Clinical Efficacy of Fidarestat, a Novel Aldose Reductase Inhibitor, for Diabetic Peripheral Neuropathy

Abstract

A 52-week multicenter placebo-controlled double-blind parallel group study OBJECTIVE -The purpose of this study was to evaluate the efficacy of fidarestat, a novel aldose reductase (AR) inhibitor, in a double-blind placebo controlled study in patients with type 1 and type 2 diabetes and associated peripheral neuropathy.RESEARCH DESIGN AND METHODS -A total of 279 patients with diabetic neuropathy were treated with placebo or fidarestat at a daily dose of 1 mg for 52 weeks. The efficacy evaluation was based on change in electrophysiological measurements of median and tibial motor nerve conduction velocity, F-wave minimum latency, F-wave conduction velocity (FCV), and median sensory nerve conduction velocity (forearm and distal), as well as an assessment of subjective symptoms.RESULTS -Over the course of the study, five of the eight electrophysiological measures assessed showed significant improvement from baseline in the fidarestat-treated group, whereas no measure showed significant deterioration. In contrast, in the placebo group, no electrophysiological measure was improved, and one measure significantly deteriorated (i.e., median nerve FCV). At the study conclusion, the fidarestat-treated group was significantly improved compared with the placebo group in two electrophysiological measures (i.e., median nerve FCV and minimal latency). Subjective symptoms (including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia) benefited from fidarestat treatment, and all were significantly improved in the treated versus placebo group at the study conclusion. At the dose used, fidarestat was well tolerated, with an adverse event profile that did not significantly differ from that seen in the placebo group.CONCLUSIONS -The effects of fidarestat-treatment on nerve conduction and the subjective symptoms of diabetic neuropathy provide evidence that this treatment alters the progression of diabetic neuropathy. Diabetes Care 24:1776 -1782, 2001D iabetic neuropathy is a degenerative disorder triggered by persistent hyperglycemia. The degenerative changes, consisting of axonal atrophy, demyelination, nerve fiber loss, and disordered nerve fiber repair, develop and progress even in the early stage of diabetes. Axonal atrophy, demyelination, and disordered repair can be clinically assessed as a decline in nerve conduction velocity. During hyperglycemia, nerve maturation secondary to nerve fiber loss is also disturbed. Abnormal excitement of these immaturely regenerated nerve fibers causes spontaneous pain, numbness, and paresthesia (1-3). In the majority of patients, these changes, characteristic of diabetic neuropathy, considerably deteriorate the quality of life.After the onset of subjective symptoms, only palliative treatments are currently available. Accordingly, early diagnosis and treatment before the onset of subjective symptoms is considered essential. Diabetic neuropathy is a long-term complication of diabetes that should not be underestimated, bec...

Aldose reductase inhibitor fidarestat counteracts diabetes-associated cataract formation, retinal oxidative-nitrosative stress, glial activation, and apoptosis

“…The results, consistent with previous reports on the alleviation of diabetic complications with fidarestat treatment (63)(64)(65)(66), support a pathogenetic, rather than protective, role for increased aldose reductase activity in diabetic cataractogenesis and early retinopathy, and provide a rationale for the development of aldose reductase inhibitors, and, in particular, fidarestat, for their prevention and treatment.…”

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

“…In particular, a 52-week multicenter (78 centers in Japan) placebo-controlled double-blind parallel group study of the AR inhibitor fidarestat in 279 patients with type 1 and type 2 diabetes and associated peripheral neuropathy revealed beneficial effects of treatment on subjective symptoms including numbness, spontaneous pain, sensation of rigidity, paresthesia in the sole upon walking, heaviness in the foot, and hypesthesia. 105 Similar results have been achieved in the 3-year, multicenter (112 centers in Japan), comparative Aldose Reductase InhibitorDiabetes Complications Trial in 594 subjects with diabetic neuropathy, in which numbness of limbs, sensory abnormalities, and cramping were alleviated in patients treated with the AR inhibitor epalrestat compared with the placebo group. 106 A more recent open-label pilot study (12 hospitals in Japan, 22 patients) revealed beneficial effect of fidarestat on vibration perception threshold of the upper and lower limbs and subjective symptoms of PDN, such as severity of numbness in the lower limbs, heaviness in the foot, coldness and hot flushes in the lower limbs, smarting pain causing difficulty in walking, sensation as if walking on sand, sensation as if walking on an uneven road, spontaneous pain in the lower limbs, and dizziness.…”

“…35,36 Glutamate concentrations in the peripheral nerve system are reduced by AR inhibitor, 35 vasodilator, 122 and antioxidant 123 treatments-and all these treatments also alleviate symptoms of diabetic neuropathic pain in diabetic animal models 19,20 -22,77,78,99,102 and in human subjects. [105][106][107]111,112,114,124 Several reports indicate that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-␣) plays a role in nondiabetic painful neuropathy. [125][126][127] It is quite plausible that it also plays a role in diabetic neuropathic pain (as has been suggested 128,129 ), because TNF-␣ expression is increased in tissues of diabetic animals, and TNF-␣ induces overexpression of cyclooxygenase-2, 130,131 also implicated in diabetic hyperalgesia and allodynia.…”

Effect of the aldose reductase inhibitor fidarestat on experimental diabetic neuropathy in the rat

“…Our data showed significant effects on both NO and NBF. A previous study reported that fidarestat had stronger aldose reductase inhibition and longer half-life in the peripheral nerve than other ARIs [32]. These points could explain why fidarestat is more effective on NO and NBF in improving conduction velocity.…”

“…Fidarestat is active in several sites of action. It is a powerful ARI and reduces polyol accumulation [32]. The other mechanism is the polyol pathway being active in the endothelial cell.…”