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Saturday, August 10, 2019

HAPPY B-DAY ASPIRIN!

Ooooh, hello dear English speaking-reading-hearing listener, welcome back to me, @sciencemug, the blog/podcast/twitter&instagram accounts which tells you science stories while thinking of opening an agency for nape models and ant-sitters, aaand which talks to you thanks to the voice kidnapped via a voodoo-wireless trick, from a veeery very very dumb dude.
Aaand which does all of this in English-question-mark, a language that is to proper English what a sidereal leap on carbon sequestration technology is to something less than vital to your species as right now.
 

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Today is the birthday of a tablet of which about 50 billion are swallowed each year worldwide (1). So today I will tell you the story of its genesis. Of the birth of Aspirin.

Aspirin 3D
Aspirin 3D pic is a Public Domain image adapted by @sciencemug (source: wikia.com)

Aspirin is acetylsalicylic acid.

Well, to be more precise, “Aspirin is the first commercial name of a medication which active principle is acetylsalicylic acid.
Aspirin is first put on the market by Bayer in 1899 (P), but “the first sample of pure acetylsalicylic acid [is prepared] on 10 August 1897” (P) by Doctor Felix Hoffmann, a “chemist in the pharmaceutical laboratory of the [then] German dye manufacturer Friedrich Bayer & Co in Elberfeld” (P).

The official story goes that Hoffman’s dad suffers from rheumatism, and asks his chemistry savvy son to create something better than the medicine he is presently taking, the sodium salicycate, since that drug has heavy side effects such as gastric irritation, nausea and tinnitus (which is the annoying ringing ear) (P).
Felix, then, consults “the chemical literature[, comes] across the synthesis of acetylsalicylic acid(P), and, as above stated, makes it.

So this is what it is on the matter, and it’s all based on the account of “a footnote in a history of chemical engineering(P) written in 1934 by Albrecht Schmidt, “a chemist [...] retired from IG Farbenindustrie—the organization into which F Bayer & Co had been incorporated in 1925(P).

Felix Hoffmann
Felix Hoffmann pic is a Public Domain image adapted by @sciencemug (source: wikia.com)

The actual facts, however, are most probably different.

But before coming to them, let’s have a look on the path that leads the world to Aspirin.

About 2400 years ago Hippocrates (which is not a house moving company that uses hippos to move crates, but the father of western medicine) recommends the juice of willow leaves to ease childbirth pain (1). Five hundred years later his fellows ancient Greeks commonly use willow leaves to fight aches caused by colic and gout (1).
And Europe’s people are not the only ones to be aware of willow potential for human health: China’s, Africa’s and North America’s ones are in the knowing of it too (1).

For a while, though, willow properties get forgotten.

In 1763, then, someone refreshes everybody’s memory about that. Reverend Edward Stone (Edmund, for his pals [WN]), indeed, gives a lecture (2) to the Royal Society of London where he reports his use of the extract of willow bark to treat “aguistic intermitting disorders(2), probably malaria’s fevers, and what he calls “ague” (2), that most likely is arthritis ((1), [WN]).

During the nineteenth century, European chemists work on willow leaves and bark to extract the active principle responsible for the positive effects on humans. An Italian, a German and a French ((1), [WN]) in sequence (probably after telling each other funny jokes for decades, about each others) achieve the goal, so that humankind eventually gets the “salicin (after Salix, Latin name for willow).

Salicin, when ingested, turns into salicylic acid, which is what relieves pain, but it often irritates mouth, throat and stomach besides being so bitter that some individuals get sick because of it (1).
Moreover, to obtain salicin chemists have to slaughter trees, as 30gr of compound come from a 50 times bigger quantity of bark (1.5kg). Plus the production process is extremely long and complex (1). So, basically, salicin making is anti economical, hence chemists start looking for an artificial method to obtain it, or, more precisely, to obtain salicylic acid.
In 1860 they find a way (1), but there’s still the ugly bitterness. And, above all, what was given to people then, the sodium salicycate (the sodium salt of salicylic acid) still causes the before mentioned side effects: stomach problems, nausea and tinnitus (P).

So, dear listener, we are now in the second half of the nineteenth century, and it’s time to go back to our story.

But first, a commercial.


When you are reading a post or listening to a podcast episode about Aspirin and you get to the part of it where there is a commercial do you expect that the commercial be all about tablets, pills and medications?
You are right. 
Buy our drug which needs to be prescribed by a doctor and used only when really necessary and only at the recommended dosage and timing”!
If you do that, it’s better for you!

commercial pic by @sciencemug
Free pic by Immo Wegmann on Unsplash [Adapted by @sciencemug]

Buy our drug which needs to be prescribed by a doctor and used only when really necessary and only at the recommended dosage and timing” is not a medicine, is a candy for hypochondriacs with a deceiving morally sloppy very long name. 
Cheers!


As said, till recently it is believed that Felix Hoffmann develops Aspirin all by himself.

But “The discovery of aspirin: a reappraisal”, a 2000 paper (P) by Walter Snader (at the time deputy head of the Department of Pharmaceutical Sciences of the University of Strathclyde in Glasgow) tells it differently.

The truth unveiled by the paper is that the real person behind Aspirin is indeed a man named Arthur Eichengrün, who instructs Hoffmann, a colleague of his, to synthesize acetylsalicylic acid, with Hoffmann bluntly following indications without even knowing the aim of the work.

This new narrative is provided by the very same Arthur Eichengrün in a long neglected paper published in 1949 in the science journal Pharmazie. Five years earlier, while in a Nazi concentration camp where he is sent for being a Jew, Eichengrün writes a letter (now in the Bayer archives) where he says the same things” (P).

According to Eichengrün, whose version is fully backed up by Snader’s paper thanks to a meticulous archive work of dates comparison and fact checking, at the time of the events his goal is to obtain a salicylate that do not provoke the above mentioned side effects caused by sodium salicylate.

Eichengrün says he is in the lab when various derivatives of salicylic acid are tested by Heinrich Dreser, the at the time head of the experimental pharmacology laboratory. Always Eichengrün states that, after the test, he concludes that acetylsalicylic acid is the best compound of the batch. At a following management meeting Eichengrün proposes to start with the clinical studies, but Dreser decides otherwise wrongly believing that the drug have negative effects on the heart.

So Eichengrün smuggles the acetylsalicylic acid to his colleague, Dr. Felix Goldmann, who then involves physicians to secretly evaluate the drug. The tests on several patients are a full success, with minor side effects, but robust anti-rheumatic and powerful quick acting pain killing effects.

The trial results are sent in a report to the Bayer management, but again Dreser doesn’t support the drug, dismissing the whole thing as the “usual loud-mouthing of Berlin(P) and insisting that “the product has no value” (P).
Nevertheless, after almost 18 months of this impasse, the new head of research for Bayer, Carl Duisberg, orders a revision of Dreser conclusions and calls in an independent pharmacologist. That’s when, in Snader’s opinion, Felix Hoffmann comes into the picture to synthesize stable, pure acetylsalicylic acid on 10 August 1897, following Eichengrün instructions.

Arthur Eichengrün
Arthur Eichengrün
pic is a Public Domain image adapted by @sciencemug (source: wikia.com)

Snader, in his “The discovery of aspirin: a reappraisal” paper, writes that, among things, a crucial point is what Hoffmann writes, on the day of the synthesis, at the end of his report (presently kept in the archives of Bayer AG in Leverkusen): “Durch ihre physikalischen Eigenschaften wie eine sauren Geschmack ohne jede Atzwirkung unterscheidet sich die Acetylsalicylsäure vorteilhaft von der alicylsäure und wird dieselbe in diesem Sinne auf ihre Verwendbarkeit geprüft” (P).

Snader, in his paper, observes how the German in Hoffmann’s sentence be pretty poor so that it can easily be misread.
The translation indeed sounds: “Due to its physical properties, such as an acid taste without any corrosive action, acetylsalicylic acid differs advantageously from salicylic acid and is being examined for its usefulness with just this in mind.” (P)
It can mean that the compound “was about to be tested rather than that it was being tested” (P). However, according to Snader, the most probable reading of the phrase is that “testing of acetylsalicylic acid was already taking place at the time Hoffmann [writes]” (P), meaning that the compound had been already produced before.

Another thing that Snader takes into consideration in his paper is the 1934 Albrecht Schmidt’s account.

In his footnote, Schmidt states that Hoffmann has examined “preparations of salicylic acid derivatives which remained unnoticed amongst several prepared a long time before for other purposes” (P). Snader, though, reveals that British and US patents had been awarded in 1900 to Hoffmann’s colleague Otto Bonhoeffer for all the other non acetylsalicylic acid compounds mentioned by Schimdt. Snader writes that these patents shows “the absence of any prior mention of these compounds in the literature” (P) and, above all, “that [those] derivatives were newly prepared for the specific purpose of finding a salicylic acid derivative that would be of therapeutic value” (P). All this, Snaders concludes, not only confutes Schmidt's statement, it undermines the credibility of his whole reconstruction.

Snader, besides, has also an explanation for the reason why Eichengrün wait till 1949 to tell his truth about Aspirin.

According to Snader, Eichengrün, after acetylsalicylic acid, has a full career and life since he develops other drugs and other products, then leaves Bayer in 1908 and founds his own company becoming a successful industrialist. When the 1934 claim that Hoffmann is the one that initiated the development of Aspirin comes out, Germany is already controlled by Nazi, and Eichengrün, as a Jew, must keep a profile as low as possible to survive.

In other words, Eichengrün has to wait the end of the Nazism to be again in the position to publicly rebut the “official” story about Hoffmann’s role in creating Aspirin.

To sum up, dear listener, Snader has solid arguments for indicating Albert Eichengrün as the actual mastermind behind Aspirin, and he, Solomonic, ends his paper writing: “F Bayer & Co was truly fortunate in having Eichengrün as an employee, yet it is unlikely that he would have discovered aspirin had he not been working for the company.(P)

Oh, dear listener, if you are wondering what's Felix Hoffmann's angle on this whole story, well, the guy "repeatedly [speaks] of Dreser setting the drug aside" (P), and dies in 1946 "without ever publishing his own account of the discovery of aspirin" (P).

Ciaz!



THE PAPER THIS POST IS ABOUT (P)
P- Sneader, W. (2000). The discovery of aspirin: a reappraisal. BMJ 321, 1591–1594.

BIBLIOGRAPHY 
1- Jones, A. (2005). Chemistry: An Introduction for Medical and Health Sciences (John Wiley & Sons).
SITOGRAPHY 
WN- Pearce, J.M.S. (2014). The Controversial Story of Aspirin. Edward Stone and aspirin (worldneurologyonline.com)

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