Editing Lipoic acid (section)

==Pharmacology==

===Pharmacokinetics===
A 2007 human [[pharmacokinetic]] study of sodium RLA demonstrated the maximum concentration in plasma and bioavailability are significantly greater than the free acid form, and rivals plasma levels achieved by intravenous administration of the free acid form.<ref name="ReferenceB">{{cite journal |last1= Carlson |first1= DA |last2= Smith |first2= AR |last3= Fischer |first3= SJ |last4= Young |first4= KL |last5= Packer |first5= L |display-authors= 4 |title= The plasma pharmacokinetics of R-(+)-lipoic acid administered as sodium R-(+)-lipoate to healthy human subjects |journal= Alternative Medicine Review |volume= 12 |issue= 4 |date= December 2007 |pages= 343–51 |pmid= 18069903 |url= http://www.altmedrev.com/publications/12/4/343.pdf |access-date= 2014-07-06 |archive-date= 2017-08-08 |archive-url= https://web.archive.org/web/20170808231646/http://altmedrev.com/publications/12/4/343.pdf |url-status= dead }}</ref> Additionally, high plasma levels comparable to those in animal models where Nrf2 was activated were achieved.<ref name="ReferenceB"/>

The various forms of LA are not bioequivalent.<ref name="Kleeman">{{cite conference |last1= Kleeman |first1= A |last2= Borbe |first2= HO |last3= Ulrich |first3= H |chapter= Thioctic Acid-Lipoic Acid |title= Thioctsäure: Neue Biochemische, Pharmakologische und Klinische Erkenntnisse zur Thioctsäure |trans-title= Thioctic Acid. New Biochemistry, Pharmacology and Findings from Clinical Practice with Thioctic Acid |pages= 11–26 |editor1-last= Borbe |editor1-first= HO |editor2-last= Ulrich |editor2-first= H |conference= Symposium at Wiesbaden, DE, 16–18 February 1989 |date= 1991 |location= Frankfurt, DE |publisher= Verlag |isbn= 9783891191255}}</ref> Very few studies compare individual enantiomers with racemic lipoic acid. It is unclear if twice as much racemic lipoic acid can replace RLA.<ref name="ReferenceB"/>

The toxic dose of LA in cats is much lower than that in humans or dogs and produces hepatocellular toxicity.<ref>{{cite journal |last1= Hill |first1= AS |last2= Werner |first2=JA |last3= Rogers |first3= QR |last4= O'Neill |first4= SL |last5= Christopher |first5= MM |display-authors= 4 |title= Lipoic acid is 10 times more toxic in cats than reported in humans, dogs or rats |journal= Journal of Animal Physiology and Animal Nutrition |volume= 88 |issue= 3–4 |date= April 2004 |pages= 150–6 |pmid= 15059240 |doi= 10.1111/j.1439-0396.2003.00472.x}}</ref>

===Pharmacodynamics===
The mechanism and action of lipoic acid when supplied externally to an organism is controversial. Lipoic acid in a cell seems primarily to induce the oxidative stress response rather than directly scavenge free radicals. This effect is specific for RLA.<ref name= "Shay08"/> Despite the strongly reducing milieu, LA has been detected intracellularly in both oxidized and reduced forms.<ref name="Packer1995">{{cite journal |doi= 10.1016/0891-5849(95)00017-R |pmid= 7649494 |last1= Packer |first1= L |last2= Witt |first2= EH |last3= Tritschler |first3= HJ |title= Alpha-lipoic acid as a biological antioxidant |journal= [[Free Radical Biology and Medicine]] |volume= 19 |issue= 2 |date= August 1995 |pages= 227–50}}</ref> LA is able to scavenge reactive oxygen and reactive nitrogen species in a biochemical assay due to long incubation times, but there is little evidence this occurs within a cell or that radical scavenging contributes to the primary mechanisms of action of LA.<ref name= "Shay08"/><ref name="ReferenceC">{{cite journal |pmid= 19664690 |pmc= 2756298 |last1= Shay |first1= KP |doi= 10.1016/j.bbagen.2009.07.026 |last2= Moreau |first2= RF |last3= Smith |first3= EJ |last4= Smith |first4= AR |last5= Hagen |first5= TM |display-authors= 4 | title = Alpha-lipoic acid as a dietary supplement: Molecular mechanisms and therapeutic potential |journal= [[Biochimica et Biophysica Acta (BBA) - General Subjects]] |volume= 1790 |issue= 10 |date= October 2009 |pages= 1149–60}}</ref> The relatively good scavenging activity of LA toward [[hypochlorous acid]] (a bactericidal produced by neutrophils that may produce inflammation and tissue damage) is due to the strained conformation of the 5-membered dithiolane ring, which is lost upon reduction to DHLA. In cells, LA is reduced to dihydrolipoic acid, which is generally regarded as the more bioactive form of LA and the form responsible for most of the antioxidant effects and for lowering the redox activities of unbound iron and copper.<ref>{{cite journal |last1= Haenen |first1= GRMM |last2= Bast |first2= A |year= 1991 |title= Scavenging of hypochlorous acid by lipoic acid |journal= [[Biochemical Pharmacology (journal)|Biochemical Pharmacology]] |pmid= 1659823 |volume= 42 |issue= 11 |pages= 2244–6 |doi= 10.1016/0006-2952(91)90363-A }}</ref> This theory has been challenged due to the high level of reactivity of the two free sulfhydryls, low intracellular concentrations of DHLA as well as the rapid methylation of one or both sulfhydryls, rapid side-chain oxidation to shorter metabolites and rapid efflux from the cell. Although both DHLA and LA have been found inside cells after administration, most intracellular DHLA probably exists as mixed disulfides with various cysteine residues from cytosolic and mitochondrial proteins.<ref name=Carlson08>{{cite book |last1= Carlson |first1= DA |last2= Young |first2= KL |last3= Fischer |first3= SJ |last4= Ulrich |first4= H|title=Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects|chapter= Ch. 10: An Evaluation of the Stability and Pharmacokinetics of R-lipoic Acid and R-Dihydrolipoic Acid Dosage Forms in Plasma from Healthy Human Subjects |pages= 235–70 |editor1=Mulchand S. Patel |editor2=Lester Packer |date=2008}}</ref> Recent findings suggest therapeutic and anti-aging effects are due to modulation of signal transduction and gene transcription, which improve the antioxidant status of the cell. However, this likely occurs via pro-oxidant mechanisms, not by radical scavenging or reducing effects.<ref name= "Shay08"/><ref name="ReferenceC"/><ref name="Shay in Packer"/>

All the [[disulfide]] forms of LA (R/S-LA, RLA and SLA) can be reduced to [[DHLA]] although both tissue specific and stereoselective (preference for one enantiomer over the other) reductions have been reported in model systems. At least two cytosolic enzymes, [[glutathione reductase]] (GR) and [[thioredoxin reductase]] (Trx1), and two mitochondrial enzymes, [[lipoamide dehydrogenase]] and [[thioredoxin reductase]] (Trx2), reduce LA. SLA is stereoselectively reduced by cytosolic GR whereas Trx1, Trx2 and lipoamide dehydrogenase stereoselectively reduce RLA. (''R'')-(+)-lipoic acid is enzymatically or chemically reduced to (''R'')-(-)-dihydrolipoic acid whereas (''S'')-(-)-lipoic acid is reduced to (''S'')-(+)-dihydrolipoic acid.<ref>{{cite journal |pmid= 8769129 |last1= Arnér |first1= ES |doi= 10.1006/bbrc.1996.1165 |last2= Nordberg |first2= J |last3= Holmgren |first3= A |title= Efficient reduction of lipoamide and lipoic acid by mammalian thioredoxin reductase |journal= [[Biochemical and Biophysical Research Communications]] |volume= 225 |issue= 1 |date= August 1996 |pages= 268–74}}</ref><ref>{{cite journal |doi= 10.1667/0033-7587(2003)159[0484:RROCDA]2.0.CO;2 |pmid= 12643793 |last1= Biaglow |first1= JE |last2= Ayene |first2= IS |last3= Koch |first3= CJ |last4= Donahue |first4= J |last5= Stamato |first5= TD |last6= Mieyal |first6= JJ |last7= Tuttle |first7= SW |display-authors= 4 |title= Radiation response of cells during altered protein thiol redox |journal= Radiation Research |volume= 159 |issue= 4 |date= April 2003 |pages= 484–94   |bibcode= 2003RadR..159..484B |s2cid= 42110797 }}</ref><ref>{{cite journal |doi= 10.1016/S0891-5849(96)00400-5 |pmid= 8981046 |last1= Haramaki |first1= N |last2= Han |first2= D |last3= Handelman |first3= GJ |last4= Tritschler |first4= HJ |last5= Packer |first5= L |display-authors= 4 |title= Cytosolic and mitochondrial systems for NADH- and NADPH-dependent reduction of alpha-lipoic acid |journal= [[Free Radical Biology and Medicine]] |volume= 22 |issue= 3 |year= 1997 |pages= 535–42}}</ref><ref>{{cite journal |doi= 10.1016/0006-2952(95)00084-D |pmid= 7632170 |last1= Constantinescu |first1= A |last2= Pick |first2= U |last3= Handelman |first3= GJ |last4= Haramaki |first4= N |last5= Han |first5= D |last6= Podda |first6= M |last7= Tritschler |first7= HJ |last8= Packer |first8= L |display-authors= 4 |title= Reduction and transport of lipoic acid by human erythrocytes |journal= [[Biochemical Pharmacology (journal)|Biochemical Pharmacology]] |volume= 50 |issue= 2 |date= July 1995 |pages= 253–61}}</ref><ref>{{cite journal |pmid= 16650819 |last1= May |first1= JM |doi= 10.1016/j.bbrc.2006.04.065 |last2= Qu |first2= ZC |last3= Nelson |first3= DJ |title= Cellular disulfide-reducing capacity: An integrated measure of cell redox capacity |journal= [[Biochemical and Biophysical Research Communications]] |volume= 344 |issue= 4 |date= June 2006 |pages= 1352–9}}</ref><ref>{{cite journal |doi= 10.1016/S0891-5849(02)00862-6 |pmid= 12086686 |last1= Jones |first1= W |last2= Li |first2= X |last3= Qu |first3= ZC |last4= Perriott |first4= L |last5= Whitesell |first5= RR |last6= May |first6= JM |display-authors= 4 |title= Uptake, recycling, and antioxidant actions of alpha-lipoic acid in endothelial cells |journal= [[Free Radical Biology and Medicine]] |volume= 33 |issue= 1 |date= July 2002 |pages= 83–93}}</ref><ref>{{cite journal |last1= Schempp |first1= H |last2= Ulrich |first2= H |last3= Elstner |first3= EF |title= Stereospecific reduction of R(+)-thioctic acid by porcine heart lipoamide dehydrogenase/diaphorase |journal= [[Zeitschrift für Naturforschung C]] |volume= 49 |issue= 9–10 |pages= 691–2 |year= 1994 |pmid= 7945680 |doi= 10.1515/znc-1994-9-1023 |doi-access= free }}</ref> Dihydrolipoic acid (DHLA) can also form intracellularly and extracellularly via non-enzymatic, [[thiol-disulfide exchange|thiol-disulfide exchange reactions]].<ref>{{cite book |last1= Biewenga |first1= GP |last2= Haenen |first2= GRMM |last3= Bast |first3= A |chapter= Ch. 1: An Overview of Lipoate Chemistry |editor1-last= Fuchs |editor1-first= J |editor2-last= Packer |editor2-first= L |editor3-last= Zimmer |editor3-first= G |title= Lipoic Acid In Health & Disease |publisher= [[CRC Press]]  |year= 1997 |pages= [https://books.google.com/books?id=ksWdMbxa5FkC&pg=PA1 1–32] |isbn= 9780824700935}}</ref>

RLA may function ''in vivo'' like a B-vitamin and at higher doses like plant-derived nutrients, such as [[curcumin]], [[sulforaphane]], [[resveratrol]], and other nutritional substances that induce [[Drug metabolism#Phase II – conjugation|phase II detoxification enzymes]], thus acting as cytoprotective agents.<ref name="Shay in Packer">{{cite book |last1= Shay |first1= KP |last2= Shenvi |first2= S |last3= Hagen |first3= TM |chapter= Ch. 14 Lipoic Acid as an Inducer of Phase II Detoxification Enzymes Through Activation of Nr-f2 Dependent Gene Expression|title=Lipoic Acid: Energy Production, Antioxidant Activity and Health Effects|pages= 349–71 |editor1=Mulchand S. Patel |editor2=Lester Packer |date=2008}}</ref><ref>{{cite journal |last1=Lii |first1= CK |last2= Liu |first2= KL |last3= Cheng |first3= YP |last4= Lin |first4= AH |last5= Chen |first5= HW |last6= Tsai |first6= CW |display-authors= 4 |title= Sulforaphane and alpha-lipoic acid upregulate the expression of the pi class of glutathione S-transferase through c-jun and Nrf2 activation |journal= [[Journal of Nutrition]] |volume= 140 |issue= 5 |pages= 885–92 |date= May 2010 |pmid= 20237067 |doi= 10.3945/jn.110.121418 |doi-access= free }}</ref> This stress response indirectly improves the antioxidant capacity of the cell.<ref name= "Shay08">{{cite journal |pmid= 18409172 |last1= Shay |first1= KP |doi= 10.1002/iub.40 |last2= Moreau |first2= RF |last3= Smith |first3= EJ |last4= Hagen |first4= TM |title= Is alpha-lipoic acid a scavenger of reactive oxygen species in vivo? Evidence for its initiation of stress signaling pathways that promote endogenous antioxidant capacity |journal= IUBMB Life |volume= 60 |issue= 6 |date= June 2008 |pages= 362–7 |s2cid= 33008376 |doi-access=  }}</ref>

The (''S'')-enantiomer of LA was shown to be toxic when administered to thiamine-deficient rats.<ref>{{cite journal |doi= 10.1016/0003-9861(60)90051-5 |pmid= 13825981 |last1= Gal |first1= EM |last2= Razevska |first2= DE |title= Studies on the in vivo metabolism of lipoic acid. 1. The fate of DL-lipoic acid-S35 in normal and thiamine-deficient rats |journal= [[Archives of Biochemistry and Biophysics]] |volume= 89 |date= August 1960 |pages= 253–61 |issue= 2}}</ref><ref name="Gal1965">{{cite journal |doi= 10.1038/207535a0 |pmid= 5328673 |last1= Gal |first1= EM |title= Reversal of selective toxicity of (-)-alpha-lipoic acid by thiamine in thiamine-deficient rats |journal= [[Nature (journal)|Nature]] |volume= 207 |issue= 996 |date= July 1965 |page= 535|bibcode= 1965Natur.207..535G |s2cid= 4146866 |doi-access= free }}</ref>

Several studies have demonstrated that SLA either has lower activity than RLA or interferes with the specific effects of RLA by [[competitive inhibition]].<ref>{{cite patent |inventor1-last= Ulrich |inventor1-first= H |inventor2-last= Weischer |inventor2-first= CH |inventor3-last= Engel |inventor3-first= J |inventor4-last= Hettche |inventor4-first= H |title= Pharmaceutical compositions containing R-alpha-lipoic acid or S-alpha.-lipoic acid as active ingredient |country= US |number= 6271254 |gdate= 2001-08-07 |status= patent |assign1= ASTA Pharma |fdate= 1998-02-02 |pridate= 1989-11-09 |postscript= .}}</ref><ref>{{cite journal |pmid= 8673020 |last1= Kilic |first1= F |last2= Handelman |first2= GJ |last3= Serbinova |first3= E |last4= Packer |first4= L |last5= Trevithick |first5= JR |display-authors= 4 |title= Modelling cortical cataractogenesis 17: In vitro effect of a-lipoic acid on glucose-induced lens membrane damage, a model of diabetic cataractogenesis |journal= Biochemistry and Molecular Biology International |volume= 37 |issue= 2 |date= October 1995 |pages= 361–70}}</ref><ref>{{cite conference |last1= Artwohl |first1= M |last2= Schmetterer |first2= L |last3= Rainer |first3= G |last4= unknown |display-authors= 3 |date= September 2000|title= Modulation by antioxidants of endothelial apoptosis, proliferation, & associated gene/protein expression |conference= 36th Annual Meeting of the European Association for the Study of Diabetes, 17–21 September 2000, Jerusalem, Israel. |journal= [[Diabetologia]] |volume= 43 |issue= Suppl 1 |page= Abs 274 |publication-date= August 2000 |no-pp= yes |pmid= 11008622}}</ref><ref>{{cite journal |pmid= 9252495 |last1= Streeper |first1= RS |last2= Henriksen |first2= EJ |last3= Jacob |first3= S |last4= Hokama |first4= JY |last5= Fogt |first5= DL |last6= Tritschler |first6= HJ |display-authors= 4 |title= Differential effects of lipoic acid stereoisomers on glucose metabolism in insulin-resistant skeletal muscle |journal= [[American Journal of Physiology|AJP: Endocrinology and Metabolism]] |volume= 273 |issue= 1 Pt 1 |date= July 1997 |pages= E185–91|doi= 10.1152/ajpendo.1997.273.1.E185 }}</ref><ref>{{cite journal |pmid= 14991456 |last1= Frölich |first1= L |last2= Götz |first2= ME |last3= Weinmüller |first3= M |last4= Youdim |first4= MB |last5= Barth |first5= N |last6= Dirr |first6= A |last7= Gsell |first7= W |last8= Jellinger |first8= K |last9= Beckmann |first9= H |last10= Riederer |first10= P |display-authors= 4 |title= (r)-, but not (s)-alpha lipoic acid stimulates deficient brain pyruvate dehydrogenase complex in vascular dementia, but not in Alzheimer dementia |journal = Journal of Neural Transmission |volume= 111 |issue= 3 |date= March 2004 |pages= 295–310 |doi= 10.1007/s00702-003-0043-5|s2cid= 20214857 }}</ref>