The prevention of biochemical changes in lens, retina, and nerve of galactosemic dogs by the aldose reductase inhibitor AL01576.
Normal eight month old beagle dogs were fed a diet of 30% galactose for a period of two weeks. One group of dogs was untreated while three other groups were orally dosed with 0.25, 1.0, and 5.0 mg/kg of the aldose reductase inhibitor (ARI), AL01576. No visible changes were observed in the lens but glutathione (GSH) and inositol were depleted while dulcitol was elevated. These biochemical changes closely parallel those found in the (two week) streptozotocin induced diabetic rat. In contrast with the diabetic rat model, retina and nerve inositol was not found to differ from normal in spite of significant dulcitol accumulation. Plasma AL01576 was found to be inversely correlated with lens dulcitol concentration. When plasma AL0P1576 concentration was greater than 1 microgram/mL (5 mg/kg), there was a 95% reduction in dulcitol concentration (relative to untreated), while concentrations of 0.2 to 0.2 mg/mL (1 mg/kg) of AL01576 resulted in a dulcitol reduction of at least 70%. Retina and nerve dulcitol concentrations of galactosemic dogs were similarly diminished by AL01576 treatment. The dog model exhibits a biochemical profile of change and responsiveness to ARI therapy similar to that observed in hyperglycemic rats. Changes in retina morphology in diabetic and galactosemic dogs has been shown to closely resemble those occurring in human diabetics; these early biochemical events may also parallel.
Lou
M F
MF
Cataract Research Group, Alcon Laboratories, Inc., Fort Worth, Texas.
Dickerson
J E
JE
Chandler
M L
ML
Brazzell
R K
RK
York
B M
BM
D000284:Administration, Oral; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000704:Analysis of Variance; D000818:Animals; D004285:Dogs; D005449:Fluorenes / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D004376:Galactitol / Q000378:metabolism; D005690:Galactose; D005693:Galactosemias / Q000188:drug therapy* / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D006827:Hydantoins / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology*; D007294:Inositol / Q000378:metabolism; D007908:Lens, Crystalline / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D012160:Retina / Q000187:drug effects / Q000378:metabolism*; D012584:Sciatic Nerve / Q000378:metabolism*; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*
D005449:Fluorenes; D006827:Hydantoins; C052241:imirestat; D004376:Galactitol; D007294:Inositol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase; D005978:Glutathione; D005690:Galactose