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; 1958.1958:

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 Bioenahnced™ dosage forms over other R-Lipoic Acid prodcuts.

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 - GeroNova begins writing and publishing the results of our work over the last 7 years and completes a human PK study using Na-RALA.