R-Lipoic Acid Timeline

  • 1.5 billion to 500 million years ago

    Eukaryotes develop mitochondria and begin using R-Lipoic Acid to generate NADH and ATP. Microbiology & Molecular Biology Reviews, Vol. 64 (4) 786-820; (2000).

  • 1937-1951

    Several groups identify a crude factor that increases ATP production in growth mediums, alternately designated Protogen A, Pyruvate Oxidation factor (POF), or Acetate Replacing Factor. JACS. 75, (6) 1267-70; (1953) and references therein.

  • 1951

    Lester Reed isolates 30 mg of a pure yellow substance from ten tons of beef liver in a joint project with Eli Lilly. Science 114, 93 (1951).

  • 1951

    Eli Lilly chemists characterize the compound as (+)-1, 2-dithiolane valeric acid. The absolute configuration was unknown. The common name, alpha Lipoic Acid (ALA) differentiates it from the partially oxidized B-Lipoic Acid (a thiosulfinate), and to highlight both its lipophilic and hydrophilic structure. It is also called thioctic acid, particularly in Europe, a contraction of thiol and octanoic acid. JACS. 75 (16) 1267-70 (1953).

  • 1952

    The first successful synthesis of racemic alpha Lipoic Acid was achieved. As a result, the liver extraction was never repeated. It is significant to realize neither racemic alpha Lipoic Acid nor S- Lipoic Acid, which do not occur in nature, existed before this synthesis. JACS 75 1263 1267-70 (1952).

  • 1954

    The first resolution into (+)-alpha Lipoic Acid and (-)-alpha Lipoic Acid was accomplished and (+)-alpha Lipoic Acid was shown to have POF 188% greater than (-)-alpha Lipoic Acid. This is the first report of biological differences between the enantiomers. JACS 77:5144 (1955).

  • 1955

    International Symposium on Thioctic Acid (Naples, Italy). Racemic alpha Lipoic Acid is an “anti-toxin” and it is of extremely low toxicity in humans. alpha Lipoic Acid protects against CCl4, Hg, As. Universita di Napoli. Chem & Ind, 508, Nov;1955.

  • 1956

    Shirosa reported Lipoic Acid lowered blood sugar by 15% within 15 minutes of injection. Boll. Soc. Ital. Biol. Sper.32 725-72;1956.

  • 1957

    Kofler reports rac- alpha Lipoic Acid is an antidote to radiation poisoning. Boll. Soc. Ital. Biol. Sper.33 408-409; 1957.

  • 1958

    US and Japanese government co-sponsor a program to treat the survivors of Hiroshima and Nagasaki with ALA. Results were poor and the project was abandoned after a few years.

  • 1958

    Reiss reports that heart sarcomeres (mitochondria) poisoned with an arsenical poison regained normal function upon exposure to (+)-ALA but NOT (-)-ALA. J Biol Chem.Oct; 233 (4): 789-93; 1958, J Biol Chem. Mar; 231 (1): 557-69; 1958

  • 1959

    Rosenberg and Culik report ALA is antioxidant. Arch Biochem Biophys 80: 86-93; 1959.

  • 1960

    Gal reports thiamine deficient rats undergo “sudden death” when administered rac-ALA. Arch Biochem Biophys 89, 253 (1960).

  • 1965

    Gal shows that the unnatural (-)-ALA and NOT (+)-ALA was responsible for death in thiamine deficient rats and proposed a thiamine-SH/SLA disulfide a toxic metabolite was the mechanism. Nature, No. 4996; July;535 (1965).

  • 1966

    ALA is approved in Germany for treatment of diabetic neuropathy. Lipoic Acid in Health and Disease; 4.

  • 1978

    Marnett and Egan report ALA inhibits COX and reduces inflammation. Prostaglandins, Dec; 16 (6):861-9 (1978).

  • 1983

    Golding’s assigns (+)-ALA as R-(+)-ALA and the unnatural enantiomer S-(-)-ALA. JCS Chem Comm. 1051-1053 (1983).

  • 1983

    Heinz Ulrich, Asta Medica initiates research and clinical use of R-Lipoic Acid and R-dihydroLipoic Acid. Lipoic Acid in Health and Disease, Preface vii.

  • 1983

    Degussa begins research and commercial development of racemic Lipoic Acid. Degussa Patent 4,705,867.

  • 1984

    Chernobyl disaster survivors are given Alpha Lipoic Acid and Vitamin E together and discover a significant (4 fold) enhancement of effect. Lipoic Acid in Health and Disease, 189.

  • 1988

    Lester Packer at UC Berkeley begins research interest in the biochemistry of Lipoic Acid. The Antioxidant Miracle, Lester Packer & Carol Coleman; John Wiley & Sons, Inc. 1999.

  • 1992

    Ulrich reports dihydroLipoic Acid is a more potent anti-inflammatory agent in multiple models of inflammation than racemic Lipoic Acid. US Patent 5,084,481.

  • 1994

    Alpha Lipoic Acid introduced into the nutritional supplement market branded as an “antioxidant”.

  • 1995

    Fuchs reports that oral R-Lipoic Acid is a more effective antioxidant than racemic alpha Lipoic Acid. Skin Pharm; 7: 278-284, 1994.

  • 1997

    Ulrich, Packer and Klip report that only R-Lipoic Acid and R-dihydroLipoic Acid are useful for treating diabetes, measured in terms of the effects on Glut 4 and PDH. US Patent 5,693,664.

  • 1998

    Ulrich reports R-Lipoic Acid is a more effective anti-inflammatory than racemic alpha Lipoic Acid by a factor of 10; 4.9 mg/kg vs. 49.3 mg/kg in the carageenan paw edema model. US Patent 5,728735.

  • 1999

    R-Lipoic Acid and Acetyl-L-Carnitine combination rejuvenate geriatric rats and correlates to changes in brain protein carbonyls, and improved mitochondrial function. FASEB J. 13,411-418.

  • 2000

    Carlson and Kaufman began synthesis and commercial development of R-Lipoic Acid.

  • 2001

    R-Lipoic Acid is commercially available from China and appears in the nutritional supplement market.

  • 2001

    Nobel Prize in Chemistry shared by for Asymmetric Catalysis leads to new, “Green” routes to produce R-Lipoic Acid.

  • 2001

    Low quality, polymerized R-Lipoic Acid capsules on the market.

  • 2002

    GeroNova introduces K-RALA®, the stabilized potassium salt of R-Lipoic Acid.

  • 2003

    New pharmacokinetic research by GeroNova shows the superiority of Bio-enhanced® dosage forms over other R-Lipoic Acid products.

  • 2004

    GeroNova offers R-dihydroLipoic Acid in a supplement with R-Lipoic Acid and as a bulk raw material.

  • 2005

    GeroNova performs human plasma studies comparing R-Lipoic Acid, R-dihydroLipoic Acid and a 50/50 mixture and proves they each have a unique PK profile. The results also indicate sustained blood levels of R-Lipoic Acid, proving that R-dihydroLipoic Acid is more stable in plasma than previously reported and acts as a lipophilic delivery system for the unstable R-Lipoic Acid.

  • 2006

    GeroNova launches the stable, water soluble and high bioavailability form of R-Lipoic Acid, Na-RALA.

  • 2007-2013

    GeroNova writes and publishes the results of our work over the last 12 years and completes a human PK study using Na-RALA.