The structure of human aldose reductase bound to the inhibitor IDD384.

The crystallographic structure of the complex between human aldose reductase (AR2) and one of its inhibitors, IDD384, has been solved at 1.7 A resolution from crystals obtained at pH 5.0.

Tissue selective inhibition of prostaglandin biosynthesis by etodolac.

Inflammation is a complex process involving numerous mediators. Because prostaglandins (PG) have been implicated as mediators in all stages of inflammation, inhibition of their synthesis provides the basis for the therapeutic effects of nonsteroidal antiinflammatory drugs (NSAID). Treatment with NSAID is usually accompanied by gastric side effects, attributed to interference with the formation of cytoprotective PG in gastric mucosa.

Aminoguanidine does not inhibit aldose reductase activity in galactose-fed rats.

Aminoguanidine, nucleophilic hydrazine derivative, has been shown to inhibit diamine oxidase, the formation of advanced glycation endproducts, nitric oxide synthase, and catalase. Prompted by the reports that aminoguanidine also inhibits aldose reductase (AR), we have investigated the effect of aminoguanidine, 1,3-diaminoguanidine, and methylguanidine on AR activity in vitro, and in vivo. In vitro, we have measured the inhibition of AR isolated from bovine lenses; in vivo, we have examined the effect on the galactitol levels in the red blood cells, sciatic nerve, retina, and lens of rats administered the test compounds for 11 days in the drinking water and, for the last 4 days, given access to a 20% galactose diet.

Tolrestat pharmacokinetics in rat peripheral nerve.

The clinical efficacy of an aldose reductase (AR) inhibitor in diabetic polyneuropathy depends on its bioavailability at the site(s) of AR in peripheral nerves. Accordingly, the link between the concentration of the AR inhibitor, tolrestat, and the extent of its inhibition of the AR-catalyzed polyol production was investigated in sciatic nerves of galactosemic rats. Tolrestat was administered by gavage (1 x 150 mg/kg, or 5, and 15 mg/kg/day for 15 days to attain steady state as estimated from the 53-h half-life of tolrestat determined in rat nerve); subsequently, at six time intervals, ranging from 4 to 59 days, rats were given access for 4 days to a 20% galactose diet, and killed.

Aldose reductase inhibitors as pathobiochemical probes.

In tissues susceptible to damage from chronic diabetes, excess glucose is metabolized by aldose reductase (AR) to sorbitol. Originally, AR-catalyzed sorbitol formation (and accumulation) was found in the diabetic lens; the cataractogenicity of this process was proven by preventing cataract formation with an AR inhibitor (ARI). These findings were extended to the hypothesis that, in diabetic tissues, excessive intracellular sorbitol formation initiates a cascade of metabolic abnormalities which gradually progress to loss of functional and structural integrity.