title: 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.
authors.affiliation: N30 Pharma LLC, Boulder, CO 80301, USA. dot@n30pharma.com
authors.forename: Dorothy B
authors.initials: DB
authors.lastname: Colagiovanni
authors.forename: Daxa
authors.initials: D
authors.lastname: Borkhataria
authors.forename: Doug
authors.initials: D
authors.lastname: Looker
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuler
authors.forename: Corinna
authors.initials: C
authors.lastname: Bachmann
authors.forename: Peter
authors.initials: P
authors.lastname: Sagelsdorff
authors.forename: Naveed
authors.initials: N
authors.lastname: Honarvar
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Rosenthal
mesh_terms: D000280:Administration, Inhalation; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D023381:Endpoint Determination; D004912:Erythrocytes; D005260:Female; D008297:Male; D009566:Nitrates / Q000097:blood / Q000493:pharmacokinetics / Q000652:urine; D019055:No-Observed-Adverse-Effect Level; D051381:Rats; D017208:Rats, Wistar; D026422:S-Nitrosoglutathione / Q000493:pharmacokinetics* / Q000633:toxicity*; D012756:Sheep; D018675:Toxicity Tests / Q000379:methods*
chemical_list: D009566:Nitrates; D026422:S-Nitrosoglutathione