Epalrestat: A Review of its Pharmacology, and Therapeutic Potential in Late-Onset Complications of Diabetes Mellitus

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Abstract

Synopsis

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.

Synopsis

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.

Synopsis

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.

Synopsis

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.

Synopsis

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.

Pharmacology

The sorbitol (polyol) metabolic pathway, an alternative glucose reduction pathway involving the enzymes aldose reductase and sorbitol dehydrogenase, is thought to be activated by hyperglycaemic conditions. Intracellular accumulation of sorbitol during hyperglycaemia is considered to be at least partially responsible for the pathogenesis of late-onset complications of diabetes mellitus. Epalrestat, an uncompetitive aldose reductase inhibitor, significantly reduces intracellular sorbitol accumulation in sciatic nerve, erythrocytes and ocular tissues from animal models, and in erythrocytes in humans with diabetes mellitus, without affecting glucose levels. Epalrestat also increased sodium-dependent myoinositol uptake into sciatic nerve tissue in rats and skin fibroblasts from patients with diabetes, and attenuated nerve conduction velocity and retinal changes commonly seen in patients with diabetic neuropathy and retinopathy, respectively.

Pharmacology

In healthy volunteers, distribution of epalrestat is rapid and peak plasma concentrations are reached 1 to 2 hours after oral doses of 50 to 200mg. The elimination half-life is about 1 hour, and unchanged epalrestat and sulphate conjugates of the mono- and dihydroxyphenyl metabolites are found in the urine.

Therapeutic Potential

Oral epalrestat 150 mg/day for 12 weeks produced improvements in motor and sensory nerve conduction velocity, and vibration sensation perception compared with placebo, in patients with diabetic neuropathy. Subjective symptoms including pain, numbness, hyperaesthesia, coldness in the extremities, muscular weakness, dizziness, orthostatic fainting, and constipation/diarrhoea also improved. A comparison with historical controls showed similar benefits, as did a comparison with methylcobalamine. These findings are supported by the results of noncomparative trials of 4 weeks' to 1 years' duration, including a total of 365 patients with diabetic neuropathy.

Therapeutic Potential

Comparative studies of 1 or 3 years' duration in patients with diabetic retinopathy show that epalrestat 300 mg/day is significantly more effective than placebo or no treatment, in improving or preventing deterioration of ocular signs and symptoms.

Therapeutic Potential

Epalrestat appears to be most effective in patients in whom diabetes mellitus is less severe and where late-onset complications are recent.

Tolerability

Epalrestat has been well tolerated in mainly noncomparative Japanese clinical trials of up to 3 years' duration. Adverse events reported most frequently were minor liver enzyme elevations, diarrhoea, erythema, skin bullae and elevated serum creatinine levels. Epalrestat was as well tolerated as placebo and methylcobalamine in comparative trials.

Dosage and Administration

The recommended dosage of oral epalrestat is 50mg 3 times daily before meals. Epalrestat is particularly recommended for use in patients with high glycosylated haemoglobin levels (indicating failure to control hyperglycaemia), despite standard pharmacological and nonpharmacological intervention. Alternative treatment should be considered if an adequate response to epalrestat is not observed after 12 weeks of therapy.

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