The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects

GeroNova Research, Inc., 4677 Meade St, Richmond, California 94804, USA.
Alternative medicine review: a journal of clinical therapeutic (Impact Factor: 3.83). 01/2008; 12(4):343-51.
Source: PubMed

ABSTRACT The racemic mixture, RS-(+/-)-alpha-lipoic acid (rac-LA) has been utilized clinically and in a variety of disease models. Rac-LA and the natural form, R-lipoic acid (RLA), are widely available as nutritional supplements, marketed as antioxidants. Rac-LA sodium salt (NaLA) or rac-LA potassium salt (KLA) has been used to improve the aqueous solubility of LA. STUDY RATIONALE: Several in vitro and animal models of aging and age-related diseases have demonstrated efficacy for the oral solutions of LA salts in normalizing age-related changes to those of young animals. Other models and studies have demonstrated the superiority of RLA, the naturally occurring isomer over rac-LA. Despite this, RLA pharmacokinetics (PK) is not fully characterized in humans, and it is unknown whether the concentrations utilized in animal models can be achieved in vivo. Due to its tendency to polymerize, RLA is relatively unstable and suffers poor aqueous solubility, leading to poor absorption and low bioavailability. A preliminary study demonstrated the stability and bioavailability were improved by converting RLA to its sodium salt (NaRLA) and pre-dissolving it in water. The current study extends earlier findings from this laboratory and presents PK data for the 600-mg oral dosing of 12 healthy adult subjects given NaRLA. In addition, the effect of three consecutive doses was tested on a single subject relative to a one-time dosing in the same subject to determine whether plasma maximum concentration (Cmax) and the area under the plasma concentration versus time curve (AUC) values were comparable to those in animal studies and those achievable via intravenous infusions in humans.
Plasma RLA was separated from protein by a modification of a published method. Standard curves were generated from spiking known concentrations of RLA dissolved in ethanol and diluted in a phosphate-buffered saline (PBS) into each individual's baseline plasma to account for inter-individual differences in protein binding and to prevent denaturing of plasma proteins. Plasma RLA content was determined by the percent recovery using high-performance liquid chromatography (electrochemical/coulometric detection) (HPLC/ECD).
As anticipated from the preliminary study, NaRLA is less prone to polymerization, completely soluble in water, and displays significantly higher Cmax and AUC values and decreased time to maximum concentration (Tmax) and T1/2 values than RLA or rac-LA. In order to significantly extend Cmax and AUC, it is possible to administer three 600-mg RLA doses (as NaRLA) at 15-minute intervals to achieve plasma concentrations similar to those from a slow (20-minute) infusion of LA. This is the first study to report negligible unbound RLA even at the highest achievable plasma concentrations.

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Available from: Anthony Smith, May 22, 2015
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    • "The next day, 6 mM glucose was added to the glucose-treated groups (glucose group, Glu) while the control group was kept in DMEM with 4.5 g/L glucose. Cells were then treated with 0.2 mM LA for 48 h, a concentration that can be achieved in human blood plasma after ingestion of a supplement [21]. LA was dissolved in ethanol to prepare a stock solution of 100 mM, and glucose was dissolved in water to prepare a solution of 1 M. Palmitic acid (PA) was prepared as previously described [22]. "
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    ABSTRACT: The activation of sterol regulatory element binding proteins (SREBPs) is regulated by insulin-induced genes 1 and 2 (Insig-1 and Insig-2) and SCAP. We previously reported that feeding R-α-lipoic acid (LA) to Zucker diabetic fatty (ZDF) rats improves severe hypertriglyceridemia. In this study, we investigated the role of cyclic AMP-responsive element binding protein H (CREBH) in the lipid-lowering mechanism of LA and its involvement in the SREBP-1c and Insig pathway. Incubation of McA cells with LA (0.2 mM) or glucose (6 mM) stimulated activation of CREBH. LA treatment further induced mRNA expression of Insig-1 and Insig-2a, but not Insig-2b, in glucose-treated cells. In vivo, feeding LA to obesity-induced hyperlipidemic ZDF rats activated hepatic CREBH and stimulated transcription and translation of Insig-1 and Insig-2a. Activation of CREBH and Insigs induced by LA suppressed processing of SREBP-1c precursor into nuclear SREBP-1c, which subsequently inhibited expression of genes involved in fatty acid synthesis, including FASN, ACC and SCD-1, and reduced triglyceride (TG) contents in both glucose-treated cells and ZDF rat livers. Additionally, LA treatment also decreased abundances of very low density lipoprotein (VLDL)-associated apolipoproteins, apoB100 and apoE, in glucose-treated cells and livers of ZDF rats, leading to decreased secretion of VLDL and improvement of hypertriglyceridemia. This study unveils a novel molecular mechanism whereby LA lowers TG via activation of hepatic CREBH and increased expression of Insig-1 and Insig-2a to inhibit de novo lipogenesis and VLDL secretion. These findings provide novel insight into the therapeutic potential of LA as an anti-hypertriglyceridemia dietary molecule. Copyright © 2015 Elsevier Inc. All rights reserved.
    The Journal of nutritional biochemistry 05/2015; 26(9). DOI:10.1016/j.jnutbio.2015.03.011 · 3.79 Impact Factor
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    • "The most pronounced activity of (+)-thioctic acid is probably related to its more favorable kinetic profile and better plasma bioavailability. Oral administration of (+)-thioctic acid to healthy volunteers results in a kinetic profile similar to that of intravenously administered (+/−)-thioctic acid, although plasma accumulation was quantitatively different for intravenous compared to the oral formulation of the compound [54, 55]. The intravenous is the only administration route of thioctic acid for which controlled studies have clearly documented a clinical efficacy in the treatment of diabetic neuropathy [56]. "
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    ABSTRACT: Peripheral neuropathies are heterogeneous disorders presenting often with hyperalgesia and allodynia. This study has assessed if chronic constriction injury (CCI) of sciatic nerve is accompanied by increased oxidative stress and central nervous system (CNS) changes and if these changes are sensitive to treatment with thioctic acid. Thioctic acid is a naturally occurring antioxidant existing in two optical isomers (+)- and (-)-thioctic acid and in the racemic form. It has been proposed for treating disorders associated with increased oxidative stress. Sciatic nerve CCI was made in spontaneously hypertensive rats (SHRs) and in normotensive reference cohorts. Rats were untreated or treated intraperitoneally for 14 days with (+/-)-, (+)-, or (-)-thioctic acid. Oxidative stress, astrogliosis, myelin sheets status, and neuronal injury in motor and sensory cerebrocortical areas were assessed. Increase of oxidative stress markers, astrogliosis, and neuronal damage accompanied by a decreased expression of neurofilament were observed in SHR. This phenomenon was more pronounced after CCI. Thioctic acid countered astrogliosis and neuronal damage, (+)-thioctic acid being more active than (+/-)- or (-)-enantiomers. These findings suggest a neuroprotective activity of thioctic acid on CNS lesions consequent to CCI and that the compound may represent a therapeutic option for entrapment neuropathies.
    12/2013; 2013(1):985093. DOI:10.1155/2013/985093
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    • "Carlson et al. reported that 600 mg oral dosing of 12 healthy subjects with sodium salt conjugated R-LA resulted in peak serum LA levels between 10.6–33.8 μg/ml (Carlson et al., 2007). However, it is unknown if higher concentrations can be achieved since LA is rapidly taken up by eurythrocytes and other cell types, and is quickly metabolized. "
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    ABSTRACT: The antioxidant lipoic acid (LA) treats and prevents the animal model of multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE). In an effort to understand the therapeutic potential of LA in MS, we sought to define the cellular mechanisms that mediate the effects of LA on human natural killer (NK) cells, which are important in innate immunity as the first line of defense against invading pathogens and tumor cells. We discovered that LA stimulates cAMP production in NK cells in a dose-dependent manner. Studies using pharmacological inhibitors and receptor transfection experiments indicate that LA stimulates cAMP production via activation of the EP2 and EP4 prostanoid receptors and adenylyl cyclase. In addition, LA suppressed interleukin (IL)-12/IL-18 induced IFNgamma secretion and cytotoxicity in NK cells. These novel findings suggest that LA may inhibit NK cell function via the cAMP signaling pathway.
    Journal of Neuroimmunology 07/2008; 199(1-2):46-55. DOI:10.1016/j.jneuroim.2008.05.003 · 2.47 Impact Factor
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