The forgotten magic potion

Life allowed me to wear many hats, play several roles and pose in sometimes ridiculous postures. None, however, gave me the confidence of having it mastered in a previous life like the time I impersonated a medieval sorceress. It was roughly a year ago during a quite unusual academe debate scenario. The imaginary play took place during a massive … flood.

“The year is 2020. A freak incident causes the waters of Lake Erie to swell, flooding the UB campus. As the waters continue to rise, food becomes scarce and hope for survival dims.

Suddenly, ships appear on the horizon to rescue survivors. As luck would have it, all the ships begin to sink, except for one. As that ship is ready to leave, the passengers find themselves in a dilemma. There are six survivors left to board the ship — all UB professors — but only one seat in the ship is still available. The faculty members represent different disciplines at the university, and each one believes he or she can help build a strong, new civilization.

So, which professor — and discipline — is worth saving?”

https://www.buffalo.edu/ubnow/campus.host.html/content/shared/university/news/ub-reporter-articles/stories/2016/02/mcdevitt_life_raft.detail.html

Hey, how could I have NOT impersonated my profession by disguising myself into a sorceress in such a scenario?? Long story short, I didn’t get on the boat and, no, I didn’t place them under a spell either! However, the event made me think, and think, and think again: sorcerers and sorceresses WERE pharmacists – without a doubt. If I would be to make full use of my powers today – meaning apply all I learned and not be regulated by the board of pharmacy or the FDA – my work will be the weirdest art, certainly resembling sorcery! I mean, seriously! Just think about all the boilings and extractions I’d have to go through to give someone a freakin’ headache medication. I would look like a stinky, ugly and maleficent witch all until the moment the headache was be over. Then I’d suddenly become the sorceress (or the enchantress?), meaning that I’d win my positive and healing fame for the unexplained miracles of my power.

You may not know that more than half of the drug recipes in the world’s oldest papyrus – the Ebers Papyrus (1500 BC)- are still unchanged in today’s pharmacy practice. We re-learned old tricks and applied new techniques, we synthesized new molecules, but quite frankly failed to give the fully-deserved credit to the science of the pharmakon. The knowledge behind the preparation of a pharmakon (i.e. a biologically active substance) some thousands of years ago was similar to what we know today. The teachings and records were also very similar to how we teach pharmacy and pharmacology today. We didn’t know these masters to have been called pharmacists, but we surely know that the medicine they made was “pharmakon”. Perhaps the “translator, traitor” (i.e. lat. traduttore traditore) missed the nuance of the the pharmakon-maker? Who knows?

In any case, the moment in time seeded in me the curiosity of exploring what would pharmacy have been without the explosion of technology and drug-making of the 20th century? For instance, human history knows about the French lilac, or Goat’s Rue, since centuries ago (read my previous post about it, here). “Sorcerers” knew about its use for diabetes treatment, although they did not know to call it so back then. They knew someone had developed diabetes if that one was unusually thirsty, peed frequently and the urine taste was sweet. Fantastic how simple and straight-forward type 2 diabetes was! No finger-stick, no hemoglobin a1c, no glucose tolerance test, no insurance billing, nothing like that! The “sorcerer” then went on to harvest the French lilac along stream banks were the plant enjoyed the moist soil. There was no shortage of it as the livestock did not like its taste. In fact, livestock will eat the grass around the French lilac making room for it to thrive and spread, thereby being ready for harvest at quite any time. Blooming beautifully ornamental flowers, the plant was often planted in the gardens, soon spreading from its native place in the North of Africa to Europe, Asia, and even North America, by 1890.

goatsrue
Goat’s Rue (Galega officinalis) – USDA APHIS PPQ – Oxford, North Carolina , USDA APHIS PPQ, Bugwood.org

French lilac today is declared a class A federal noxious weed by the United States Department of Agriculture. The plant is thought to be an ecological threat as feeding trials of livestock apparently demonstrated that plant would actually kill goat, sheep, and cattle. I find this information somehow misleading, especially I know of the Goat rue (French lilac) being used as a galactagogue (i.e. stimulates milk production) in sheep. Naturally, too much may become toxic…in any case, with the plant not being too palatable, animals do not rush into consuming concerning amounts of it anyway. How interesting though that humans were treated with French lilac potions for hundreds of years and only the curative properties of the plant were described! Clearly, these thoughts triggered similar curiosities in other pharmakon producing colleagues of mine as early as the 17th century. Back then, Nicholas Culpeper described for the first time the use of French lilac for the treatment of a malady resembling type 2 diabetes. Toward the end of the 19th century chemists even identified a substance that seemed to be responsible for the effective treatment of the malady with French lilac: it was guanidine! In not more than two decades, the purification of guanidine allowed the demonstration of its glucose-lowering properties. Interestingly, however, in 1920 this Middle-Aged magic potion of Galega officinalis, alias French lilac, a.k.a. Goat’s rue, gained significant attention. Chemists discovered that the actual alkaloid responsible for the glucose-lowering effect was galegine, a derivative of guanidine also called isoamylene guanidine. Galegine was also less toxic…however, chemists thought of, and planned for, rather synthesizing a biguanide molecule similar in size and effect to galegine, rather than purifying galegine from the original herb that grew basically anywhere and everywhere in the world. Presently, the “weed” is prohibited for cultivation due to its extreme potential for spreading…that is on a side topic, though.

Metformin landmark events
Bailey CJ (2017). Metformin: historical overview. Diabetologia. doi: 10.1007/s00125-017-4318-z.

Nearly a century ago (1922), Werner and Bell synthesized the first dimethylguanidine derivatives, among which metformin. The event wasn’t followed by press. Recently this year (2017), Bailey noted in one of his papers about metformin that “the information was disregarded and forgotten”. This happened despite the announcement of Frank et al in 1927 about their newly synthesized synthalin, another biguanide that had glucose-lowering properties but unexpected toxicity. Some studies came soon under the magnifier glass of Lilly Research Laboratories, but on molecule structures less similar to metformin.

Two decades of silence followed, all until the search for an effective antimalarial drug became the chemistry’s main quest. Metformin was rediscovered as an antimalarial drug and even used in the treatment of influenza under the coordination of Eusebio Garcia – a famous infection diseases expert in the Philippines. Little is known about how metformin made it into his hands and why the name of the actual drug was changed to flumamineIt was by then 1949. Garcia notes that the molecule was discovered incidentally when he tried an antimalarial on a case of influenza. He reported a nearly miraculous cure. He also attributed the antimalarial effect to the glucose-lowering properties of the molecule despite the fact that he never checked glucose levels in his patients. Some gossip also points at the potential tentative of Garcia to claim the fame, but such rumors are yet to be clarified. Interestingly, between 1922 and 1949, we witness nearly three decades of a molecule apparently searching for a disease despite of it being successfully developed to lower glucose based on an ancient concept of French lilac utilization as a diabetes remedy. Why did this happen? None knows! Bizarre, isn’t it?

“There are endless generic lessons for medical research thinly disguised within the history of metformin. With hindsight, we are reminded that time spent searching early original literature can save valuable laboratory time, effort and money: vital clues can be concealed amidst throw-away observations in other areas of research.We are also reminded that the selection and interpretation of experimental models is fundamental, scrutiny within a drug class can reveal important differences, and we don’t have to know exactly how a drug works to reap benefit, but we do need to appreciate how to use it safely.”

Bailey CJ (2017). Metformin: historical overview. Diabetologia. doi: 10.1007/s00125-017-4318-z.

In 1950s, the French scientist Jean Sterne (1909-1997) heard about Garcia’s comment that flumamine would lower glucose levels. An endocrinologist, Sterne became immediately interested in the molecule and this is how he came to select dimethyl biguanide as the best candidate for a clinical trial at the hospital Laennec from Paris. He named the drug “Glucophage”, or “the glucose eater” (“gluco-” from glucose and “phage” from the Greek φαγός – phagos – for glutton). The drug was metformin. Arguably, the selection of the dimethyl biguanide instead of the purified galegine was a combined matter of the simplicity of synthesis vs the natural compound extraction and – why not say it? – the protection a patent and modern marketing could provide for a novel compound over a simple ancient herbal remedy. I may be wrong! I don’t know, I am just hypothesizing. There is a vaguely accessible track history about how this happened. We know that Lilly Research Laboratories had themselves some work on this terrain and is hard to believe that Sterne was foreign of these interests. The history is written by the winners and the winner that time was metformin. However, the truth remains unclear to these days! For all we care at this point in time, Sterne’s pick revolutionized the medicine and launched THE DRUG that prevented more cancer deaths than any other molecule in the history of mankind! How could anyone judge his decision?! The man seemed to have taken the PERFECT decision by all the possible measures, including the history-making measure! What would have galegine done? We don’t know. We don’t need to know. We have metformin and it works and we should use it to its fullest potential!

knight-2611672_1280Stay tuned for my next post to learn more about the making of phenformin, the drug that gave its oldest sibling – metformin – the kiss of death. Soon after the birth of phenformin, a war of hatred between the two molecules started. A war that resembled a Medieval fight to rule the crown, a rivalry spanning over many decades with implications lasting to this day in time. I can’t wait to tell you more soon – stay healthy until then!

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Werner E, Bell J. The preparation of methylguanidine and of b,b-dimethylguanidine by the interaction of dicyanidiamide and methyl ammonium and dimethylammonium chlorides respectively. J Chem Soc Trans. 1922;121:1790-1794.
Frank, Nothmann and Wagner. Klin. Wochschr. 1926, 5, 2100.
Frank. Naturwissenschaften. 1927,15,213.
Hesse G, Taubmann G. The effect of biguanide and its derivatives on glucose metabolism. Arch Exp Path Pharmacol 1929;142:290-308
E Y Garcia, J. Philippine Med. Assoc. , 1950, 26, 287.
Ungar G, Freedman L, Shapiro SL. Pharmacological studies of a new oral hypoglycemic drug. Proc Soc Exp Biol Med 1957;95:190-2.
Witters LA (2001). The blooming of the Frech lilac. J Clin Invest. 108(8):1105-7.
Gonzalez-Andre F, Redondo P, Pescado R and Urbano B. (2004) Management of Galega officinalis L. and preliminary results on its potential for milk production improvement in sheep. New Zealand Journal of Agricultural Research 47: 233-245.
Bailey CJ, Day C (2004). Metformin: its botanical background. Practical Diabetes Int. 21(3):115-117.
Bailey CJ, Campbell IW, Chan JCN, Davidson JA, Howlett HCS, Ritz P (eds). 2007. Metformin: the Gold Standard. A Scientific handbook; Chichester: Wiley. Chapter 1: Galegine and anti diabetic plants
Bailey CJ (2017). Metformin: historical overview. Diabetologia. doi: 10.1007/s00125-017-4318-z.

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Dr. Alice

I teach people how drugs work, when they are needed, and why. My expertise as a pharmacist and researcher allows me to determine whether taking or not taking a drug will pose any risk given all current circumstances that apply at this moment. Many times we don't know unless we try, but other many times walking the extra mile pays off giving in return more wonderful moments and more to give to others.

9 thoughts on “The forgotten magic potion

  1. Hi, this is the first article regarding galega officinalis which makes sense. I am growing that plant and wanted to know more about it. There is a bunch of articles stating that goat’s rue tea is good for nursing mothers without mentioning that it is toxic. And another bunch of articles telling that it was used for diabetes but was too toxic. That’s clearly a contradiction and I want to find out what is true. There is as well mentioned that goat’s rue is toxic while fresh but another article states that drying has no impact on tocicity. The tocicity for lifestock is equaly confusing. Do you know any further reading?

    1. Thank you for your comment, very glad to hear that you found it useful! There is literature out there that people are misinterpreting grossly. I copy-pasted below two links to the articles that identified 5g/kg to be a dose at which we should expect toxicity. The data basically shows that about half of the animals receiving (i.e. forced to eat) 5g/kg of Galega officinalis died. What I find interesting is that a) no animal in the right mind will ever go ahead to eat that much (it tastes bad!) and b) 5g/kg is an awful lot. A black tea bag contains ~2g of tea. If a 70kg person would be to take 5g/kg of regular black tea, that will be 350g or ~10 ounces. Chances are that the respective person WILL die if no emergency help will be implemented immediately. In fact, since the theobromine LD50 (lethal dose for 50% of the animals ingesting it) is 1000mg/kg and a 2g black tea bag contains a bit over 250mg, it seems that it wouldn’t take much more black tea than Galega officinalis to kill someone (2gx4bagsx70kg=560g black tea). Bottom line: since nobody in the right mind will ever use that much black tea, neither would one use that much Galega officinalis!

      https://www.ncbi.nlm.nih.gov/pubmed/3188360
      https://www.ncbi.nlm.nih.gov/pubmed/18055147

      1. Thanks! I liked the tea example. It is not very clear from your articel: do you think that the plant galega officinalis is less toxic that its synthetic counterparts? I actually tried to feed it to my sheep and thought she would love it and give me more milk, she did not even nibble on it and did not give more milk. What about log term use? Diabetics have to take a drug over long term. Sorry, I am neither a doctor nor a herbalist.

        1. Good questions! The makers of the synthetic derivatives abandoned many of them because of toxicity, so they were not free of toxicity. We do not have (or I did not have access to) systematic studies evaluating efficacy vs toxicity of the plant. Given the age of such plant-based treatment, we cannot expect to find historically documented “systematic evidence” to the extent of the evidence provided by today’s clinical trials.
          Yeah, not surprised that the sheep did not nibble on it. Animals don’t like it, it isn’t palatable at all. That’s the best proof against the theory that it is dangerous for them. There are many “poisonous” plants/animals, but they aren’t necessarily food choices. The vast majority of the synthetic drugs are “poisons”; we know that and we don’t eat them instead of a meal!
          There is published evidence out there stating that Galega officinalis was used (long ago) for the treatment of diabetes and as a galactagogue. Neither effects could have occurred after one single dose. So, yes, I would have expected longer (safe) use for one to see these results!
          Again, very good questions, thank you!

Let me know your thoughts or questions!