Acute toxicity studies of alpha-ketoglutarate: a promising antidote for cyanide poisoning.
Recently we have shown that cyanide poisoning by the oral (p.o.) route could be antagonized significantly by pretreatment or simultaneous treatment of alpha-ketoglutarate (alpha-KG), administered p.o. in rodents. The protective effect of alpha-KG was dose dependent (0.125-2.0 g kg(-1)) and the effect was significant at a dose above 1.0 g kg(-1). In order to establish the safety of alpha-KG, various haematological, biochemical and histological parameters were studied following p.o. administration of 2.0 g kg(-1)alpha-KG in female rats, and various physiological parameters were studied following p.o. administration of 2.0 or 4.0 g kg(-1)alpha-KG in anaesthetized male rats. The p.o. LD(50) of alpha-KG in male and female rats was >5.0 g kg(-1) and no toxic signs were observed in the surviving animals. Except for an increase in plasma alkaline phosphatase and urea levels after 1 h and a decrease in inorganic phosphorus levels after 7 days of treatment, no significant change in haematology, biochemistry or histology of the vital organs were observed. Mean arterial pressure and neuromuscular transmission were decreased at 4.0 g kg(-1)alpha-KG but other physiological variables such as heart rate, respiratory rate, rectal temperature, left ventricular pressure (systolic), arterial pressure (systolic) and arterial pressure (diastolic) were not altered. The changes observed at 4.0 g kg(-1)alpha-KG are unlikely to be of toxicological concern. The results indicate that alpha-KG at 2.0 g kg(-1) (p.o.)-a dose offering maximum antidotal efficacy-is non-toxic and therefore can be considered suitable for cyanide poisoning.
Bhattacharya
R
R
Division of Pharmacology and Toxicology, Defence Research and Development Establishment, Jhansi Road, Gwalior 474002, India.
Kumar
D
D
Sugendran
K
K
Pant
S C
SC
Tulsawani
R K
RK
Vijayaraghavan
R
R
D000284:Administration, Oral; D000469:Alkaline Phosphatase / Q000097:blood; D000818:Animals; D000931:Antidotes / Q000009:adverse effects* / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D007656:Ketoglutaric Acids / Q000009:adverse effects* / Q000494:pharmacology*; D007928:Lethal Dose 50; D008297:Male; D010758:Phosphorus / Q000097:blood; D011041:Poisoning / Q000188:drug therapy; D011042:Poisons / Q000009:adverse effects; D011190:Potassium Cyanide / Q000506:poisoning; D011837:Radiation-Protective Agents / Q000009:adverse effects* / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D014508:Urea / Q000097:blood
D000931:Antidotes; D007656:Ketoglutaric Acids; D011042:Poisons; D011837:Radiation-Protective Agents; D010758:Phosphorus; D014508:Urea; D000469:Alkaline Phosphatase; D011190:Potassium Cyanide