Alpha Lipoic Acid


Clinical Studies
References


Alpha Lipoic Acid (ALA) is a sulfur-containing vitamin-like phytonutrient with antioxidant properties. It enhances effects of other antioxidants to fight free radicals and improve recovery. It is an insulin potentiator that may be, in some respects, the very best insulin mimick. It may enhance insulin sensitivity, improving the body's ability to add lean mass and reduce fat. Alpha Lipoic Acid is a co-factor for creatine in energy metabolism.

ALA may inhibit the replication of HIV. It may be beneficial in diabetes type II, hyperglycemia, HIV, glaucoma, hepatitis and obesity.


Published Clinical Studies
Alpha Lipoic Acid

Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study.

Morcos M, Borcea V, Isermann B, Gehrke S, Ehret T, Henkels M, Schiekofer S, Hofmann M, Amiral J, Tritschler H, Ziegler R, Wahl P, Nawroth PP.

Diabetes Res Clin Pract. 2001 Jun; 52(3):175-83.

Department of Internal Medicine I, University of Heidelberg, Bergheimerstr. 58, 69115 Heidelberg, Germany. michael_morcos@med.uni-heidelberg.de

Oxidative stress plays a central role in the pathogenesis and progression of late microangiopathic complications (diabetic nephropathy) in diabetes mellitus. Previous studies suggested that treatment of diabetic patients with the antioxidant alpha-lipoic acid reduce oxidative stress and urinary albumin excretion. In this prospective, open and non-randomized study, the effect of alpha-lipoic acid on the progression of endothelial cell damage and the course of diabetic nephropathy, as assessed by measurement of plasma thrombomodulin and urinary albumin concentration (UAC), was evaluated in 84 patients with diabetes mellitus over 18 months. Forty-nine patients (34 with Type 1 diabetes, 15 with Type 2 diabetes) had no antioxidant treatment and served as a control group. Thirty-five patients (20 with Type 1 diabetes, 15 with Type 2 diabetes) were treated with 600 mg alpha-lipoic acid per day. Only patients with an urinary albumin concentration <200 mg/l were included into the study. After 18 months of follow up, the plasma thrombomodulin level increased from 35.9+/-9.5 to 39.7+/-9.9 ng/ml (P<0.05) in the control group. In the alpha-lipoic acid treated group the plasma thrombomodulin level decreased from 37.5+/-16.2 to 30.9+/-14.5 ng/ml (P<0.01). The UAC increased in patients without alpha-lipoic acid treatment from 21.2+/-29.5 to 36.9+/-60.6 ng/l (P<0.05), but was unchanged with alpha-lipoic acid. It is postulated that the significant decrease in plasma thrombomodulin and failure of UAC to increase observed in the alpha-lipoic acid treated group is due to antioxidative effects of alpha-lipoic acid, and if so that oxidative stress plays a central role in the pathogenesis of diabetic nephropathy. Furthermore, progression of the disease might be inhibited by antioxidant drugs. A placebo-controlled study is needed.

PMID: 11323087 [PubMed - indexed for MEDLINE]

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Alpha-lipoic acid: a multifunctional antioxidant that improves insulin sensitivity in patients with type 2 diabetes.

Evans JL, Goldfine ID.

Diabetes Technol Ther. 2000 Autumn; 2(3):401-13.

Medical Research Institute, San Bruno, California 94066, USA. jevans@lipoic.com

Alpha-Lipoic acid (LA) is a disulfide compound that is produced in small quantities in cells, and functions naturally as a co-enzyme in the pyruvate dehydrogenase and alpha-ketoglutarate dehydrogenase mitochondrial enzyme complexes. In pharmacological doses, LA is a multifunctional antioxidant. LA has been used in Germany for over 30 years for the treatment of diabetes-induced neuropathy. In patients with type 2 diabetes, recent studies have reported that intravenous (i.v.) infusion of LA increases insulin-mediated glucose disposal, whereas oral administration of LA has only marginal effects. If the limitations of oral therapy can be overcome, LA could emerge as a safe and effective adjunctive antidiabetic agent with insulin sensitizing activity.

PMID: 11467343 [PubMed - indexed for MEDLINE]

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Nutrients and HIV: part three - N-acetylcysteine, alpha-lipoic acid, L-glutamine, and L-carnitine.

Patrick L.

Altern Med Rev. 2000 Aug; 5(4):290-305.

The role of antioxidants in preventing apoptosis and viral activation in HIV is well documented. N-acetylcysteine, glutathione, and alpha-lipoic acid have been shown to interrupt the process of viral activation and CD4 cell death. L-glutamine has been shown to improve glutathione levels and significantly increase lean body mass in HIV infection. The literature on the use of L-carnitine and acetyl-L-carnitine in treating mitochondrial toxicity, both in muscle and nerve pathologies is relevant in nutritional treatment of HIV, given the mitochondrial toxicity of nucleoside analog reverse transcriptase inhibitor therapy. The current use of highly active antiviral therapies, their toxicity, and significant failure rates have created the need for a more conservative reassessment of HIV treatment. The adjunctive use of nutrient therapy in the treatment of HIV is reviewed here.

PMID: 10956377 [PubMed - indexed for MEDLINE]

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A conservative triple antioxidant approach to the treatment of hepatitis C. Combination of alpha lipoic acid (thioctic acid), silymarin, and selenium: three case histories.

Berkson BM.

Med Klin. 1999 Oct 15; 94 Suppl 3:84-9.

Integrative Medical Center of New Mexico, New Mexico State University, Las Cruces, USA. burt@zianet.com

BACKGROUND: There has been an increase in the number of adults seeking liver transplantation for hepatitis C in the last few years and the count is going up rapidly. There is no reliable and effective therapy for chronic hepatitis C since interferon and antivirals work no more than 30% of the time, and liver transplant surgery is uncertain and tentative over the long run. This is because, ultimately, residual hepatitis C viremia infects the new liver. Furthermore, liver transplantation can be painful, disabling and extremely costly.

TREATMENT PROGRAM: The author describes a low cost and efficacious treatment program in 3 patients with cirrhosis, portal hypertension and esophageal varices secondary to chronic hepatitis C infection. This effective and conservative regimen combines 3 potent antioxidants (alpha-lipoic acid [thioctic acid], silymarin, and selenium) that possess antiviral, free radical quenching and immune boosting qualities.

CONCLUSION: There are no remarkably effective treatments for chronic hepatitis C in general use. Interferon and antivirals have less than a 30% response rate and because of the residual viremia, a newly transplanted liver usually becomes infected again. The triple antioxidant combination of alpha-lipoic acid, silymarin and selenium was chosen for a conservative treatment of hepatitis C because these substances protect the liver from free radical damage, increase the levels of other fundamental antioxidants, and interfere with viral proliferation. The 3 patients presented in this paper followed the triple antioxidant program and recovered quickly and their laboratory values remarkably improved. Furthermore, liver transplantation was avoided and the patients are back at work, carrying out their normal activities, and feeling healthy. The author offers a more conservative approach to the treatment of hepatitis C that is exceedingly less expensive. One year of the triple antioxidant therapy described in this paper costs less than $2,000, as compared to more than $300,000 a year for liver transplant surgery. It appears reasonable, that prior to liver transplant surgery evaluation, or during the transplant evaluation process, the conservative triple antioxidant treatment approach should be considered. If this is a significant betterment in the patient's condition, liver transplant surgery may be avoided.

PMID: 10554539 [PubMed - indexed for MEDLINE]

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Beneficial effects of alpha-lipoic acid and ascorbic acid on endothelium-dependent, nitric oxide-mediated vasodilation in diabetic patients: relation to parameters of oxidative stress.

Heitzer T, Finckh B, Albers S, Krohn K, Kohlschutter A, Meinertz T.

Free Radic Biol Med. 2001 Jul 1; 31(1):53-61.

Universitatsklinikum Hamburg-Eppendorf Klinik und Poliklinik fur Innere Medizin, Abteilung Kardiologie, Hamburg, Germany. heitzer@uke.uni-hamburg.de

The impairment of nitric oxide (NO)-mediated vasodilation in diabetes has been attributed to increased vascular oxidative stress. Lipoic acid has been shown to have substantial antioxidative properties. The aim of this study was to assess the effect of lipoic acid on NO-mediated vasodilation in diabetic patients in comparison with the well-recognized effect of ascorbic acid. Using venous occlusion plethysmography, we examined the effects of lipoic acid (0.2 mM) and ascorbic acid (1 and 10 mM) on forearm blood flow responses to acetylcholine, sodium nitroprusside and concomitant infusion of the NO-inhibitor, N(G)-monomethyl-L-arginine, in 39 diabetic patients and 11 control subjects. Plasma levels of antioxidants and parameters of lipid peroxidation were measured and correlated to endothelial function tests. Lipoic acid improved NO-mediated vasodilation in diabetic patients, but not in controls. NO-mediated vasodilation was improved by ascorbic acid at 10 mM, but not 1 mM. Improvements of endothelial function by ascorbic acid and lipoic acid were closely related. The beneficial effects of lipoic acid were positively related to plasma levels of malondialdehyde and inversely related to levels of ubiquinol-10. These findings support the concept that oxidative stress contributes to endothelial dysfunction and suggest a therapeutic potential of lipoic acid particularly in patients with imbalance between increased oxidative stress and depleted antioxidant defense.

PMID: 11425490 [PubMed - indexed for MEDLINE]

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Alpha-lipoic acid in liver metabolism and disease.

Bustamante J, Lodge JK, Marcocci L, Tritschler HJ, Packer L, Rihn BH.

Free Radic Biol Med. 1998 Apr; 24(6):1023-39.

Department of Molecular and Cell Biology, University of California, Berkeley 94720-3200, USA.

R-alpha-Lipoic acid is found naturally occurring as a prosthetic group in alpha-keto acid dehydrogenase complexes of the mitochondria and as such plays a fundamental role in metabolism. Although this has been known for decades, only recently has free supplemented alpha-lipoic acid been found to affect cellular metabolic processes in vitro, as it has the ability to alter the redox status of cells and interact with thiols and other antioxidants. Therefore, it appears that this compound has important therapeutic potential in conditions where oxidative stress is involved. Early case studies with alpha-lipoic acid were performed with little knowledge of the action of alpha-lipoic acid at a cellular level, but with the rationale that because the naturally occurring protein bound form of alpha-lipoic acid has a pivotal role in metabolism, that supplementation may have some beneficial effect. Such studies sought to evaluate the effect of supplemented alpha-lipoic acid, using low doses, on lipid or carbohydrate metabolism, but little or no effect was observed. A common response in these trials was an increase in glucose uptake, but increased plasma levels of pyruvate and lactate were also observed, suggesting that an inhibitory effect on the pyruvate dehydrogenase complex was occurring. During the same period, alpha-lipoic acid was also used as a therapeutic agent in a number of conditions relating to liver disease, including alcohol-induced damage, mushroom poisoning, metal intoxification, and CCl4 poisoning. Alpha-Lipoic acid supplementation was successful in the treatment for these conditions in many cases. Experimental studies and clinical trials in the last 5 years using high doses of alpha-lipoic acid (600 mg in humans) have provided new and consistent evidence for the therapeutic role of antioxidant alpha-lipoic acid in the treatment of insulin resistance and diabetic polyneuropathy. This new insight should encourage clinicians to use alpha-lipoic acid in diseases affecting liver in which oxidative stress is involved.

PMID: 9607614 [PubMed - indexed for MEDLINE]

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Antioxidant and prooxidant activities of alpha-lipoic acid and dihydrolipoic acid.

Moini H, Packer L, Saris NE.

Toxicol Appl Pharmacol. 2002 Jul 1; 182(1):84-90.

Department of Applied Chemistry and Microbiology, PB 56 Viikki Biocenter, FIN-00014, University of Helsinki, Helsinki, Finland. hmoini@usc.edu

Reactive oxygen (ROS) and nitrogen oxide (RNOS) species are produced as by-products of oxidative metabolism. A major function for ROS and RNOS is immunological host defense. Recent evidence indicates that ROS and RNOS may also function as signaling molecules. However, high levels of ROS and RNOS have been considered to potentially damage cellular macromolecules and have been implicated in the pathogenesis and progression of various chronic diseases. alpha-Lipoic acid and dihydrolipoic acid exhibit direct free radical scavenging properties and as a redox couple, with a low redox potential of -0.32 V, is a strong reductant. Several studies provided evidence that alpha-lipoic acid supplementation decreases oxidative stress and restores reduced levels of other antioxidants in vivo. However, there is also evidence indicating that alpha-lipoic acid and dihydrolipoic acid may exert prooxidant properties in vitro. alpha-Lipoic acid and dihydrolipoic acid were shown to promote the mitochondrial permeability transition in permeabilized hepatocytes and isolated rat liver mitochondria. Dihydrolipoic acid also stimulated superoxide anion production in rat liver mitochondria and submitochondrial particles. alpha-Lipoic acid was recently shown to stimulate glucose uptake into 3T3-L1 adipocytes by increasing intracellular oxidant levels and/or facilitating insulin receptor autophosphorylation presumably by oxidation of critical thiol groups present in the insulin receptor beta-subunit. Whether alpha-lipoic acid and/or dihydrolipoic acid-induced oxidative protein modifications contribute to their versatile effects observed in vivo warrants further investigation.

PMID: 12127266 [PubMed - indexed for MEDLINE]

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Burning mouth syndrome (BMS): an open trial of comparative efficacy of alpha-lipoic acid (thioctic acid) with other therapies.

Femiano F.

Minerva Stomatol. 2002 Sep; 51(9):405-9.

Stomatology Clinic II, University of Medicine and Surgery, Naples, Italy.

BACKGROUND:
Alpha-lipoic acid (ALA) is a potent antioxidant mitochondrial coenzyme, trometamol salt of thioctic acid, shown in clinical studies to be neuroprotective and in a preliminary study to have an effect on the symptomatology of Burning Mouth Syndrome (BMS).

METHODS:
We were interested in extending our studies as to whether alpha-lipoic acid might improve the symptomatology in BMS and therefore carried out a larger open controlled clinical study on the effects of alpha-lipoic acid on BMS symptomatology.

RESULTS:
We have examined the effects on 4 groups of 20 patients with BMS of ALA, compared with bethanecol, Biotene and placebo, and found ALA of remarkable benefit with minimal adverse effects.

CONCLUSIONS:
These results suggest that double-blind randomized controlled multicenter studies of ALA are indicated.

PMID: 12473978 [PubMed - indexed for MEDLINE]

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Alpha-lipoic acid and cardiovascular disease.

Wollin SD, Jones PJ.

School of Dietetics and Human Nutrition, McGill University, Ste-Anne-de-Bellevue, Quebec, Canada.

Alpha-lipoic acid (ALA) has been identified as a powerful antioxidant found naturally in our diets, but appears to have increased functional capacity when given as a supplement in the form of a natural or synthetic isolate. ALA and its active reduced counterpart, dihydrolipoic acid (DHLA), have been shown to combat oxidative stress by quenching a variety of reactive oxygen species (ROS). Because this molecule is soluble in both aqueous and lipid portions of the cell, its biological functions are not limited solely to one environment. In addition to ROS scavenging, ALA has been shown to be involved in the recycling of other antioxidants in the body including vitamins C and E and glutathione. Not only have the antioxidant qualities of this molecule been studied, but there are also several reports pertaining to its blood lipid modulating characteristics, protection against LDL oxidation and modulation of hypertension. Therefore, ALA represents a possible protective agent against risk factors of cardiovascular disease (CVD). The objective of this review is to examine the literature pertaining to ALA in relation to CVD and describe the most powerful actions and potential uses of this naturally occurring antioxidant. Despite the numerous studies on ALA, many questions remain relating to the use of ALA as a supplement. There is no consensus on dosage, dose frequency, form of administration, and/or preferred form of ALA. However, collectively the literature increases our understanding of the potential uses for supplementation with ALA and identifies key areas for future research.

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Alpha lipoic acid: a novel treatment for depression.

Salazar MR.

Amherst College, Amherst, Massachusetts, USA.

Med Hypotheses. 2000 Dec; 55(6):510-2.

Insulin resistance has been associated with people diagnosed with depression. Conversely, it has also been documented that diabetics have an increased risk of depression. Evidence suggests that insulin activity plays a role in serotonergic activity by increasing the influx of tryptophan into the brain. This increased influx of tryptophan has been shown to result in an increase in serotonin synthesis. In accordance with the serotonin theory of depression, it may be possible to treat depression by increasing insulin activity. The antioxidant alpha lipoic acid has been shown to increase insulin sensitivity and is used to treat people with diabetes. Therefore, the nutrient alpha lipoic acid should be clinically tested as an adjunct treatment for depression.

PMID: 11090300 [PubMed - indexed for MEDLINE]

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Pharmacokinetics, tolerability, and fructosamine-lowering effect of a novel, controlled-release formulation of alpha-lipoic acid.

Evans JL, Heymann CJ, Goldfine ID, Gavin LA.

Endocr Pract. 2002 Jan-Feb; 8(1):29-35.

Northern California Diabetes Institute, Seton Medical Center, Dale City, CA 94015, USA.

OBJECTIVE:
To determine the pharmacokinetics, safety, and tolerability of a novel, controlled-release oral formulation of alpha-lipoic acid (LA) and to investigate whether sustaining the concentration of LA in plasma would have a beneficial effect on glycemic control in patients with type 2 diabetes.

METHODS:
For the pharmacokinetic study, a single, 600-mg dose of either controlled-release LA (CRLA) or quick-release LA (QRLA) was administered orally to 12 normal human subjects. The plasma profile of LA was determined for 24 hours after administration of the dose, and pharmacokinetic analyses were performed. For the safety and tolerability study, 21 patients with type 2 diabetes were given 900 mg of CRLA daily for 6 weeks, followed by 1,200 mg of CRLA daily for an additional 6 weeks. Active treatment was followed by a 3-week washout period. Throughout the study, patients continued to take their prestudy antidiabetic medications, which included metformin (Glucophage), sulfonylureas (Amaryl, glyburide, and Glucotrol), acarbose (Precose), troglitazone (Rezulin), and insulin (either as monotherapy or in combination). CRLA was evaluated for safety and tolerability as well as for effects on glycemic control.

RESULTS:
The Tmax (time to maximal plasma concentration) of LA administered as CRLA was 1.25 hours and was approximately 2.5-fold longer in comparison with the Tmax for QRLA (Tn,5X = 0.5 hour; P<0.02). No severe side effects or changes in either liver or kidney function or hematologic profiles were noted after the administration of CRLA. In 15 patients, the mean plasma fructosamine concentration was reduced from 313 to 283 micromol/L (P<0.05) after 12 weeks of treatment with CRLA.

CONCLUSION:
CRLA increased the plasma concentration of LA over time in healthy subjects, and CRLA was safe, well tolerated, and effective in reducing plasma fructosamine in patients with type 2 diabetes.

PMID: 11951812 [PubMed - indexed for MEDLINE]

PMA/IoM-stimulated HPBL, whereas it inhibited these in HPBL

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References

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