felix_hoffmann

Felix Hoffmann (1868-1946)

This story begins with Herr Hoffmann’s rheumatism.

During the 1890s this German industrialist had been suffering badly and had been medicating himself with salicylic acid — the standard treatment of the day. However, while this drug soothed his pains, it had significant side effects, including gastric irritation, nausea and tinnitus. Moreover, it had a terribly bitter taste making it almost unpalatable for daily use.

He complained to his son Felix and asked him if an alternative could be found. His son was Dr Felix Hoffmann, who in 1897 was a 29-year old chemist working for the German pharmaceutical company, Friedrich Bayer & Co in Elberfeld.

Aspirin

Felix Hoffmann was working in the newly established chemistry and pharmacology laboratory at Bayer under the leadership of Heinrich Dreser. Dreser was a highly methodical researcher who is credited with introducing large-scale animal testing to the pharmaceutical industry. But he was also an astute businessman who could see the commercial potential of exciting new products.

On Tuesday, 10 August 1897 Hoffmann, at his laboratory bench in Elberfeld, modified salicylic acid and synthesized the derivative acetylsalicylic acid. This was subsequently tested in animal studies and found to have anti-inflammatory, analgesic and antipyretic properties. After initially dismissing it because of concerns that it may have cardiac side-effects, Dreser was eventually persuaded of the huge commercial opportunity that acetylsalicylic acid offered and it was brought to market in 1899 under the trade name Aspirin, first as a powder and then as tablets. The drug quickly found favour and it has been in continuous use for more than century.

Acetylsalicylic acid received its trade name, Aspirin, from Dreser, but there are two schools of thought about why he chose this name. Meadowsweet is a plant that contains salicylaldehyde, which can be oxidized to salicylic acid. The genus name of this herb is Spirea and thus the German name for the acid derived from it was Spirsäure and its acetylated form, Acetylspirsäure, which could easily be truncated to Aspirin.   Rather more romantically, he may have known about the patron saint of headaches St Aspirinius and named his new analgesic after him.

This account of Aspirin’s invention has, however, recently been challenged as a piece of Nazi revisionist history. Perhaps the true inventor of Aspirin was the Jewish chemist Arthur Eichengrün (1867-1949), who claimed while he was interred in Theresienstadt concentration camp and afterwards that Hoffmann had been working under him at the time and that he had led clinical experiments (many of which were surreptitious) to examine the effectiveness of acetylsalicylic acid that had led to it being brought to market in 1899.

Bayer have refuted this claim, pointing out that Eichengrün was not Hoffmann’s superior (they were almost exact contemporaries) and citing the US Patent for Aspirin which was clearly submitted in 1900 in the name of Felix Hoffmann. At the time of the submission, Eichengrün was still a Bayer employee and if his later story were true why was the issue not raised then?

Whatever the truth of the matter, Bayer’s fortunes were to be built on the launch of one of the most widely used drugs in history. In 2000, it was estimated that fifty thousand tons of acetylsalicylic acid are produced annually and that the average consumption is 80 tablets per person per year.

But, Hoffmann’s work that summer of 1897 was not over yet.

Opiates

The process of acetylation had been used before and would be again in order to alter a natural compound’s structure in the hope of either enhancing its efficacy or minimizing its side effects. Perhaps because of Hoffmann’s success with salicylic acid, Dreser asked him to work on another compound just a few days later. Dreser was known to keep a keen eye on the literature and regularly searched through archives in the hope of turning up a new and commercially viable line of research. Twenty-three years earlier the English chemist CR Alder Wright, working at St Mary’s in London had been experimenting with morphine. He had acetylated it and, although he did not pursue the development of the product, he did publish his preliminary findings, which Dreser had uncovered. Opium had of course been in use for millennia and its most abundant active component, morphine, had been extracted in around 1804 by a young apprentice pharmacist, Friedrich Wilhelm Sertürner.

Heroin

After morphine, the second most abundant active component in opium, 3-methylmorphine or codeine, was isolated in 1832 by the French chemist and pharmacologist Pierre Jean Robiquet. Dreser had previously worked on the chemistry of codeine and, like all in the pharmaceutical industry at the time, he was keen to develop new non-addictive alternatives to these opiates. Perhaps, acetylation would do the trick.

On Saturday 21 August 1897, at the same bench where just over ten days before he had successfully acetylated salicylic acid to produce Aspirin, Felix Hoffmann was working on morphine. He used Wright’s method to add two acetyl groups and produced diacetyl morphine or as it has become known diamorphine — the drug that Bayer would subsequently market under the trade name Heroin. The name derived from the German word heroisch, meaning heroic or great — which was how those Bayer employees who sampled the new drug reported their feelings. The demand for a safer opiate at the time had little to do with pain relief, but more to do with cough suppression. This was the age of tuberculosis and various other respiratory problems and debilitating coughs were a significant clinical problem.

The Bayer chemists found that heroin was more potent than morphine or codeine, but concluded erroneously that it was associated with less respiratory depression. In 1898, it was brought to market as a safer, more potent cough suppressant and advertising of the time emphasized this indication. Within 12 months of its launch, Bayer was manufacturing a ton of Heroin a year and exporting it to more than 20 countries. Almost immediately the drug created controversy with one clinician claiming it to be ‘the digitalis of the respiration’ and another an ‘extremely dangerous poison.’ Time would reveal the highly addictive properties of Heroin and result in its restricted use or complete ban.

The success of these drugs and the story behind their invention prompts an important question. Who actually invented Aspirin and Heroin?

Both drugs had been synthesized before 1897. Acetylsalicylic acid had been produced in France in 1853 by the French chemist Charles Frédéric Gerhardt and later by German chemists who correctly worked out its chemical structure, while diacetyl morphine had first been synthesized in England in 1874 by the English chemist CR Alder Wright.

However, at least in the case of acetylsalicylic acid, the method used by Hoffmann resulted in a purer, more stable form of the drug. Moreover, it was the realization in the Bayer laboratory of their commercial potential that transformed two relatively insubstantial reports of organic synthesis into blockbuster products.

While Hoffmann is credited with their synthesis at the laboratory bench during that remarkable summer of 1897 and while Eichengrün was undoubtedly involved to some extent, it is hard to imagine that either drug would have reached the market in quite the way they did without the influence of Dreser, who may be seen as the driving force behind both drugs. Thus, it is Heinrich Dreser who can perhaps rightly claim to be the true inventor of both Aspirin and Heroin.

Aftermath

What became of Dreser, Hoffmann and Eichengrün? Dreser’s contract with Bayer allowed him to benefit financially from the sales of the drugs that he developed and as such he became very wealthy and retired early. Some claim that he became addicted to one of his own drugs — heroin — and he died aged 64 in Switzerland.

Hoffmann was promoted, and shortly after his productive summer of 1897 he was made head of the pharmaceutical marketing department, where he remained until his retirement. To move one of your most creative organic chemists from the lab where he had synthesized not one but two of the most important drugs in history, to a desk in a marketing department seems a strange decision — at least to anyone who has not worked in the modern pharmaceutical industry where such restructurings and redeployments are bewilderingly commonplace. Hoffmann too died in Switzerland, aged 78.

Eichengrün left Bayer in 1908 to set up his own highly successful pharmaceutical and chemical company and he held over 40 patents. A Jewish industrialist working in Nazi Germany, he naturally came into conflict with the authorities and spent some time in a concentration camp where he made his initial claims of his involvement with the development of Aspirin. He pursued this on his release and published a detailed account shortly before his death in 1949 at the age of 82.

Interestingly, while there has been a lengthy dispute over claims to the invention of Aspirin, there has never been the same scramble to take credit for Heroin. What is not in doubt is that both drugs began their commercial futures on a laboratory bench in Bayer’s laboratory during two summer weeks in 1897. Their impacts on human suffering, both as a relief and as a cause have since been incalculable.

Conclusions

With the addition of a functional side group, Hoffmann was able to transform two well-known and well-established, although imperfect, treatments into new drugs. His efforts, and those of the many other chemists working at similar laboratory benches across the world, led to an explosion of new compounds, a small number of which would ultimately make it to the pharmacy shelves.

As we move from the simple extraction of pharmacologically active compounds from plants and other natural sources to the manipulation of those molecules to create new entities we enter a new and exciting era of drug discovery.

© Allan Gaw 2016

 

This is an extract from my new book, which will be published on March 1, 2016 and is available for pre-order from amazon:

Testing the Waters

Lessons from the History of Drug Research

What can we learn from the past that may be relevant to modern drug research?

In this book Allan Gaw shows us how the past can illuminate the present and help us understand where we are and how we have come to be here. We will start in a world, more than two thousand years ago, long before science, but where highly disciplined minds could still formulate rigorous strategies for the evaluation of new drugs. We will move forward to see the parts played by an Emperor’s physician in Ancient Rome, a Persian philosopher and a country doctor in England. We will visit the battlefields of Europe, the laboratory benches of a German drug company and see the parts played by serendipity and innovation in the development of new drugs. In the early 20th century we will see that tragedy can be the result of inadequate testing of medicines as well as being the catalyst for change. And, we will discover how the story of one sleeping tablet changed everything.

http://www.amazon.com/Testing-Waters-Lessons-History-Research-ebook/dp/B01AXBM0WQ/

Screen Shot 2015-10-14 at 21.22.11

 

My other books available on kindle:

Screen Shot 2015-01-18 at 17.19.43Screen Shot 2015-01-18 at 17.19.00BIS Cover copyScreen Shot 2015-01-18 at 17.19.29Screen Shot 2015-01-18 at 17.18.54Screen Shot 2015-01-18 at 17.19.37Screen Shot 2015-01-18 at 17.19.16Screen Shot 2015-01-18 at 17.19.58Screen Shot 2015-01-18 at 17.20.06

 

Advertisements