Chapter 26. Bayer (Pharmaceuticals)

 

Alkaloids. There is a considerable number of nitrogeneous compounds, found in plants, which combine with acids to form crystalline salts in the same way that the amines do. Some of these are comparatively simple amines, but most of them are complex in their structure. Many of them have some very marked physiological action as poisons or as medicines. Many which are poisonous are used as medicines in small doses.

Nicotine, C10H14N2, is a colorless oil found in tobacco, which contains from 2 to 8 per cent of the alkaloid. It is very poisonous.

Coniine, C8H17N, the alkaloid of hemlock, is also a liquid. It is historically interesting as the active principle of the fatal draught taken by Socrates.

Atropine, C17H23O3N, is found in Atropa belladonna. It is used to dilate the pupil of the eye and is an active poison.

Cocaine, C17H21O4N, is found in coca leaves. It is used to produce local anaesthesia. A careful study of cocaine has shown that it is a derivative of benzoic acid and the group derived from that acid is chiefly effective in giving to it its valuable qualities. On the basis of this discovery other alkaloids having, in part, a similar structure have been prepared. Some of these retain the anaesthetic effect of cocaine and are less poisonous.

Morphine, C17H19O3N.H2O, is the most important alkaloid of opium and is the chief constituent which gives to laudanum and paragoric their poisonous and sedative qualities. Paragoric also contains camphor and aromatic oils which may have as much effect as the morphine. Opium is obtained from the poppy.

Quinine, C20H24O2N2, is obtained from Peruvian bark. It is a specific in malarial fevers.

Strychnine, C21H22O2N2, is found in Strychnos nux vomica. It is a violent poison, producing convulsions. A dose of 0.06 gram is considered fatal. In small doses it is a powerful stimulant.

 — William Noyes, Textbook of Chemistry, 1913 AD [1]

26.1.

Drugs! Now that's a business. Eye of newt, wing of bat, flower of poppy, these are the stuff that dreams are made of. Up until the twentieth century, pretty much all drugs were 100% natural, meaning they were extracted from plants or animals; just grind up your plant or animal and extract it with hot water or alcohol just the same as if you were making tea or dye. These days, folks tend to think that "natural" is the same thing as "safe." Just try telling that to Socrates or Cleopatra or Napoleon or anyone else who was poisoned before 1900. No sir, some of the most powerful drugs and poisons around are completely natural. But because the plants and animals they come from don't grow just anywhere, drugs that come from far away places tend to be expensive. For example, quinine comes from the bark of the Peruvian cinchona tree. Quinine acts as an antipyretic, reducing fevers in victims of malaria and other tropical diseases. But the cinchona tree won't grow in England, which is why William Perkin tried to make quinine from coal tar in 1856, on account of England had plenty of coal. Of course, he didn't succeed in making quinine; he made mauve instead and that started the whole synthetic dye industry going. But you knew all that from Chapter 22.

The beginnings of the scientific revolution in medicine predate the synthetic dye industry by half a century. Davy had begun his career in 1808 studying the anaesthetic effects of nitrous oxide (laughing gas). Faraday had revealed the anaesthetic properties of ether in 1818. Liebig had prepared chloroform in 1831 and Robert Liston had first used it as a surgical anaesthetic in 1846. Joseph Lister had introduced phenol as a surgical antiseptic in 1867—

Which brings us back to coal tar derivatives. In 1853 Hermann Kolbe synthesized salicylic acid from phenol and carbon dioxide. Salicylic acid turned out to have antipyretic properties similar to salicin, an extract of the bark of the white willow tree. Though cheaper than quinine, salicylic acid had some whopping side effects: nausea, ringing in the ears, and whatnot. Then in 1886 two interns Kahn and Hepp were testing naphthalene for the treatment of intestinal parasites. Patients didn't get any relief from their worms, but the naphthalene reduced their fevers. In a second round of testing, naphthalene killed the worms but didn't help with the fevers. On closer examination Kahn and Hepp found that the first bottle of "naphthalene" had actually been mis-labeled. Consulting the manufacturer, the dye works of Kalle & Company, they found it to be a common dye intermediate, acetanilide. Acetanilide was such a common intermediate, in fact, that there was no hope of patenting it. So instead of marketing acetanilide under its chemical name, as was the custom, Kalle & Company took out a trademark on the brand name, Antifebrin, and began promoting it as an antipyretic. The brand name drug had been born.

Pharmacists, of course, were outraged because they were used to providing generic drugs by their chemical names. But if doctors wrote prescriptions for Antifebrin, pharmacists were forbidden by law to substitute what they knew to be the identical and less expensive acetanilide. And no competitive dye house had an incentive to market acetanilide since it could not be protected by patent. The most they could hope for was that one of their own dye intermediates might prove pharmacologically active.

When Antifebrin was introduced by Kalle, Carl Duisberg was the head of research and patenting for Farbenfabriken vormals Friedrich Bayer, one of the many German dye companies. Faced with the disposal of thirty thousand kilos of waste para-nitrophenol, Duisberg challenged his chemists to turn it into a drug. The result was acetophenetidine, marketed by Bayer as an antipyretic and analgesic (pain reliever) under the brand name, Phenacetin. With fewer side effects than Antifebrin, Phenacetin was a cash cow for Bayer, the first of many; in 1898 Bayer introduced a new-and-improved, non-addictive alternative to morphine, then used to treat tuberculosis. Because it made patients feel heroic, Bayer marketed the wonder drug under the brand name, Heroin.

Don't tell me you're going to tell them how to make Heroin! Have you no shame? Have you no sense? Have you no fear of prosecution?

Figment! Did you have a pleasant sulk? I was wondering whether you would ever come back.

You're going to get the Author arrested. What kind of stories do you imagine he'll write for us from the Powhatan Correctional Facility?

Keep your pants on. Heroin is too hard for a beginner to make. I think acetanilide would be a better choice.

I think you ought to have your eight-eyed head examined. Regular use of acetanilide kills red blood cells and turns peoples' skins blue.

Obviously a safer alternative to acetanilide was needed. The year following its introduction of safe, effective Heroin, Bayer came out with a new antipyretic with many fewer side effects than either acetanilide or acetophenetidine. Like its predecessors, acetylsalicylic acid (ASA) had been invented years before and was not patentable under German law. Consequently Bayer chose to market it under the brand name, Aspirin.

The American patent system was a wee bit more accommodating than it was in Germany and the United States had already become the largest market for Bayer dyes. Not only did Bayer have the trademark, Aspirin, it held a US patent. With patent protection, Bayer could sell Aspirin at a higher price than in Europe, and American firms were unable to manufacture the generic ASA. But Bayer recognized that when its seventeen-year patent expired, duties on imported drugs would give American rivals the upper hand. In 1903 Farbenfabriken Bayer began manufacturing Aspirin in New York State through its American subsidiary, the Bayer Company. By manufacturing Aspirin in the United States, Bayer would be able to circumvent the import duties. And by promoting Aspirin (not acetylsalicylic acid), Bayer hoped that the brand name would be so firmly entrenched in the medical community that when the patent expired, rival manufacturers of ASA would be unable to compete in the American market. By 1909, Aspirin accounted for 31% of Bayer's US sales.[2]

It was a good plan except for one little glitch; "ethical drugs," the equivalent of modern prescription drugs, were sold through pharmacies, which provided their own packaging. Thus consumers would be unaware of the Bayer trademark. If you wanted to provide your own packaging, you had to put out patent medicines, which were looked down upon by doctors and pharmacists. Ethical drugs had to be tested and proven safe; patent medicines could make whatever claims they wanted and it was up to the customer to decide whether they worked or not. Doctors and pharmacists would boycott any company that tried to sell both ethical drugs and patent medicines. Bayer had positioned itself in the ethical drug market and as such was prohibited from advertising to the general public.

To get around this restriction without offending doctors and pharmacists, Bayer started stamping the Bayer logo into each tablet in 1914. That way, the public would come to know Bayer as the genuine producer of Aspirin. It was pure genius. And it worked. In fact, it worked too well for Bayer's own good. The United States entered the First World War in 1917 and German-owned companies were placed in trust, to be returned at the end of the war. The Bayer Company was cut off from Farbenfabriken Bayer, though its German-born managers were loyal to the parent company. But financial and political scandals resulted in the arrest of the American management team and the seizing of Bayer's American assets. These assets, including the American patents and trademarks, were sold to the highest bidder at the end of 1918, just as the war was ending. The buyer was Sterling Products, manufacturer of such patent medicines as Neuralgine (a headache remedy), No-To-Bac (a nicotine cure), Danderine (a dandruff remedy), and California Fig Syrup (a laxative). Bayer Aspirin was about to go over-the-counter.

In 1919 the co-founder of Sterling, William Weiss, had the temerity to approach Duisberg at Farbenfabriken Bayer with a request for assistance in getting the Bayer Company plants operational, as no one at Sterling knew how to run the equipment. Duisberg had assumed that after the war, Farbenfabriken Bayer would resume its operations in the United States. Now he found that not only had Bayer lost its chemical plants in New York, it had also lost its US rights to the "Bayer" and "Aspirin" trademarks. Even if Farbenfabriken Bayer built new manufacturing facilities in the US, it would be unable to market its ASA as Bayer Aspirin. During the war Duisberg had forged a cartel of the German chemical giants, Bayer, Hoechst, BASF, and AGFA to form IG Farben, of which he was chairman of the board. And now this brash American hay-seed had the audacity to offer Bayer the "opportunity" to sell Bayer products exclusively through Sterling when it became clear that Sterling would be unable to manufacture these products itself.

Now hold on there, cowboy. Sterling had split off all but the Aspirin business into its subsidiary, the Winthrop Chemical Company. Sterling knew everything it needed to make Bayer Aspirin. The Bayer Aspirin business was booming, thank you very much, on account of Sterling's advertising genius. It just needed a little help with the sixty-three other Bayer pharmaceuticals to which Winthrop now held the US patents. If Farbenfabriken Bayer would help Winthrop out in the technical department, Sterling would make Bayer a household name.

Bayer was already a household name! Bayer had discovered the analgesic properties of ASA. Bayer had made Bayer Aspirin the universal choice for pain relief. Bayer still held the trademark throughout most of the world. Bayer's American trademarks and patents had been stolen from it during the war; Sterling had simply bought stolen goods. Bayer was happy to reimburse Sterling for its expense, perhaps make Sterling a subsidiary of Bayer. Otherwise, Bayer would see to it that Sterling was known throughout the world as the fake Bayer.

The fake Bayer in Germany, maybe, but in 1919 Sterling bought the rights to Bayer patents and trademarks in England and its sales in South America were booming, thanks to its advertising prowess. No sir, Bayer would deal with Sterling or be relegated to just another producer of ASA. Sterling offered 50% of the Winthrop profits in exchange for technical help. Sterling would have exclusive rights to sell Bayer products, including Bayer Aspirin, in the United States, Canada, Great Britain, Australia, and South Africa. After all, Bayer was good at making; Sterling was good at selling. It would be a win/win situation.

Farbenfabriken Bayer would control the Bayer trademarks and patents over the rest of the world. Sterling would refrain from using Bayer trademarks on Danderine, Fig Syrup, or any of its other snake-oil remedies and would not use Sterling trademarks on any Bayer products. The deal was struck on April 9, 1923 and Bayer Aspirin lived a double life for the next seventy-one years. Then on November 2, 1994 SmithKline Beecham bought Sterling Winthrop from Eastman Kodak. The next day it sold the North American over-the-counter component of the business, including the Bayer trademarks, for 1 billion dollars to Miles, Inc., a wholly owned subsidiary of Bayer.

Well, Sterling may have been carved up, scattered to the four winds like so many spiders, but along the way it changed the way that drugs are marketed. Over-the-counter medications are no longer the untested patent medicines of yesteryear. No, these days the market for untested cures belongs to herbal remedies and food supplements. The big drug companies make both prescription and over-the-counter drugs, advertising both kinds of medicine to the general public. And Bayer would begin the twenty-first century as the fourth largest chemical company in the world.[3] Not bad for a dye company.

Notes

[1]

Reference [21], pp. 342-343.

[2]

Reference [64], p. 35.

[3]

Reference [54], July 29, 2002, p. 16.