I’m only a monthly contributor here but between being a SBM reader and having my own blogs, I often grow weary of the blind criticism that researchers and drug companies couldn’t care less about traditional folk medicines as drug products. My laboratory spends every single day working on natural product extracts in the search for compounds that may have selective effectiveness against cancer. So, this is a bit of a sore spot for me.
Two papers this week from Cancer Prevention Research on the potential anticancer effects of a diabetes drug (Nathan Seppa story here) remind me to tell the story of a Middle Ages European herbal medicine used to treat polyuria that gave rise to one of the most widely prescribed drugs in the world, metformin (Glucophage in the US). Metformin, known chemically as a biguanide, dimethylguanide to be precise, traces its roots to the plant Galega officinalis. Known as goat’s rue, French lilac, or professor weed, this plant was shown to be a rich source of guanidine and a less toxic compound later called galegin or galegine (isoamyline guanidine).
Although used as an herbal medicine in Europe for centuries, especially in France, this classic 1918 paper (free PDF) in the Journal of Biological Chemistry was perhaps the first widely-recognized report of the hypoglycemic effect of guanidine. The study was conducted in rabbits by CK Watanabe at Yale University. (P.S. Thank you, JBC, for making your archives freely available – the JBC was founded in 1909 by my blog nymsake, pharmacologist John Jacob Abel.)
While guanidine was to toxic for use in humans, pre-World War II researchers in Germany began synthesizing analogs called synthelins, biguanides with long carbon chains between the guanide moieties. A Parisian physician and clinical pharmacologist, Jean Sterne, probably played the most pivotal role in getting this class of compounds into clinical use. In the 1950s he held both academic and pharmaceutical industry positions, the latter at Aron Laboratories.
While there, Sterne’s group investigated a series of biguanidines that included metformin, a deceptively simple molecule. and they published a crucial paper in 1957 where he coined the name Glucophage for metformin, “glucose eater.” The paper was written in French and appeared in the less-widely read Maroc Medical journal. A paper that appeared later that year in Proceedings of the Society for Experimental Biology and Medicine on a related compound, phenformin, is more widely cited – the authors were then at the US Vitamin Corporation.
A long series of clinical studies with the biguanides ensued over decades but it was the acquisition of Aron Laboratories by Lipha Pharmaceuticals in 1995 that led metformin to come to the US market. It’s a fascinating story that gave rise to a multi-billion dollar market of Glucophage and related dosage forms. And that’s without even getting into studies this week on the potential anticancer effects of metformin – that story is for another day.
There are two superb papers you must read if you want more details on the history of metformin. An unparalleled, short, and free-access history of metformin written by Clifford Bailey and Caroline Day at the Aston University diabetes research group in Birmingham, UK, can be found here (PDF). Much of the historical information I’ve provided here comes from that paper. Second, to accompany the two papers in this month’s issue of Cancer Prevention Research Michael Pollack at McGill University in Montreal wrote an excellent overview of metformin and the critical gaps in our knowledge to investigate and potentially implement the use of the compound in cancer prevention and, possibly, treatment.