title: Accelerated stability and bioassay of a new oral α-ketoglutarate formulation for treating cyanide poisoning.
abstract: BACKGROUND
  Due to several limitations of existing cyanide antidotes, α-ketoglutarate (α-KG) has been proposed as a promising treatment for cyanide.
  
  
  OBJECTIVE
  This study reports the accelerated stability and bioassay of a new oral α-KG formulation.
  
  
  METHODS
  Amber-colored PVDF bottles containing 100 ml of 10% α-KG in 70% sorbitol, preservative (sodium methyl paraben and sodium propyl paraben), sweetener (sodium saccharine), flavor (American ice-cream soda and peppermint) and color (tartrazine), at pH 7.0-8.0 were stored in stability chamber (40 ± 2 °C and 75 ± 5% humidity) for 6 months in a GMP compliant facility. Various physical (pH, color, evaporation, extractable volume and clarity), chemical (identification and quantification of active ingredient) and microbiological (total aerobic count) analyses, together with protection studies were carried periodically in mice. Acute toxicity of the formulation and bioavailability of α-KG were assessed in rats at the beginning of the experiment.
  
  
  RESULTS
  No physical changes and microbiological growth were observed in the formulation. After 6 months, α-KG content in the formulation diminished by ∼24% but its protective efficacy against cyanide remained at 5.9-fold. Protection was further characterized spectrophotometrically by disappearance of α-KG spectrum in the presence of cyanide, confirming cyanohydrin formation. Oral LD50 of α-KG formulation in rats was >7.0 g/kg body weight, and did not produce any acute toxicity of clinical significance. Also, an appreciable amount of α-KG was measured in blood.
  
  
  CONCLUSIONS
  As per the guidelines of International Conference on Harmonization, the new α-KG formulation exhibited satisfactory stability, bioefficacy and safety as cyanide antidote.
authors.affiliation: Pharmacology and Toxicology Division, Defence Research and Development Establishment, Gwalior , Madhya Pradesh , India and.
authors.forename: Rahul
authors.initials: R
authors.lastname: Bhattacharya
authors.forename: Natarajan
authors.initials: N
authors.lastname: Gopalan
authors.forename: Anil Kumar
authors.initials: AK
authors.lastname: Singh
authors.forename: Poonam
authors.initials: P
authors.lastname: Singh
authors.forename: Shiv Kumar
authors.initials: SK
authors.lastname: Yadav
authors.forename: Pooja
authors.initials: P
authors.lastname: Rao
authors.forename: Saurabh
authors.initials: S
authors.lastname: Shrivastava
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000931:Antidotes / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D001681:Biological Assay; D001682:Biological Availability; D002626:Chemistry, Pharmaceutical; D004339:Drug Compounding; D004355:Drug Stability; D004356:Drug Storage; D005260:Female; D007656:Ketoglutaric Acids / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D011190:Potassium Cyanide / Q000506:poisoning*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors; D023382:Toxicity Tests, Acute
chemical_list: D000931:Antidotes; D007656:Ketoglutaric Acids; D011190:Potassium Cyanide