Methods of treating acute respiratory distress syndrome with activators of Tie-2
Disclosed herein are methods for treating acute respiratory distress syndrome, lung injury, respiratory failure, and associated conditions using activators of Tie-2 and inhibitors of HPTPβ. The methods include reducing vascular leak and permeability, reducing edema, reducing inflammation, and increasing oxygen exchange capacity in the lungs.
1 . A method of treating a lung condition selected from the group consisting of acute lung injury, acute hypoxemic respiratory failure, acute respiratory distress syndrome, and COVID-19 in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a Tie-2 activator;
wherein the Tie-2 activator is a compound of the formula:
or a pharmaceutically-acceptable salt, tautomer, or zwitterion thereof, wherein the administration increases an oxygenation index in the subject by about 1 to about 20 as compared to absence of administration.
2 . The method of claim 1 , wherein the compound is:
or a pharmaceutically-acceptable salt or zwitterion thereof.
3 . The method of claim 1 , wherein the administration increases an oxygenation index in the subject by about 1 to about 20 within 72 hours after administration.
4 . The method of claim 1 , wherein the administration reduces a mean airway pressure required to be applied by a ventilator to the subject by about 1 cm H 2 O to about 30 cm H 2 O as compared to absence of administration.
5 . The method of claim 1 , wherein the administration increases a PaO 2 /FiO 2 ratio in the subject by about 1 to about 100 as compared to absence of administration.
6 . The method of claim 1 , wherein the administration reduces an acute lung injury score in the subject by 1 to 4 as compared to absence of administration.
7 . The method of claim 1 , wherein the administration modulates a sequential organ failure assessment (SOFA) score in the subject by 1 to 24 as compared to absence of administration.
8 . The method of claim 1 , wherein the administration modulates a change in a level of a plasma concentration in the subject after administration, wherein the plasma concentration is selected from the group consisting of plasma Ang-2 concentration, plasma Ang-2/Ang-1 ratio, plasma IL-6 concentration, plasma IL-8 concentration, plasma TNFα concentration, plasma D-dimer concentration, and plasma CRP concentration.
9 . The method of claim 1 , wherein the Tie-2 activator is administered to the subject as a unit dosage form comprising a pharmaceutically-acceptable excipient.
10 . The method of claim 1 , wherein the administration is a continuous infusion, wherein the continuous infusion lasts for about 1 hour to about 2.5 hours.
11 . The method of claim 1 , wherein the administration is selected from the group consisting of subcutaneous, intravenous, bolus intravenous injection, and continuous intravenous infusion.
12 . The method of claim 1 , wherein the lung condition is selected from the group consisting of acute respiratory distress syndrome (ARDS), and COVID-19.
13 . A method of treating acute respiratory distress syndrome in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a Tie-2 activator in a unit dosage form, wherein the Tie-2 activator is a compound of the formula:
wherein the administration increases an oxygenation index in the subject by about 1 to about 20 as compared to absence of administration within 7 days after administration, wherein the therapeutically-effective amount is about 10 mg to about 40 mg, wherein the subject is infected with SARS-COV-2, and wherein the administration treats acute respiratory distress syndrome in the subject.
14 . A method of treating a COVID-19 in a subject in need thereof, the method comprising administering to the subject a therapeutically-effective amount of a Tie-2 activator in a unit dosage form, wherein the Tie-2 activator is a compound of the formula:
wherein the administration increases an oxygenation index in the subject by about 1 to about 20 as compared to absence of administration within 7 days after administration, wherein the therapeutically-effective amount is about 10 mg to about 40 mg, wherein the subject is infected with SARS-COV-2, and wherein the administration treats COVID-19 in the subject.
15 . The method of claim 13 , wherein the administration is subcutaneous, intravenous, or inhalation.
16 . The method of claim 14 , wherein the administration is subcutaneous, intravenous, or inhalation.
17 . The method of claim 13 , wherein the Tie-2 activator is:
or a pharmaceutically-acceptable salt or zwitterion thereof.
18 . The method of claim 14 , wherein the Tie-2 activator is:
or a pharmaceutically-acceptable salt or zwitterion thereof.