Eukaryotes develop mitochondria and begin using R-Lipoic Acid to generate NADH and ATP. Microbiology & Molecular Biology Reviews, Vol. 64 (4) 786-820; (2000).
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.
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).
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).
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).
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).
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.
Shirosa reported Lipoic Acid lowered blood sugar by 15% within 15 minutes of injection. Boll. Soc. Ital. Biol. Sper.32 725-72;1956.
Kofler reports rac- alpha Lipoic Acid is an antidote to radiation poisoning. Boll. Soc. Ital. Biol. Sper.33 408-409; 1957.
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.
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
Rosenberg and Culik report ALA is antioxidant. Arch Biochem Biophys 80: 86-93; 1959.
Gal reports thiamine deficient rats undergo “sudden death” when administered rac-ALA. Arch Biochem Biophys 89, 253 (1960).
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).
ALA is approved in Germany for treatment of diabetic neuropathy. Lipoic Acid in Health and Disease; 4.
Marnett and Egan report ALA inhibits COX and reduces inflammation. Prostaglandins, Dec; 16 (6):861-9 (1978).
Golding’s assigns (+)-ALA as R-(+)-ALA and the unnatural enantiomer S-(-)-ALA. JCS Chem Comm. 1051-1053 (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.
Degussa begins research and commercial development of racemic Lipoic Acid. Degussa Patent 4,705,867.
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.
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.
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.
Alpha Lipoic Acid introduced into the nutritional supplement market branded as an “antioxidant”.
Fuchs reports that oral R-Lipoic Acid is a more effective antioxidant than racemic alpha Lipoic Acid. Skin Pharm; 7: 278-284, 1994.
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.
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.
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.
Carlson and Kaufman began synthesis and commercial development of R-Lipoic Acid.
R-Lipoic Acid is commercially available from China and appears in the nutritional supplement market.
Nobel Prize in Chemistry shared by for Asymmetric Catalysis leads to new, “Green” routes to produce R-Lipoic Acid.
Low quality, polymerized R-Lipoic Acid capsules on the market.
GeroNova introduces K-RALA®, the stabilized potassium salt of R-Lipoic Acid.
New pharmacokinetic research by GeroNova shows the superiority of Bio-enhanced® dosage forms over other R-Lipoic Acid products.
GeroNova offers R-dihydroLipoic Acid in a supplement with R-Lipoic Acid and as a bulk raw material.
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.
GeroNova launches the stable, water soluble and high bioavailability form of R-Lipoic Acid, Na-RALA.
GeroNova writes and publishes the results of our work over the last 12 years and completes a human PK study using Na-RALA.