Evaluation of ranirestat for the treatment of diabetic neuropathy.
BACKGROUND
Pharmacologic maintenance of normoglycemia in diabetes cannot prevent the eventual complications mainly due to protein glycation-induced cell death, dysregulated antioxidant defense and signal transduction in affected tissues. The rate-limiting enzyme of this process, aldose reductase, is therefore a pharmacologic target. To date, nine inhibitors of this enzyme have been developed. Ranirestat has completed two Phase III clinical trials. The objective of this evaluation is to summarize and provide expert opinion on the status of ranirestat with an emphasis on its pharmacokinetics in the context of its potential effects to prevent/treat diabetic complications.


METHODS
A qualitative systematic literature search of PubMed through November 2013 using MeSH terms - aldose reductase inhibitors, diabetic neuropathy, AS-3201, ranirestat, diabetic complications and pharmacokinetics/pharmacodynamics - identified relevant publications limited to human and rodent (mouse and rat) and English-language studies.


CONCLUSIONS
Ranirestat is a well-tolerated front-line inhibitor. It reproducibly exhibits some degree of measurable objective beneficial outcomes in diabetic neuropathy. It is the furthest advanced in clinical trials with some depth of supporting preclinical data. Trials in subjects with newly diagnosed neuropathy along with the identification of objective biomarkers/measurements of efficacy will be critical in identifying the real value and effect of ranirestat.
University of Pittsburgh School of Medicine, Children's Hospital of Pittsburgh, Department of Pathology and Immunology , 4401 Penn Avenue, Pittsburgh, PA 15224 , USA +1 412 692 8127 (voice) ; +1 412 692 7515 ; ngiann1@pitt.edu.
Nick
N
Giannoukakis
D000449:Aldehyde Reductase / Q000037:antagonists & inhibitors; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D002986:Clinical Trials as Topic; D003929:Diabetic Neuropathies / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D051379:Mice; D011719:Pyrazines / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D015203:Reproducibility of Results; D013141:Spiro Compounds / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*
D015415:Biomarkers; D004791:Enzyme Inhibitors; D011719:Pyrazines; D013141:Spiro Compounds; D000449:Aldehyde Reductase; C115070:ranirestat
AS-3021; aldose reductase inhibitors; diabetes mellitus; diabetic complications; pharmacokinetics; polyol pathway; ranirestat