Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study

Goto, Yukio; Hotta, Nigishi; Shigeta, Yukio; Sakamoto, Nobuo; Kikkawa, Ryuichi

doi:10.1016/0753-3322(96)82642-4

Cited by 75 publications

(59 citation statements)

References 12 publications

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“…Although the present study did not employ a controlled design, numbness was improved in 78% of the patients during the study period, a finding that is compatible with results reported in a previous controlled study with epalrestat (Goto, Hotta, Shigeta, Sakamoto, & Kikkawa, 1995). Because nerve function test JDC MS 05-1783 Rev1 results are known to bear no relationship to the severity of symptoms (Greene et al, 1981), it is probable that ARI treatment can improve subjective symptoms without any effect on nerve function.…”

Section: Discussionsupporting

confidence: 77%

“…In placebo-controlled double-blind studies (Goto, Hotta, Shigeta, Sakamoto, & Kikkawa, 1995;Hotta et al, 2001), ARI treatment has been reported to improve not only nerve conduction velocity but also various subjective symptoms of diabetic neuropathy. Although the present study did not employ a controlled design, numbness was improved in 78% of the patients during the study period, a finding that is compatible with results reported in a previous controlled study with epalrestat (Goto, Hotta, Shigeta, Sakamoto, & Kikkawa, 1995).…”

Section: Discussionmentioning

confidence: 99%

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Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy

Ando

Takamura

Nagai

et al. 2006

Journal of Diabetes and its Complications

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The relationship between the effect of aldose reductase inhibitors (ARIs) on the activation of the polyol pathway and on diabetic neuropathy has not been fully established. To address this issue, we investigated the effect of epalrestat (150 mg/day), an ARI, on erythrocyte sorbitol levels as an index of polyol activation and on nerve function test results in 43 patients with diabetic peripheral polyneuropathy. After 6 months of epalrestat administration, erythrocyte sorbitol levels did not decrease in patients as a whole. However, a decrease in erythrocyte sorbitol levels during epalrestat administration was significantly correlated with baseline erythrocyte sorbitol levels (ρ = -.47, P < .01): the higher the level at baseline, the greater the decrease after epalrestat treatment. Moreover, the mean sorbitol level during epalrestat treatment was associated with the beneficial effect of epalrestat on vibration sensitivity as measured with a C-128 tuning fork (ρ = -.66, P < .01) and/or a pallesthesiometer TM-31A (ρ = .53, P < .05). On the other hand, erythrocyte sorbitol levels did not reflect the prognosis of nerve conduction velocity. These findings at least partly suggest a causal relationship between polyol activation and the development of diabetic neuropathy. ARI treatment may be clinically useful in the control of polyol activation, especially in patients with excessive accumulation of sorbitol.

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Section: Discussionsupporting

confidence: 77%

Section: Discussionmentioning

confidence: 99%

Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy

Ando

Takamura

Nagai

et al. 2006

Journal of Diabetes and its Complications

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“…In this regard, JNK may act in concert with p38 MAP kinase [8]. This also suggests a mechanism by which aldose reductase inhibitors may act to prevent or reduce pain in diabetic neuropathy, as they undoubtedly do in animal models [18,19] and possibly also in patients [5,20,21].…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of c-Jun N-terminal kinase (JNK) in sensory neurones of diabetic rats, with possible effects on nerve conduction and neuropathic pain: prevention with an aldose reductase inhibitor

2006

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Aims/hypothesis: This study was designed to determine whether diabetes in rats is associated with phosphorylation of c-Jun N-terminal kinase (JNK) and one of its transcription factors, c-Jun, in sensory neurones innervating the lower limb. We also sought to determine which neuronal phenotypes are affected and to examine the effect of aldose reductase inhibition on JNK and c-Jun phosphorylation. Methods: Diabetes was induced in rats using streptozotocin. Phosphorylation of JNK and c-Jun in lumbar dorsal root ganglia was determined by binding of phospho-specific antibodies using western blots and immunocytochemistry. Neuronal phenotypes were characterised by binding of N52 (an antibody that recognises the heavy neurofilament protein; for large-diameter mechanoceptors) and of calcitonin gene-related peptide and the plant glycoprotein lectin IB4 (for nociceptors). The efficacy of the aldose reductase inhibitor fidarestat was determined by measuring polyol pathway metabolites in sciatic nerve, and functionally by measuring the conduction velocity of motor and sensory nerves. Results: In control rats, activated JNK and c-Jun were primarily associated with mechanoceptors; in diabetes this was increased, but a greater increase was seen in nociceptors. Phosphorylation was prevented in all cells by fidarestat, which normalised polyol pathway metabolites as well as motor nerve and sensory nerve conduction velocity. Conclusions/interpretation: Fidarestat-sensitive phosphorylation of JNK and c-Jun occurs in fast-conduction mechanoceptors-the same class of neurones that registers the changes in sensory nerve conduction velocity-and in nociceptors. This supports the notion that mitogen-activated protein kinase phosphorylation, via the polyol pathway, may convert the direct effects of raised glucose into impaired nerve conduction and neuropathic pain. For proof of this we await the availability of specific JNK antagonists formulated for in vivo use.

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“…The present study was conducted to investigate the effect of an ARI, epalrestat (14,15), on autonomic nerve functions in patients with mild diabetic neuropathy by using the pupillary light reflex test. The effect on somatic nerve functions was also examined by measuring the minimum latency of the F-wave, which is a sensitive and reliable parameter of nerve conduction (16 -19).…”

mentioning

confidence: 99%

Aldose Reductase Inhibition Ameliorates Pupillary Light Reflex and F-Wave Latency in Patients With Mild Diabetic Neuropathy

et al. 2001

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OBJECTIVE -The present study was conducted to investigate the effect of an aldose reductase inhibitor, epalrestat, on autonomic and somatic neuropathy at an early stage in type 2 diabetic patients by assessing the pupillary light reflex and minimum latency of the F-wave. RESEARCH DESIGN AND METHODS-A total of 30 diabetic patients with subclinical or mild diabetic neuropathy were randomly allocated to a control group (n ϭ 15) and epalrestat (150 mg/day) group (n ϭ 15). After 24 weeks, the pupillary light reflex test, cardiovascular autonomic function tests, and nerve conduction study were performed.RESULTS -The beneficial effect of epalrestat on the pupillary light reflex was observed in the minimum diameter after light stimuli (P ϭ 0.044), constriction ratio (P ϭ 0.014), and maximum velocity of constriction (P ϭ 0.008). Among cardiovascular autonomic nerve functions, the ratio of the longest expiratory R-R interval to the shortest inspiratory R-R interval during deep breathing was significantly improved by epalrestat (P ϭ 0.037). Minimum latencies of F-wave of median and tibial motor nerves were significantly shortened by epalrestat (P ϭ 0.002 and P ϭ 0.001, respectively); however, no significant effects were observed in motor or sensory nerve conduction velocity.CONCLUSIONS -These observations suggest that epalrestat may have therapeutic value at the early stage of diabetic neuropathy and that the pupillary light reflex and minimum latency of F-wave may be useful indicators of diabetic neuropathy. Diabetes Care 24:1093-1098, 2001D iabetic neuropathy is generally classified into somatic and autonomic neuropathy. Although somatic neuropathy can be characterized by symptoms such as numbness, paresthesia, and abnormal sensation, the symptoms of autonomic neuropathy do not appear until the advanced stage.Diabetic autonomic neuropathy causes functional disorders of many organs, such as cardiovascular, gastrointestinal, genitourinary, metabolic, and pupillary dysfunctions. Among these, cardiovascular autonomic neuropathy may increase the risk of sudden death and affects the mortality of diabetic patients (1,2). Therefore, the diagnosis and treatment of autonomic neuropathy at an early stage is important for the management of diabetic patients.It is well known that diabetic autonomic neuropathy develops within a short duration of diabetes even when somatic neuropathy is not apparent (3,4). Furthermore, the abnormalities in pupillary functions can be detected earlier than those in cardiovascular autonomic functions and are considered the earliest signs of diabetic autonomic neuropathy (5-10). Therefore, the pupillary light reflex test has been used for evaluating diabetic autonomic neuropathy.It has been demonstrated that strict glycemic control can decrease the incidence of diabetic complications, including autonomic neuropathy (11). However, it is impossible to completely prevent the development of diabetic complications by glycemic control alone, except by performing a pancreas transplantation. Therefore, different t...

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Effects of an aldose reductase inhibitor, epalrestat, on diabetic neuropathy. Clinical benefit and indication for the drug assessed from the results of a placebo-controlled double-blind study

Cited by 75 publications

References 12 publications

Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy

Erythrocyte sorbitol level as a predictor of the efficacy of epalrestat treatment for diabetic peripheral polyneuropathy

Phosphorylation of c-Jun N-terminal kinase (JNK) in sensory neurones of diabetic rats, with possible effects on nerve conduction and neuropathic pain: prevention with an aldose reductase inhibitor

Aldose Reductase Inhibition Ameliorates Pupillary Light Reflex and F-Wave Latency in Patients With Mild Diabetic Neuropathy

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