Alpha Lipoid acid

Alpha lipoid acid (ALA, synonyms: thioctic acid; 6,8-thioctic acid; 6,8-dithioctane acid and 1,2-dithiol-3-valeric acid), a potent anti-oxidant, is implicated in the treatment of complications of diabetes, in particular painful diabetic neuropathy (PDN). In this section we will discuss the properties of ALA and both its rationale and evidence for clinical use in the treatment of PDN.

Background

Peripheral neuropathy is a microvascular complication of diabetes which is present in approximately 28.5 percent of all patients[1]. The clinical symptoms range from decreased sensation to neuropathic pain (i.e. PDN). The latter may present as intermittent or chronic tingling, burning cramps, ache and/or pain which typically worsens during night and is localized predominantly in the feet [2]. Subsequently, PDN has a substantial, negative, impact on the quality of life [3]. Besides optimizing glycaemic control the current approach to neuropathy consists of analgesic to relieve of symptoms; antidepressants, anti-epileptics and opiates are frequently used. Despite all these interventions and effort from both patients and health care providers, PDN remains difficult to treat [4].

Rationale

Although the pathogenesis of diabetic neuropathy is multifactorial there is overwhelming evidence that the development of microvascular complications, including PDN is related to the level of glucose dysregulation of an extended period of time [5]. The increased production of free oxygen radicals in the mitochondria (i.e. oxidative stress) induces neurovascular defects that results in endoneurial hypoxia and subsequent nerve dysfunction (2). Therefore, interventions which lower the amount of free oxygen radicals, such as administration of ALA, provide a rationale in treating PDN.

Pharmacology

ALA is an eight-carbon disulfide that contains a single chiral center and an asymmetric carbon, thus resulting in two possible optical isomers: R-ALA and S-ALA. The R-isomer is synthesized endogenously and binds to proteins. Humans can synthesize ALA de novo in the liver from fatty acids and cysteine, but in very small amounts. Therefore, ALA needs to be absorbed from exogenous sources such as spinach, broccoli, and yeast extracts. For therapeutic purposes, the R-ALA form is usually administered as a racemic mixture of R-ALA and S-ALA. In animal models ALA has shown to reduce both micro-and macrovascular complications [6][7].

Clinical Studies

The effects of ALA as treatment for neuropathic pain in humans were recently analyzed in a meta-analysis which included all, qualitative sound, randomized controlled trials. In these trials ALA was given as a intravenous (dose 100-1200mg per day during 3 weeks) or an oral dose (dose 600-1800mg per day during 3-5weeks) [8]. All analyzed studies showed a significant improvement after ALA administration. Overall analysis among 653 patients, mostly diabetes type 2, showed an average reduction of 50% in the total symptom score after both oral and intravenous administration during 3 weeks at a dosage of at least 600mg per day [9]. However, as the total symptom score in the placebo controlled also decreased, the relative reduction of oral ALA treatment was less than 30%, which is considered a clinical threshold for a relevant reduction on the total symptom scale.

Summary

In conclusion, the effects of oral ALA administration are encouraging but not conclusive. Intravenous administration of ALA for PDN leads to a relieve of symptoms in the short term and may therefore be considered a treatment for patients who do not respond to common therapy. However further investigation needs to be performed to establish long-term results of ALA administration.

References

  1. ^ Young MJ, Boulton AJ, MacLeod AF, Williams DR, Sonksen PH. A multicentre study of the prevalence of diabetic peripheral neuropathy in the United Kingdom hospital clinic population. Diabetologia. 1993 feb;36(2):150–4

  2. ^ Ziegler D. Painful diabetic neuropathy: advantage of novel drugs over old drugs? Diabetes Care. 2009 nov;32 Suppl 2:S414–419.

  3. ^ Benbow SJ, Wallymahmed ME, MacFarlane IA. Diabetic peripheral neuropathy and quality of life. QJM. 1998 nov;91(11):733–7.

  4. ^ Daousi C, Benbow SJ, Woodward A, MacFarlane IA. The natural history of chronic painful peripheral neuropathy in a community diabetes population. Diabet. Med. 2006 sep;23(9):1021–4.

  5. ^ The effect of intensive diabetes therapy on the development and progression of neuropathy. The Diabetes Control and Complications Trial Research Group. Ann. Intern. Med. 1995 apr 15;122(8):561–8.

  6. ^ Lin J, Bierhaus A, Bugert P, Dietrich N, Feng Y, Vom Hagen F, e.a. Effect of R-(+)-alpha-lipoic acid on experimental diabetic retinopathy. Diabetologia. 2006 mei;49(5):1089–96.

  7. ^ Yi X, Maeda N. alpha-Lipoic acid prevents the increase in atherosclerosis induced by diabetes in apolipoprotein E-deficient mice fed high-fat/low-cholesterol diet. Diabetes. 2006 aug;55(8):2238–44.

  8. ^ Mijnhout GS, Kollen BJ, Alkhalaf A, Kleefstra N, Bilo HJG. Alpha lipoic Acid for symptomatic peripheral neuropathy in patients with diabetes: a meta-analysis of randomized controlled trials. Int J Endocrinol. 2012;2012:456279.

  9. ^ Ziegler D, Hanefeld M, Ruhnau KJ, Meissner HP, Lobisch M, Schütte K, e.a. Treatment of symptomatic diabetic peripheral neuropathy with the anti-oxidant alpha-lipoic acid. A 3-week multicentre randomized controlled trial (ALADIN Study). Diabetologia. 1995 dec;38(12):1425–33.

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