title: Withdrawal of the aldose reductase inhibitor tolrestat in patients with diabetic neuropathy: effect on nerve function. The Tolrestat Study Group.
abstract: A double-blind, placebo-controlled clinical trial was conducted to study the effects of discontinuing tolrestat, an aldose reductase inhibitor, on peripheral sensorimotor diabetic neuropathy. After an average of 4.2 years of continuous tolrestat use, 372 patients were randomly assigned to either placebo or continued tolrestat therapy and were followed for 52 weeks. After 3 months, patients who perceived worsening of symptoms of neuropathy were allowed to switch once to the alternate treatment group while maintaining the double-blind. Patients assigned to placebo had significant deterioration in motor nerve conduction velocity (MNCV) while those maintained on tolrestat did not (p < 0.05). The 28 patients who were randomly assigned to tolrestat and elected to switch to placebo had a significant deterioration in MNCV while the 36 assigned to placebo who switched to tolrestat had a significant improvement (p < 0.05). Treatment differences in favor of tolrestat were observed for sensation in the toes as well as for pain (p < 0.05). These data indicate that withdrawal from long-term treatment with tolrestat has a detrimental effect on several measures of diabetic neuropathy, whereas continuation of treatment is associated with stabilization of these measures, suggesting a continued role for polyol pathway activity in late neuropathy.
authors.affiliation: Diabetes Research and Training Center, Washington University School of Medicine, St. Louis, Missouri.
authors.forename: J V
authors.initials: JV
authors.lastname: Santiago
authors.forename: P H
authors.initials: PH
authors.lastname: Snksen
authors.forename: A J
authors.initials: AJ
authors.lastname: Boulton
authors.forename: A
authors.initials: A
authors.lastname: Macleod
authors.forename: M
authors.initials: M
authors.lastname: Beg
authors.forename: W
authors.initials: W
authors.lastname: Bochenek
authors.forename: G J
authors.initials: GJ
authors.lastname: Graepel
authors.forename: B
authors.initials: B
authors.lastname: Gonen
mesh_terms: D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors*; D001786:Blood Glucose / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000097:blood / Q000503:physiopathology; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000503:physiopathology; D003929:Diabetic Neuropathies / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology*; D004311:Double-Blind Method; D005260:Female; D006442:Glycated Hemoglobin / Q000032:analysis; D006801:Humans; D008297:Male; D008475:Median Nerve / Q000503:physiopathology; D008875:Middle Aged; D009281:Naphthalenes / Q000627:therapeutic use*; D009431:Neural Conduction; D010146:Pain / Q000503:physiopathology; D010525:Peripheral Nerves / Q000503:physiopathology*; D010919:Placebos; D013497:Sural Nerve / Q000503:physiopathology; D014459:Ulnar Nerve / Q000503:physiopathology
chemical_list: D000449:Aldehyde Reductase; D001786:Blood Glucose; D006442:Glycated Hemoglobin; D009281:Naphthalenes; D010919:Placebos; C040550:tolrestat