Bdnf

Nerve regeneration, growth "

Ineffective

LCFA metabolism #

Acetyl-L-carnitine

LCFA accumulation "

Ineffective

NEG "

Aminoguanidine

AGE accumulation "

Withdrawn

Abbreviations: AE, adverse events; AGE, advanced glycation end products; BDNF, brain-derived neurotrophic factor; EFA, essential fatty acids; LCFA, long-chain fatty acids; NBF, nerve blood flow; NEG, non-enzymatic glycation; RCTs, randomized clinical trials.

Abbreviations: AE, adverse events; AGE, advanced glycation end products; BDNF, brain-derived neurotrophic factor; EFA, essential fatty acids; LCFA, long-chain fatty acids; NBF, nerve blood flow; NEG, non-enzymatic glycation; RCTs, randomized clinical trials.

the ARI trials so far do not appear to reflect a meaningful magnitude of a treatment effect. In a recent 1-year phase II trial of zenarestat including 208 patients with diabetic polyneuropathy a dose-dependent improvement in small myelinated fiber loss and peroneal NCV was observed, but subsequent large phase III trials of zenarestat had to be prematurely terminated due to a significant deterioration in renal function in some patients.

A 52-week controlled multicenter trial of fidarestat (1 mg/day) including 279 patients with diabetic polyneuropathy showed an improvement in F-wave conduction velocity and reduction in neuropathic symptoms. No significant adverse reactions to fidarestat were observed in this trial (50). However, no phase III trials are available for this compound.

In an open randomized multicenter study 289 diabetic patients with DSP were treated with epalrestat (150 mg/day), while 305 patients served as untreated controls. After 3 years epalrestat treatment prevented deterioration in median sensory NCV, MFWL, and VPT. Numbness, sensory deficits, and crampi were also improved. However, this study was biased by its uncontrolled design, i.e., control group without treatment (51).

Ranirestat, a novel ARI was evaluated in a phase II study over 60 weeks. Peroneal MNCV, sural sensory NCV, and VPT were improved during treatment with ranirestat (20 mg/ day), without any relevant adverse events (52). These data require confirmation in phase III trials.

y-Linolenic Acid

Two multicenter trials have demonstrated improvement in neuropathic deficits and NCV after 1 year of treatment with y-linolenic acid (GLA) in diabetic peripheral neuropathy (53). However, since GLA could not be licensed on the basis of these data in the UK, no further trials have been initiated.

a-Lipoic Acid (Thioctic Acid)

There is accumulating evidence suggesting that free radical-mediated oxidative stress is implicated in the pathogenesis of diabetic neuropathy by inducing neurovascular defects that result in endoneurial hypoxia and subsequent nerve dysfunction. Antioxidant treatment with a-lipoic acid has been shown to prevent these abnormalities in experimental diabetes, thus providing a rationale for a potential therapeutic value in diabetic patients (Table 6). In Germany, a-lipoic acid is licensed and used for treatment of symptomatic diabetic neuropathy since more than 40 years. According to a meta-analysis comprising 1258 patients infusions of a-lipoic acid (600 mg i.v./day) ameliorated neuropathic symptoms and deficits after 3 weeks, while the ALADIN III Study showed oral treatment with 600 mg t.i.d. resulted in a favorable effect on neuropathic deficits after 6 months (54,55). Moreover, the SYDNEY 2 Trial suggests that treatment for 5 weeks using 600 mg of a-lipoic acid orally q.d. reduces the chief symptoms of diabetic polyneuropathy including pain, paresthesias, and numbness to a clinically meaningful degree (56). In a multicenter, randomized, double-masked, parallel-group clinical trial (NATHAN 1) including 460 diabetic patients with stage 1 or stage 2a DSP were randomly assigned to oral treatment with a-lipoic acid 600 mg q.d. (n = 233) or placebo (n = 227) for 4 years. After 4 years some neuropathic deficits and symptoms, but not NCV were improved, and the drug was well tolerated throughout the trial (57). Clinical and postmarketing surveillance studies have revealed a highly favorable safety profile of this drug.

Vasodilators

Microvascular changes of the vasa nervorum and reduced endoneurial blood flow resulting in hypoxia are thought to be important factors in the pathogenesis of diabetic neuropathy. Thus, there is solid theoretical background to support treatment with vasodilating drugs (Table 5). In a 1-year trial including 41 normotensive patients with mild neuropathy several attributes of NCV, but not neuropathic symptoms and deficits were improved after 1 year of treatment with the ACE inhibitor trandolapril (58). Further studies are clearly needed to define the therapeutic role of ACE inhibitors in diabetic neuropathy.

Several open-label trials from Japan reported pain relief after treatment with vasodilating agents such as the prostacyclin (PGI ) analogs iloprost or beraprost and the prostaglandin derivative PGE . aCD reported relief of pain or dysesthetic symptoms after 2,

TABLE 6 Randomized Double-Blind Placebo-Controlled Trials of a-Lipoic Acid (Thioctic Acid) in Diabetic Peripheral and Cardiac Autonomic Neuropathy

Trial

Number (n)

Dose (mg)

Duration

Effects

Safety

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