , wherein the NO-releasing compound is a pharmaceutically acceptable nitrite.