Long-Term Effects of Ranirestat (AS-3201) on Peripheral Nerve Function in Patients With Diabetic Sensorimotor Polyneuropathy

Abstract

OBJECTIVES -We aimed to determine whether ranirestat, an aldose reductase inhibitor, maintains the improved nerve function observed in patients with diabetic sensorimotor polyneuropathy (DSP) after completing a 12-week nerve biopsy study.RESEARCH DESIGN AND METHODS -Patients with mild to moderate DSP, as determined by the presence of sural nerve responses, were enrolled in a double-blind, placebocontrolled biopsy trial and randomized to placebo or 5 or 20 mg/day ranirestat for 12 weeks. Patients completing this biopsy study were offered a 48-week extension at the same ranirestat dose or at 5 mg/day ranirestat if they were originally treated with placebo. Electrophysiological tests, the Toronto Clinical Neuropathy Score, and vibration perception thresholds (VPTs) were performed at entry and at 12 (end of the biopsy study) and 60 (end of the 48-week extension) weeks.RESULTS -Peroneal motor nerve conduction velocity (NCV) improved in the 20-mg/day group following 60 weeks of treatment. Sural and median sensory NCV improved after both 12 and 60 weeks of treatment with 20 mg/day. VPT improved after 60 weeks of treatment with 20 mg/day. Ranirestat was well tolerated with no difference in adverse events between the 5-and 20-mg/day groups.CONCLUSIONS -Twenty milligrams ranirestat per day improves NCV and VPT following 60 weeks of administration. The improved sensory nerve function observed after 12 weeks of therapy was maintained at 60 weeks, and improved motor nerve function was observed at 60 weeks. Diabetes Care 29:68 -72, 2006

Fluorine in medicinal chemistry: Recent therapeutic applications of fluorinated small molecules

“…The fluorinated hydantoin fidarestat (23) and the cyclic amides minalrestat (24) and ranirestat (25) are in preclinical or clinical trials [39]. Long-term treatment with ranirestat was recently reported to produce and maintain improved nerve function in patients with diabetic sensorimotor polyneuropathy [40].…”

Diabetic Polyneuropathy in Type 2 Diabetes Mellitus: Inflammation, Oxidative Stress, and Mitochondrial Function

“…Ranirestat is the most studied ARI in clinical trials. At first, in patients with mild to moderate DPN, great improvements in nerve conduction velocities above 1 m/s and vibration perception thresholds were observed, with promising results even in long-term evaluations [172, 173]; however, recent studies have been controversial, with no effect on efficacy endpoints and a mild improvement of less than 1.2 m/s in peroneal motor nerve conduction velocity with ranirestat [174] and no difference in clinical assessments compared to placebo [175]. …”

Diabetic neuropathy and the sensory apparatus “meissner corpuscle and merkel cells”

“…The integumentary system contains sensory axons which conduct different sensory stimuli to the spinal cord. The array of conductance includes touch, pressure, cold and heat, and pain, and all are mediated by small c fibers and or fine myelinated axons (Bril and Buchanan, 2006; Obrosova et al, 2010). …”