Action of L-citrulline to prevent or treat endothelial dysfunction

Inventors

KALSI, Gurdyal • BARR, Frederick • Pasternack, Gary • Summar, Marshall

Assignees

Vanderbilt University • Asklepion Pharmaceuticals LLC

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.

Core Innovation

The invention relates to treating endothelial dysfunction in a patient by administering an effective amount of L-citrulline (citrulline). The effective amount is sufficient to reduce the uncoupling of endothelial nitric oxide synthase (eNOS) and/or sufficient to reduce the formation of free radicals.

Patient selection and measurable response are grounded in plasma biomarkers. The method includes patients experiencing endothelial dysfunction having plasma levels of D-dimer above 250 ng/mL, and citrulline effectiveness is defined by a detectable reduction in plasma level of angiopoietin-2.

The disclosure describes administration approaches for delivering citrulline to treat endothelial dysfunction. Citrulline can be administered orally and/or intravenously, including sequential administration in which oral and intravenous phases occur in sequence.

Claims Coverage

The partial content includes two independent claims. Across these claims, the inventive features are treating endothelial dysfunction using an effective amount of citrulline to reduce eNOS uncoupling and/or free-radical formation, with patient selection or response tied to D-dimer and angiopoietin-2, and using sequential oral and intravenous administration.

The independent claims collectively cover treating endothelial dysfunction with citrulline to reduce eNOS uncoupling and/or free-radical formation, optionally using D-dimer (>250 ng/mL) and/or angiopoietin-2 detectable reduction as defining elements, and administering citrulline in sequential oral and intravenous phases.

Stated Advantages

Documented Applications