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Table 2—

Treatment of diabetic neuropathy based on the putative pathogenetic mechanisms

AbnormalityCompoundAim of treatmentStatus of RCTs
Polyol pathway↑ Aldose reductase inhibitors Nerve sorbitol↓  
 Sorbinil  Withdrawn (AE) 
 Tolrestat  Withdrawn (AE) 
 Ponalrestat  Ineffective 
 Zopolrestat  Withdrawn (marginal effects) 
 Zenarestat  Withdrawn (AE) 
 Lidorestat  Withdrawn (AE) 
 Fidarestat  Effective in RCTs, trials ongoing 
 AS-3201  Effective in RCTs, trials ongoing 
 Epalrestat  Marketed in Japan 
Myo-inositol↓ Myo-inositol Nerve myo-inositol↑ Equivocal 
Oxidative stress↑ α-Lipoic acid Oxygen free radicals↓ Effective in RCTs, trials ongoing 
Nerve hypoxia↑ Vasodilators NBF↑  
 ACE inhibitors  Effective in one RCT 
 Prostaglandin analogs  Effective in one RCT 
 phVEGF165 gene transfer Angiogenesis↑ RCTs ongoing 
Protein kinase C↑ Protein kinase C-β inhibitor (ruboxistaurin) NBF↑ RCTs ongoing 
C-peptide↓ C-peptide NBF↑ Studies ongoing 
Neurotrophism↓ Nerve growth factor (NGF) Nerve regeneration, growth↑ Ineffective 
 BDNF Nerve regeneration, growth↑ Ineffective 
LCFA metabolism↓ Acetyl-l-carnitine LCFA accumulation↓ Ineffective 
GLA synthesis↓ γ-Linolenic acid (GLA) EFA metabolism↑ Withdrawn 
NEG↑ Aminoguanidine AGE accumulation↓ Withdrawn 
AbnormalityCompoundAim of treatmentStatus of RCTs
Polyol pathway↑ Aldose reductase inhibitors Nerve sorbitol↓  
 Sorbinil  Withdrawn (AE) 
 Tolrestat  Withdrawn (AE) 
 Ponalrestat  Ineffective 
 Zopolrestat  Withdrawn (marginal effects) 
 Zenarestat  Withdrawn (AE) 
 Lidorestat  Withdrawn (AE) 
 Fidarestat  Effective in RCTs, trials ongoing 
 AS-3201  Effective in RCTs, trials ongoing 
 Epalrestat  Marketed in Japan 
Myo-inositol↓ Myo-inositol Nerve myo-inositol↑ Equivocal 
Oxidative stress↑ α-Lipoic acid Oxygen free radicals↓ Effective in RCTs, trials ongoing 
Nerve hypoxia↑ Vasodilators NBF↑  
 ACE inhibitors  Effective in one RCT 
 Prostaglandin analogs  Effective in one RCT 
 phVEGF165 gene transfer Angiogenesis↑ RCTs ongoing 
Protein kinase C↑ Protein kinase C-β inhibitor (ruboxistaurin) NBF↑ RCTs ongoing 
C-peptide↓ C-peptide NBF↑ Studies ongoing 
Neurotrophism↓ Nerve growth factor (NGF) Nerve regeneration, growth↑ Ineffective 
 BDNF Nerve regeneration, growth↑ Ineffective 
LCFA metabolism↓ Acetyl-l-carnitine LCFA accumulation↓ Ineffective 
GLA synthesis↓ γ-Linolenic acid (GLA) EFA metabolism↑ Withdrawn 
NEG↑ Aminoguanidine AGE accumulation↓ Withdrawn 

AE, adverse event; AGE: advanced glycation end product; BDNF, brain-derived neurotrophic factor; EFA: essential fatty acid; LCFA, long-chain fatty acid; NBF, nerve blood flow; NEG, nonenzymatic glycation; RCT, randomized clinical trial.

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