title: Respiratory and cardiovascular toxicity studies of a novel antiprion compound, GN8, in rats and dogs.
abstract: Prion diseases, also known as transmissible spongiform encephalopathies, are fatal neurodegenerative disorders for which no effective curative or prophylactic method has been established. Recently, we discovered a novel antiprion compound, GN8. Administration of GN8 was found to prolong the survival of prion-infected mice. The aim of this study was to characterize the toxicological and pharmacological features of GN8 in rats and dogs treated via a single intravenous injection. Minimum lethal doses of GN8 were estimated to be approximately 60 and 40 mg/kg in rats and dogs, respectively. In the respiratory toxicity experiments, GN8 was administered to rats at doses of 0, 15.6, and 46.9 mg/kg, and rats were observed for consciousness, behavior, autonomic nervous symptoms, and body weights. GN8 was found to have little adverse effect on the rat respiratory system at a dose of 46.9 mg/kg. In the cardiovascular toxicity experiments, GN8 was administered to dogs at doses of 0, 7.8, and 31.3 mg/kg, and dogs were observed similarly. Although GN8 was found to have a slight effect on the cardiovascular system at a dose of 31.3 mg/kg, we did not find severe adverse effects of GN8 at doses sufficient for antiprion activity. This study would serve as a stepping stone to a clinical application of GN8 as an antiprion agent.
authors: Center for Emerging Infectious Diseases, Gifu University, Gifu, Japan.
authors: Junji
authors: J
authors: Hosokawa-Muto
authors: Tsutomu
authors: T
authors: Kimura
authors: Kazuo
authors: K
authors: Kuwata
mesh_terms: D000081:Acetamides / Q000008:administration & dosage / Q000737:chemistry / Q000633:toxicity*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D007275:Injections, Intravenous; D015394:Molecular Structure; D017096:Prion Diseases / Q000188:drug therapy*; D051381:Rats; D012119:Respiration / Q000187:drug effects*; D056152:Respiratory Rate / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced; D023382:Toxicity Tests, Acute
chemical_list: D000081:Acetamides