Abstract: This invention is directed to citrulline therapy, where citrulline is administered to achieve a newly recognized therapeutic window. The results of a completed clinical trial has elucidated a therapeutic window for L-citrulline. Detailed analysis of clinical outcome as a function of the dose actually received reveals that patients falling within the dosing window showed significant improved effect compared to patients receiving a dose either below or above the dosing window. Patients benefiting from this invention are patients in need of supplemental citrulline to ensure that adequate nitric oxide levels are produced by endothelial tissues.

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.