Action of L-citrulline to prevent or treat endothelial dysfunction

Patent metadata

Field	Value
Publication number	US-12064409-B2
Application number	US-202117364280-A
Country	US
Kind code	B2
Filing date	Jun 30, 2021
Priority date	Jun 22, 2021
Publication date	Aug 20, 2024
Grant date	Aug 20, 2024

Abstract

This invention provides methods for treating endothelial dysfunction by administering an effective amount of citrulline to a patient. The patients may be suffering from acute respiratory distress syndrome (ARDS), sepsis, or infection by COVID-19 (Coronavirus Disease 2019); COVID-19 patients may be at risk of developing endothelial dysfunction, or they may be experiencing endothelial dysfunction. The effective amount of citrulline is sufficient to reduce the uncoupling of endothelial nitric oxide synthase (eNOS) or to reduce the formation of free radicals. Citrulline may be administered orally; intravenously; or both orally and intravenously in a sequential manner. Sequential administration of citrulline may be in three phases, such as (a) an initial phase in which citrulline is administered orally, (b) an intermediate phase wherein citrulline is administered intravenously, and (c) a final phase wherein citrulline is administered orally. The intermediate phase may be while the patient's breathing is being assisted mechanically.

First claim

What is claimed is:

1. A method for treating endothelial dysfunction in a patient, the method comprising administering an effective amount of citrulline to the patient, wherein the effective amount of citrulline is an amount sufficient to reduce the uncoupling of endothelial nitric oxide synthase (eNOS) and/or an amount sufficient to reduce the formation of free radicals;
wherein the patient experiencing endothelial dysfunction has plasma levels of D-dimer above 250 ng/mL; and/or
wherein the effective amount of citrulline is sufficient to reduce plasma level of angiopoietin-2 by a detectable amount.

2. The method of claim 1 , wherein the endothelial dysfunction is associated with thrombosis and disseminated intravascular coagulation.

3. The method of claim 1 , wherein the patient has acute respiratory distress syndrome (ARDS), sepsis, or is infected by COVID-19 (Coronavirus Disease 2019).

4. The method of claim 1 , wherein the patient experiencing endothelial dysfunction has plasma levels of D-dimer above 250 ng/ml.

5. The method of claim 1 , wherein citrulline is administered orally; intravenously; or both orally and intravenously in a sequential manner.

6. The method of claim 5 , wherein citrulline is administered orally.

7. The method of claim 5 , wherein citrulline is administered intravenously.

8. The method of claim 5 , wherein citrulline is administered sequentially in three phases, the three phases being
a. an initial phase in which citrulline is administered orally;
b. an intermediate phase wherein citrulline is administered intravenously; and
c. a final phase wherein citrulline is administered orally.

9. The method of claim 8 wherein, in the intermediate phase, the patient's breathing is being assisted mechanically.

10. The method of claim 1 , wherein citrulline is administered in an amount effective to raise plasma citrulline level of the patient above about 37 μM/L.

11. The method of claim 1 , wherein citrulline is administered in an amount effective to raise plasma citrulline level of the patient above about 100 μM/L.

12. The method of claim 7 , wherein intravenously administered citrulline is provided as a continuous infusion at about 3 mg/kg/hour to about 12 mg/kg/hour.

13. The method of claim 12 , wherein intravenously administered citrulline is provided as a continuous infusion at about 9 mg/kg/hour.

14. The method of claim 8 , wherein, in the initial phase, citrulline is administered as a bolus at about 100-500 mg/kg.

15. The method of claim 14 , wherein the bolus of citrulline is at about 100-300 mg/kg.

16. The method of claim 15 , wherein the bolus of citrulline is at about 150 mg/kg.

17. The method of claim 8 , wherein the initial and the intermediate phases are separated by 10-24 hours.

18. The method of claim 1 , wherein the effective amount of citrulline is sufficient to reduce plasma level of angiopoietin-2 by a detectable amount.

19. A method for treating endothelial dysfunction in a patient, the method comprising administering an effective amount of citrulline to the patient, wherein the effective amount of citrulline is an amount sufficient to reduce the uncoupling of endothelial nitric oxide synthase (eNOS) and/or an amount sufficient to reduce the formation of free radicals, the method including both a phase in which citrulline is administered orally and a phase in which citrulline is administered intravenously, these phases occurring in a sequential manner.

20. The method of claim 19 , wherein citrulline is administered in an amount effective to raise plasma citrulline level of the patient above about 37, 50, 100, 150, or 200 μM/L.

Assignees

• Asklepion Pharmaceuticals Llc
• Univ Vanderbilt

Inventors

• Kalsi Gurdyal
• Barr Frederick
• Pasternack Gary
• Summar Marshall

Classifications

• A61P9/12

  Antihypertensives · CPC title

• A61P9/08

  Vasodilators for multiple indications · CPC title

• A61P31/14 Primary

  for RNA viruses · CPC title

• A61P11/00

  Drugs for disorders of the respiratory system · CPC title

• A61K31/198 Primary

  Alpha-amino acids, e.g. alanine or edetic acid [EDTA] (betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00) · CPC title