Preclinical 28-Day Inhalation Toxicity Assessment of S-Nitrosoglutathione in Beagle Dogs and Wistar Rats

Abstract

To support clinical development of S-nitrosoglutathione (GSNO) as a therapeutic agent, 28-day toxicology studies in rats and dogs were conducted. Rats (21-25/sex) and dogs (3-5/sex) were exposed for 4 hours or 1 hour, respectively, to inhaled GSNO (0, 3, 9.3, 19, and 28 mg/kg per d in rats and 0, 4.6, 9.0, and 16.2 mg/kg per d in dogs) or vehicle daily via a nebulizer. Animals were monitored throughout the 28-day dosing period and during a postexposure recovery period. Complete necropsy and tissue examinations were performed. Experimental end points included clinical pathology, toxicokinetics, and immunotoxicology. No biologically significant adverse findings were noted in either species, and the no observed adverse effect levels (NOAELs) under these conditions were the highest achieved doses (28 and 16.2 mg/kg per d in rats and dogs, respectively). These data demonstrate that GSNO is well tolerated in rodents and dogs and predict a favorable toxicity profile in humans, thus supporting future clinical development of GSNO or closely related compounds.

Stimulation of functional recovery via the mechanisms of neurorepair by S-nitrosoglutathione and motor exercise in a rat model of transient cerebral ischemia and reperfusion

“…The clinical relevance of GSNO therapy is supported by improved neurobehavioral functions even when the treatment was initiated 24 hours after IR. GSNO is an endogenous component of the human body, and its exogenous administration has no known side effects or toxicity when used for other indications (Konorev et al, 1995, Molloy et al, 1998, Aledia et al, 2002, Kaposzta et al, 2002, Snyder et al, 2002, Colagiovanni et al, 2011). These findings make GSNO an attractive candidate to be investigated in humans for neurorepair and rehabilitation following stroke.…”

“…However, the potential of combination therapy of GSNO and motor exercise and the mechanisms involved therein have not been investigated following IR. Furthermore, GSNO may have an advantage over other reported experimental drugs in IR because it is a non-toxic component of the human body, and is ultimately metabolized into beneficial -SNO/NO and GSH (Foster et al, 2009, Colagiovanni et al, 2011). …”

The nitric oxide pathway and possible therapeutic options in pre‐eclampsia

“…S ‐Nitrosoglutathione has been found to have a favourable toxicity profile in animal toxicology studies using inhalational GSNO, with no biologically significant adverse effects seen .…”

S-Nitrosoglutathione ameliorates acute renal dysfunction in a rat model of lipopolysaccharide-induced sepsis

“…This study shows, for the time, that GSNO protects against AKI in rats possibly by inhibiting inflammatory and promoting anti‐inflammatory pathways. Exogenous administration of GSNO to animals or humans has not shown any toxicity or adverse effect, supporting GSNO as a promising candidate to treat sepsis‐induced AKI.…”