Accelerated stability and bioassay of a new oralα-ketoglutarate formulation for treating cyanide poisoning

Abstract

Context: Due to several limitations of existing cyanide antidotes, a-ketoglutarate (a-KG) has been proposed as a promising treatment for cyanide. Objective: This study reports the accelerated stability and bioassay of a new oral a-KG formulation. Materials and methods: Amber-colored PVDF bottles containing 100 ml of 10% a-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 AE 2 C and 75 AE 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 a-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, a-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 a-KG spectrum in the presence of cyanide, confirming cyanohydrin formation. Oral LD 50 of a-KG formulation in rats was 47.0 g/kg body weight, and did not produce any acute toxicity of clinical significance. Also, an appreciable amount of a-KG was measured in blood. Conclusion: As per the guidelines of International Conference on Harmonization, the new a-KG formulation exhibited satisfactory stability, bioefficacy and safety as cyanide antidote.

Characterization of a Mouse Model of Oral Potassium Cyanide Intoxication

“…12 A number of compounds are being investigated for efficacy in treatment of CN intoxication. [13][14][15][16][17] However, little information is available on the effects of CN in young animals. Reports have indicated age differences in rhodanese activity, a key enzyme in degradation of CN.…”

A rationally designed molecule for removal of cyanide from human blood serum and cytochrome c oxidase

“…4 Chemical capturing of CN À and disposal of the product as safe metabolite/s is desirable to get rid of cyanide poisoning. Irrespective of a number of reports, [5][6][7][8][9][10][11][12] only a few of the compounds including hydroxocobalamin, dicyano-cobalt(III)porphyrins, vitamin B12 analogues, metallophthalocyanines and hexahydrated dichloride of cobalt(II) and nickel(II) [13][14][15][16][17][18] nd compatibility to the living system and hence safely used in scavenging CN À from the biological medium. Moreover, the limited number of available kits mainly use NO for removal of cyanide from cytochrome c oxidase.…”