Safety evaluation of α-lipoic acid (ALA)

Cremer, D.; Rabeler, R.; Roberts, Ashley; Lynch, Barry

doi:10.1016/j.yrtph.2006.06.004

Cited by 111 publications

(92 citation statements)

References 30 publications

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“…Neither hydroxycitrate nor lipoic acid are known to target DNA or to be cytotoxic to normal human cells (59,60). No demonstrable toxicity due to the long-term combination of these two drugs could be observed during this study.…”

Section: Discussionmentioning

confidence: 70%

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

Schwartz¹

2010

Oncol Rep

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Abstract. The impact of metabolic dysregulation on tumor development has long been established. We have targeted two enzymes that are altered during carcinogenesis: pyruvate dehydrogenase (PDH), which is down-regulated, and ATP citrate lyase, which is overexpressed in cancer cells. Alpha lipoic acid is a cofactor of PDH, while hydroxycitrate is a known inhibitor of ATP citrate lyase. Our hypothesis is that a combination of these drugs may have antitumoral potential. The efficacy of these molecules was screened in vitro by treatment of different human cancer and murine cell lines. Lipoic acid reduced the cell number by 10-50% depending on concentrations (0.1-10 μM) and cell types. Calcium hydroxycitrate reduced the cell number by 5-60% at different concentrations (10-500 μM). When hydroxycitrate and lipoic acid were used together, there was a major cytotoxic effect: complete cell death was seen following 8 μM lipoic acid and 300 μM hydroxycitrate treatment for 72 h. The combination of alpha lipoic acid and hydroxycitrate was administered to healthy mice, at doses currently utilized for other indications than cancer; no demonstrable toxicity was observed. The combination was used to treat mouse syngenic cancer models: MBT-2 bladder transitional cell carcinoma, B16-F10 melanoma and LL/2 Lewis lung carcinoma. The efficacy of this combination appears similar to conventional chemotherapy (cisplatin or 5-fluorouracil) as it resulted in significant tumor growth retardation and enhanced survival. This preliminary study suggests that this combination of drugs is efficient against cancer cell proliferation both in vitro and in vivo. A clinical trial is warranted.

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Section: Discussionmentioning

confidence: 70%

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

Schwartz¹

2010

Oncol Rep

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“…ALA was administered both intravenously at doses of 600–1,200 mg/day for up to 3 weeks, sometimes combined with prolonged administration of additional oral medications [30,31,32,33,34,35,36,37]. Some of these reports described less symptoms of peripheral neuropathy [30,34,35,36], while others noted no clinically meaningful effect compared with placebo [32].…”

Section: Discussionmentioning

confidence: 99%

“…No upper limit for ALA intake in humans has been established yet. In contrast, safety levels have been described for animals with pronounced species-dependent differences, showing that rats appear to be far more tolerant than many other species, such as dogs (LD 50 for dogs 400–500 mg/kg [36] vs. >2,000 mg/kg for rats [37]). Some groups reported that an oral dose of 600 mg once daily appeared to provide the optimum risk-to-benefit ratio [38].…”

Section: Discussionmentioning

confidence: 99%

Alpha-Lipoic Acid for the Prevention of Diabetic Macular Edema

et al. 2011

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Introduction: To evaluate the effect of α-lipoic acid (ALA) on the occurrence of diabetic macular edema. Methods: Randomized, double-blind, placebo-controlled, multicenter, multinational study. Patients were randomized to the treatment group with 600 mg ALA per day or the placebo group. Every 6 months stereo fundus photographs, HbA1c levels, and an ophthalmological examination were documented. The primary endpoint was the occurrence of clinically significant macular edema (CSME) within a follow-up period of 2 years. Results: We randomized 235 patients with type II diabetes mellitus into the treatment group (mean age 58.0 years) and 232 into the placebo group (mean age 57.9 years). Mean HbA1c level was 8.1, with no significant differences between the treatment (mean 8.2, SD ± 1.35) and placebo groups (mean 8.1, SD ± 1.29). HbA1c values remained constant over time. In the treatment and placebo groups, 84 and 86 patients (35.7 and 37.1%) had insulin-dependent diabetes mellitus (IDDM) with a median duration of diabetes of 9.3 versus 9.0 years in the placebo group. Visual acuity remained unchanged during the entire trial. Concerning the primary endpoint, the study provided a negative result, i.e. 26/235 patients in the treatment group and 30/232 patients in the placebo group developed CSME. Confirmatory intention-to-treat analysis of the primary endpoint revealed no statistically significant difference between groups (log-rank test, p = 0.7108, HR = 0.9057 with CI = 0.5355–1.5317). Median follow-up was identical (2.00 years). Conclusions: A daily dosage of 600 mg ALA does not prevent the occurrence of CSME in IDDM patients.

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“…One wk after diabetes induction, NAC and α-LA were administered to the diabetic treated groups by oral gavage for eight wks. The concentrations of NAC and α-LA were adjusted for a daily intake of 1.4 g/kg and 60 mg/kg, respectively, according to previous studies (22,23).…”

Section: Experimental Protocolmentioning

confidence: 99%

Inhibition of Aldehyde Dehydrogenase 2 by Oxidative Stress Is Associated with Cardiac Dysfunction in Diabetic Rats

Wang

Hao

et al. 2010

Mol Med

116

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Left ventricular (LV) dysfunction is a common comorbidity in diabetic patients, although the molecular mechanisms underlying this cardiomyopathic feature are not completely understood. Aldehyde dehydrogenase 2 (ALDH2) has been considered a key cardioprotective enzyme susceptible to oxidative inactivation. We hypothesized that hyperglycemia-induced oxidative stress would influence ALDH2 activity, and ALDH2 inhibition would lead to cardiac functional alterations in diabetic rats. Diabetes was induced by intraperitoneal (i.p.) injection of 60 mg/kg streptozotocin. Rats were divided randomly into four groups: control, untreated diabetic, diabetic treated with N-acetylcysteine (NAC) and diabetic treated with a-lipoic acid (α-LA). Cardiac contractile function, oxidative stress markers and reactive oxygen species (ROS) levels were assessed. ALDH2 activity and expression also were determined. The role of ALDH2 activity in change in hyperglycemia-induced mitochondrial membrane potential (Δψ) was tested in cultured neonatal cardiomyocytes. Myocardial MDA content and ROS were significantly higher in diabetic rats than in controls, whereas GSH content and Mn-SOD activity were decreased in diabetic rats. Compared with controls, diabetic rats exhibited significant reduction in LV ejection fraction and fractional shortening, accompanied by decreases in ALDH2 activity and expression. NAC and α-LA attenuated these changes. Mitochondrial Δψ was decreased greatly with hyperglycemia treatment, and high glucose combined with ALDH2 inhibition with daidzin further decreased Δψ. The ALDH2 activity can be regulated by oxidative stress in the diabetic rat heart. ALDH2 inhibition may be associated with LV reduced contractility, and mitochondrial impairment aggravated by ALDH2 inhibition might reflect an underlying mechanism which causes cardiac dysfunction in diabetic rats.

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Safety evaluation of α-lipoic acid (ALA)

Cited by 111 publications

References 30 publications

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

A combination of alpha lipoic acid and calcium hydroxycitrate is efficient against mouse cancer models: Preliminary results

Alpha-Lipoic Acid for the Prevention of Diabetic Macular Edema

Inhibition of Aldehyde Dehydrogenase 2 by Oxidative Stress Is Associated with Cardiac Dysfunction in Diabetic Rats

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