Nitric oxide scavengers in the treatment of shock associated with systemic inflammatory response syndrome

Shock associated with systemic inflammatory response syndrome (SIRS) is a form of distributive shock affecting over 200,000 patients per year in the US that results in 50% mortality. The role of NO in a variety of shock states has been extensively studied and has been shown to be the primary effector in endotoxin lipopolysaccharide (LPS)-induced hypotension attendant to shock associated with sepsis or presumed sepsis. NO has also been shown to be a myocardial depressant, an inhibitor of mitochondrial electron transport, an inducer of vascular leakage and an enhancer of LPS-induced cytokine release. Hence, it is involved in a wide variety of shock-related pathologies and is a key target for therapeutic intervention. Mechanism of action based therapies using NO scavengers represent a promising new approach. However, because NO is involved in such a wide variety of both physiological and pathophysiological processes, a therapy directed at NO must be selective in order to be both safe and effective. NO scavengers are comprised of two basic classes: organic molecules and metal complexes. Pyridoxalated haemoglobin polyoxyethylene conjugate (PHP) is a chemically-modified haemoglobin. It is the furthest advanced NO scavenger in clinical trials and is about to enter pivotal Phase 3 trials in patients with shock associated with SIRS.