Development of a novel glutathione repleting agent, L-2-oxothiazolidine-4-carboxylic acid (Procysteine®)

Abstract

A number of disease states are associated with episodes of acute or chronic oxidative stress, including Acute Respiratory Distress Syndrome (ARDS) and Human Immunodeficiency Virus (HIV) infection. Under conditions of oxidative stress, glutathione, a central component of the body's antioxidant defence system, is often depleted and damage to cells and tissues from reactive oxygen species can result. Therapies which replete glutathione may prevent or alleviate such damage. Several approaches to glutathione repletion are under investigation including delivering glutathione in an esterified form and increasing the supply of cysteine, which limits glutathione synthesis. L-2-oxothiazolidine-4-carboxylic acid (OTC), a cysteine prodrug, is metabolised to cysteine intracellularly, where glutathione synthesis occurs. Extensive preclinical research has demonstrated that OTC increases glutathione levels in animal models in which glutathione was depleted by oxidative stress or chemical means. In toxicology studies, Procysteine® (OTC produced by Free Radical Sciences Inc., Cambridge, Massachusetts, USA) had very low acute toxicity, was well-tolerated in repeated dosing studies and was not genotoxic. Pilot clinical trials of Procysteine® have been completed recently. In patients with ARDS, Procysteine® treatment alleviated injury to the lungs and other organs. Procysteine® treatment also yielded important clinical benefits for patients infected with HIV. Thus, preclinical and clinical studies support the conclusion that OTC is a promising, safe and efficacious therapy for clinical conditions associated with oxidative stress.