Adenine Toxicity: A Three Week Intravenous Study in Dogs

Abstract

A prolonged toxicity study was performed in Beagle dogs. The adenine was dissolved by heating in the presence of an equimolar amount of lactic acid, diluted with saline to a 2.5 or 0.5% solution and given intravenously. The dose levels were 10, 20, 35, 85 and 135 mg/kg body weight. The substance was given during three weeks (five or six days a week) and the rate of infusion was either 0.6, 7.5 or 15 g adenine/hour. At dose levels above 10 mg/kg signs of renal impairment of varying degree appeared. All three dogs on 135 mg/kg, two out of three on 85 mg/kg and one out of four on 35 mg/kg died after four infusions. Another dog on 35 mg/kg died after eleven infusions. The values for serum creatinine and blood urea nitrogen were increased. The dogs also showed impairment of urine concentrating ability. In all cases autopsy re vealed evidence of uraemia. Crystals of 2,8‐dihydroxyadenine were found in the kidneys and nephrotic tubular changes were marked. The reversibility of the renal impairment was tested in one surviving dog on 85 mg/kg. The dog recovered clinically but the histological renal alterations seemed to be irreversible. The highest dose which could be considered safe in dogs was 10 mg/kg body weight.

Proof of concept and feasibility studies examining the influence of combination ribose, adenine and allopurinol treatment on stroke outcome in the rat

“…There was also evidence of intrapelvic and intratubular calculi, mild neutrophilic pyelonephritis and moderate transitional cell hyperplasia (data not shown). Both adenine and allopurinol are known nephrotoxic agents when administered at high doses (Lindblad et al, 1973; Suzuki et al, 1984; Yokozawa et al, 1986) and their concurrent administration may have exacerbated their toxic effect.…”

“…Although we did not measure blood markers of renal function, the former suggests that the rats did not suffer from clinical renal failure, which results in decreased food intake (Lindblad et al, 1973). Minor transient histopathological kidney changes attributed to adenine, which were noted 3 days after infusion in the preliminary study, had resolved by Day 7 in kidney histology data from the main study.…”

“…Using adenine at 10 mg/kg/h, not only did the treated animals recover and survive for 7 days following tMCAO, the treatment also had no effect per se on body weight or the general condition of the animals compared to saline-treated controls. Although we did not measure blood markers of renal function, the former suggests that the rats did not suffer from clinical renal failure, which results in decreased food intake (Lindblad et al, 1973). Minor transient histopathological kidney changes attributed to adenine, which were noted 3 days after infusion in the preliminary study, had resolved by Day 7 in kidney histology data from the main study.…”