Tuy nhiên, mặc dù 25 năm của thử nghiệm lâm sàng với Aris trong bệnh thần kinh đái tháo đường, chỉ epalrestat là hiện đang có sẵn tại Nhật Bản. Hầu hết các thử nghiệm ban đầu có thể được tóm tắt như sau: • Quá nhỏ. Thuốc có hiệu lực không đủ để ức chế thần kinh tích lũy sorbitol; | 114 SECTION II DIABETIC NEUROPATHIES However despite 25 years of clinical trials with ARIs in diabetic neuropathy only epalrestat is currently available in Japan. Most of the early trials can be summarized as Too small. Drug effect inadequate to inhibit nerve sorbitol accumulation Too few. Inadequate numbers of subjects randomized Too short. Many trials only lasted weeks or months for a chronic disease of many years duration Too late. Targeting a pathogenetic mechanism is not likely to be effective when the complication is well established Too toxic. A number of ARIs were withdrawn in phase III due to hepatic or renal toxicity. Antioxidants Increased free radical production and a reduced ability to neutralize free radicals due to nicotinamide adenine dinucleotide NADH depletion partly the result of non-enzymatic glycation and polyol pathway hyperactivity supports the role of oxidative stress in the pathogenesis of neuropathy. Studies with the antioxidant alpha-lipoic acid LA have provided evidence of potential efficacy with this agent for both symptoms and signs. Two large North American European clinical trials of the efficacy of LA are in progress and should report in 2005. Gamma-linolenic acid GLA GLA can prevent abnormalities in essential fatty acid and prostanoid metabolism. GLA treatment for one year in a randomized trial resulted in improvement in electrophysiology and deficits. A LA GLA conjugate has produced impressive improvements in electrophysiological and neurochemical abnormalities in experimental diabetic neuropathy but this has not been tested in diabetic patients. Inhibitors of glycation Non-enzymatic glycation occurs in diabetes and may be an important initiating factor for nerve demyelination and may also interfere with axonal transport. Advanced glycation end products AGE can also absorb nitric oxide NO and impair nerve blood flow. Studies of aminoguanidine an inhibitor of advanced glycation have shown no benefit in diabetic nephropathy and few
