In vivo activities of aldose reductase inhibitors having a 1-(arylsulfonyl)hydantoin structure.
Two potent aldose reductase inhibitors, 1-[(2,5-dichlorophenyl)sulfonyl]hydantoin (Di-Cl-PSH) and 1-[beta-naphthyl)sulfonyl]hydantoin (beta-NSH), were tested for usefulness in the treatment of diabetic and galactosemic complications in animal experiments. Both drugs were effective for the treatment of diabetic neuropathy characterized by decreased motor nerve conduction velocity, that is, slowing of tail and sciatic-tibial motor nerve conduction velocities in streptozocin-induced diabetic rats was prevented during 3 weeks by intubating Di-Cl-PSH or beta-NSH at 50 mg/kg/day. Lenticular vacuole formation in rats fed a 30% galactose diet was blocked completely for at least 2 weeks by oral administration of Di-Cl-PSH or beta-NSH at both 30 and 100 mg/kg/day, whereas all of the eyes of vehicle-treated rats showed vacuole formation by day 4 on the galactose diet. The ED50 values of Di-Cl-PSH and beta-NSH for inhibition of sorbitol accumulation in the sciatic nerve and lens of streptozocin-induced diabetic rats were also estimated; the values of Di-Cl-PSH and beta-NSH were 1.1 and 3.4 mg/kg/day, respectively, for inhibition in the sciatic nerve and 4.8 and 16.0 mg/kg/day, respectively, for that in the lens. This study indicates that Di-Cl-PSH and beta-NSH have high potential for future clinical use as aldose reductase inhibitors.
Miwa
I
I
Department of Clinical Biochemistry, Faculty of Pharmacy, Meijo University, Nagoya, Japan.
Hirano
M
M
Kanbara
M
M
Okuda
J
J
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D002386:Cataract / Q000517:prevention & control; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology; D005693:Galactosemias / Q000150:complications; D006827:Hydantoins / Q000494:pharmacology*; D008297:Male; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013012:Sorbitol / Q000378:metabolism; D013401:Sugar Alcohol Dehydrogenases / Q000037:antagonists & inhibitors*; D014617:Vacuoles / Q000187:drug effects
D006827:Hydantoins; D013012:Sorbitol; D013401:Sugar Alcohol Dehydrogenases; D000449:Aldehyde Reductase