The effects of a new aldose reductase inhibitor (tolrestat) in galactosemic and diabetic rats

Glycolytic pathway, redox state of NAD(P)-couples and energy metabolism in lens in galactose-fed rats: effect of an aldose reductase inhibitor

“…The absence of any difference in body weights between the tolrestat treated rats and the corresponding untreated group is consistent with the results of other groups (44,46,47). The decreased body weights as well as increased plasma FFA and ketone levels in 50% galactose-fed rats imply impaired glucose utilization in this model of galactosemia.…”

“…The failure of tolrestat to prevent myo-inositol depletion, and the minimal effect of the ARI on GSH levels in galactose-fed rats, in spite of 6-days of pretreatment and the high dose of the drug, can be explained by the fact that galactitol levels (although substantially reduced by tolrestat), were still elevated more than 700-fold above control levels. The similar finding of the inability of tolrestat to cause a complete prevention of lenticular galactitol accumulation (in spite of 14-day pretreatment and lower concentration (20%) of galactose diet) has been reported by Simard-Duquesne et al (47), and can be explained by relatively slow penetration of the compound into the eye found in the studies of tolrestat metabolic disposition and pharmacokinetics (51). It seems likely that osmotic stress caused by the still high galactitol levels (35 mol/g wet weight) in 50% galactose-fed rats treated with tolrestat is sufficient to account for the almost complete myo-inositol depletion as well as markedly reduced GSH levels.…”

Inhibitory effects of chlorogenic acid on aldose reductase activity in vitro and cataractogenesis in galactose-fed rats

“…Although several reports in the literature indicate that ARIs inhibit sugar cataracts through the inhibition of enzyme AR (Unakar and Tsui, 1983;Harries et al, 1985;Unakar et al, 1985), many ARIs have side effects when administrated systemically. Moreover, it was previously reported that the effect of AR inhibitors such as epalrestat (Terashima et al, 1984), tolrestat (Simard-Duquesne et al, 1985), zenarestat (Ao et al, 1991), SG-210 (Matsui et al, 1994) and SNK-860 (Mizuno et al, 1992) on cataract formation is inadequate in spite of their potent ameliorating effect on the decreased motor nerve conduction velocity in diabetic animals. Thus, a synthetic compound such as epalrestat is not proper as an anti-cataract drug in diabetic animal model.…”

Effects of a Novel Potent Aldose Reductase Inhibitor, GP-1447, on Aldose Reductase Activity In Vitro and on Diabetic Neuropathy and Cataract Formation in Rats.

“…A number of AR inhibitors (ARIs) such as epalrestat (14), tolrestat (15), zenaresat (16), and SNK 860 (18) exhibit some beneficial effects in streptozotocin (STZ)-induced diabetic rats and some are now in clinical trials. The effects of these compounds on cataract forma tion is inadequate in spite of their potent ameliorating effect on the decreased motor nerve conduction velocity (MCV) in diabetic animals.…”