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 coul d be antagonized significantly by pretreatment or simultaneous treatment of a-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 saf ety of alpha -KG, various haematological, biochemical and histological para meters were studied following p.o. administration of 2.0 g kg(-1) alpha -KG in female rats, and various physiological parameters were studied followin g p.o. administration of 2.0 or 4.0 g kg(-1) alpha -KG in anaesthetized mal e rats. The p.o. LD50 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 dec rease in inorganic phosphorus levels after 7 days of treatment, no signific ant change in haematology, biochemistry or histology of the vital organs we re observed. Mean arterial pressure and neuromuscular transmission were dec reased 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 unlik ely 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. Copyright (C) 2001 John Wiley & Sons, Ltd.