Clinical potential of aldose reductase inhibitors in diabetic neuropathy.
Clinical potential of aldose reductase inhibitors in diabetic neuropathy.
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DOI：
10.2165/00024677-200403040-00006
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发表时间：
2004-01-01
期刊：
影响因子：
--
通讯作者：
Nakamura, Jiro
中科院分区：
文献类型：
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作者：
Hamada, Yoji;Nakamura, Jiro
在过去的几十年里，人们开发了许多醛糖还原酶抑制剂(ARI)，以期达到治疗糖尿病并发症的效果。神经病变是作为ARIS潜在靶点而被最深入研究的并发症。大多数ARI在动物模型中表现出令人满意的效果。然而，由于缺乏确凿的证据，ARIS在糖尿病患者中的临床潜力一直存在争议。这类药物的安全性也不确定。本文总结了迄今为止对糖尿病神经病变患者进行的ARIS临床试验的结果。每种ARI的疗效和毒性将通过临床数据进行简要评估。还将讨论药物疗效评价的理论背景和主要问题。总体而言，观察到的疗效因化合物而异。在大多数试验中，少数ARI在多个终点显示出良好的效果，而许多ARI的结果似乎是矛盾的。有一种药物在任何终点都几乎没有显示出积极的效果。这种差异可能至少部分归因于神经组织中多元醇途径受到不同程度的抑制，这不仅取决于药物的药代动力学特性，还取决于其对神经组织的渗透。除了每一种ARI的不确定潜力外，临床试验所用的设计和分析方法的问题可能是导致矛盾结果的原因。在大量研究中，分析的能力和试验的持续时间显然是不够的。被选为终点的各种指数不一定是敏感或可重现的。持续时间更长的研究，大规模的试验，评估神经病变的更好的方法，以及选择具有相同背景的患者，将提供更多确凿的证据。严重不良反应的风险，例如过敏反应和肝脏损伤，已导致一些ARIs从市场上撤出或不再进一步开发。然而，这些不利影响似乎不是由于醛糖还原酶活性本身的抑制，而是由于对每种化合物的特定反应。总之，充分抑制神经醛糖还原酶活性似乎有可能预防或改善糖尿病神经病变，在广泛临床应用之前，进一步开发更有效和安全的ARIs是必要的。
A number of aldose reductase inhibitors (ARIs) have been developed over the past few decades with the expectation of therapeutic effects for diabetic complications. Neuropathy is the complication that has been most intensively studied as a potential target for ARIs. Most ARIs have shown satisfactory effects in animal models. However, the clinical potential of ARIs in diabetic patients has been controversial due to the lack of conclusive evidence. The safety of this category of drugs is also uncertain. This article summarizes the results of clinical trials of ARIs for patients with diabetic neuropathy that have been performed to date. The efficacy and toxicity of each ARI will be briefly assessed by the clinical data. The theoretical background along with major issues in the evaluation of drug efficacy will also be discussed. Overall the observed efficacy varied among the compounds. A few ARIs showed favorable effects in multiple endpoints in the majority of trials, while the results from many ARIs seemed ambivalent. One drug barely exhibited positive effects on any endpoint. This discrepancy may be attributable at least in part to the different degree of inhibition of the polyol pathway in nerve tissues, which is determined not only by the pharmacokinetic properties of the drug but also by its penetration into nerve tissues. In addition to the uncertain potential of each ARI, the issues of design and analytical methods used for clinical trials may underlie the ambivalent outcomes. The power of analysis and the duration of trials were apparently inadequate in a large number of the studies. Various indices selected as endpoints are not necessarily sensitive or reproducible. Studies of longer duration, large-scale trials, better methods to assess neuropathy, and the selection of patients with a homogenous background would provide more conclusive evidence. The risk of serious adverse reactions, for example, hypersensitivity reactions and hepatic damage, has led to some ARIs being withdrawn from the market or from further development. These adverse effects, however, do not appear to result from the inhibition of aldose reductase activity per se but from specific reactions to each compound. In conclusion, sufficient inhibition of the nerve aldose reductase activity seems likely to prevent or ameliorate diabetic neuropathy, and further development of more potent and safe ARIs is necessary before extensive clinical application.