title: Epalrestat. A review of its pharmacology, and therapeutic potential in late-onset complications of diabetes mellitus.
abstract: Epalrestat is a carboxylic acid derivative which inhibits aldose reductase, an enzyme of the sorbitol (polyol) pathway. Under hyperglycaemic conditions epalrestat reduces intracellular sorbitol accumulation, which has been implicated in the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat 150 mg/day for 12 weeks improved motor and sensory nerve conduction velocity, and vibration threshold compared with baseline and placebo in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, and orthostatic fainting were also improved. Similar benefits were seen in a comparison with historical controls. Epalrestat 300 mg/day for 1 or 3 years was also significantly superior to placebo or no treatment in improving electroretinogram parameters and photo stress recovery time in patients with diabetic retinopathy. Improvements were also documented by funduscopy and fluorescein angiography. Epalrestat appeared most effective in patients with less severe diabetes mellitus and more recent development of late-onset complications. Epalrestat is apparently well tolerated with predominantly minor adverse events reported in clinical trials. Liver enzyme elevations were most commonly reported but generally resolved spontaneously on dose reduction or discontinuation. The effects of age and renal impairment on the efficacy and tolerability of epalrestat require clarification, and data on its use in other late-onset complications of diabetes such as nephropathy are also lacking. Comparisons with other aldose reductase inhibitors are also required to fully determine the role of epalrestat. The suggested ability of epalrestat to prevent the onset of diabetic complications should also be investigated. Thus, available data suggest epalrestat produces some improvement in the late-onset neuropathy and retinopathy associated with diabetes mellitus, although additional trials are required to determine whether ongoing therapy is necessary to maintain the improvements achieved and to confirm tolerability in the long term. Nevertheless, preliminary results suggest that epalrestat may be a useful drug in an area where there is a need for effective therapy.
authors.affiliation: Adis International Limited, Auckland, New Zealand.
authors.forename: J W
authors.initials: JW
authors.lastname: Steele
authors.forename: D
authors.initials: D
authors.lastname: Faulds
authors.forename: K L
authors.initials: KL
authors.lastname: Goa
mesh_terms: D000368:Aged; D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D000818:Animals; D003929:Diabetic Neuropathies / Q000188:drug therapy*; D003930:Diabetic Retinopathy / Q000188:drug therapy*; D006801:Humans; D012236:Rhodanine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D053778:Thiazolidines
chemical_list: D053778:Thiazolidines; C038131:epalrestat; D012236:Rhodanine; D000449:Aldehyde Reductase