Aspirin

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Aspirin

Overview

Aspirin is a trade name for acetylsalicylic acid (ASA), a mild, nonnarcotic analgesic that was first marketed by the Bayer Company in 1899. Until the end of World War I, the name "Aspirin" (with a capital A) was a trademark of the German firm Bayer. Aspirin quickly became one of the most widely used drugs in the world, but disputes over the discovery of aspirin were still raging at the end of the twentieth century. Often called a miracle drug, aspirin was originally prescribed for the relief of inflammation, headaches, muscle pains, and fever. Before the introduction of antibiotics, aspirin was also used in the treatment of rheumatic fever, rheumatoid arthritis, and infections. Although aspirin generally does not modify or shorten the duration of these diseases, it does relieve some of their symptoms. One hundred years after it was first marketed, scientists continue to find new uses for aspirin. Indeed, statistical evidence indicates that taking aspirin can reduce the risk of a second heart attack and may reduce the risk of heart disease, colon cancer, and preeclampsia during pregnancy.

Background

During the time of Hippocrates (460-377 b.c.), a preparation made from the bark and leaves of the willow tree was prescribed as an analgesic and antipyretic. (Analgesics are drugs that alleviate pain without affecting consciousness and antipyretics are used to reduce fevers.) The antipyretic properties of willow bark were rediscovered in the eighteenth century, but the active ingredient, salicin, was not isolated until 1828. Many other important drugs were first isolated from plant sources during the nineteenth century. Among the alkaloids purified during this time period were narcotine, morphine, emetine, strychnine, brucine, piperine, colchicine, quinine, nicotine, atropine, cocaine, and physostigmine. Chemical purification made it possible to study the active factors of these substances and to eliminate the toxic effects of impurities. Progress in pharmacology also made it possible to prescribe accurate doses of purified compounds. As scientists elucidated the chemical structures of pharmacologically active compounds, they were able to synthesize important derivatives of existing drugs and create entirely new drugs in the laboratory.

Although salicin, salicylic acid, and sodium salicylate were introduced as pain relievers in the 1870s, the salicylates caused nausea, ringing in the ears, and irritation to the stomach lining. Based on experience with other drugs, Bayer chemists hoped that adding an acetyl group to salicylic acid would make it less irritating to the stomach. (Indeed, adding acetyl groups to the morphine molecule led to the production of another highly successful Bayer product that was sold under the trademarked name "Heroin" as a new and superior cough suppressant.)

In 1897 Felix Hoffman (1868-1946), a German chemist working for Bayer, synthesized and purified acetylsalicylic acid. Two years later, the drug was given the trademark name "Aspirin" (A for acetyl chloride, spir from the plant Spiraea ulmaria, and in being a common ending for names of medicines) and was distributed to physicians and hospitals for testing. Pleased by the enthusiastic response of patients and physicians, Bayer marketed the analgesic as a safe remedy for the treatment of arthritis, joint pains, muscle pains, and fever. Aspirin was sold as a powder until 1915, when Bayer began to market Aspirin tablets. Until 1915, Aspirin, which would become one of the most popular over-the-counter drugs for self-medication, was not available to patients unless they obtained a prescription from their doctor.

Within a few years of each other, Bayer had named and marketed both Aspirin and Heroin, two drugs that were to remain among the most widely used and abused in Western society over a hundred years later. Until the end of World War I, the Bayer Company maintained its valuable trademark protection for Aspirin and Heroin. After Germany's defeat, however, Bayer was forced to give up these trademarks as part of the country's war reparations. In 1919 the Treaty of Versailles assigned Bayer's trademarks to France, England, Russia, and the United States. Eventually, "aspirin" and "heroin" became the common names of these drugs. Bayer Aspirin, however, remained the most familiar brand in what would become a highly competitive analgesic market. Advertisements touted Bayer's product as "pure aspirin, not part aspirin" and claimed that "nine out of ten doctors recommend Bayer's aspirin." Other pharmaceutical companies sold aspirin in combination with caffeine, antacids, and special coatings, but no medical studies have found any version of the drug to be better than plain aspirin for headaches, fever, and inflammation.

Bayer had established its presence in the United States as early as 1903, when Friedrich Carl Duisberg Jr. (1861-1935) came from Germany to Rensselaer, New York, to build a chemical plant. The most important product of this plant was Bayer Aspirin. Duisberg was a chemist and the founder of the industrial empire known as I.G. Farbenindustrie (or I.G. Farben), the chemical empire that became identified with Nazi Germany. After World War II, the directors of I.G. Farben were tried along with Nazi war criminals at Nuremberg.

Impact

The Bayer Company had begun as Friedrich Bayer & Company, one of Germany's first dye factories. Friedrich Bayer and Johann Friedrich Weskott established the firm in 1863. After Weskott and Bayer died, the firm was managed by Carl Rumpff, Bayer's son-in-law. The firm then became officially known as Farbenfabriken vormals Friedrich Bayer & Company ("the Dye Factory formerly known as Friedrich Bayer & Company"). When Rumpff died in 1890, Duisberg assumed leadership of the company. As the director of Bayer's research and patent program, part of Duisberg's job was to diversify production and create new products. Duisberg thought that the market for antipyretics—then limited to salicylic acid, quinine, antipyrine, and acetanilid (Antifebrin)—was promising. Acetanilid, a coal-tar derivative whose antipyretic properties were discovered in 1886, was the first German drug to be marketed by a commercial name rather than its chemical or generic name. Seeing the successful marketing of Antifebrin, Duisberg decided to enter the market for fever and pain relievers.

Ernst Arthur Eichengrün (1867-1949), a research chemist who ran the pharmaceutical section of Bayer's drug laboratory, assigned the task of producing a form of salicylic acid with fewer side effects to Felix Hoffmann. According to Hoffmann's laboratory notes, he isolated acetylsalicylic acid (ASA), a derivative of salicylic acid, on October 10, 1897. Although the same compound had been produced by the French chemist Charles Frédéric Gerhardt in 1853 and by the German chemist Karl Johann Kraut in 1869, Hoffmann's methods were an improvement over those of his predecessors.

When the drug was tested by Heinrich Dreser (1860-1924), who, as the director of the pharmacological section of Bayer's drug laboratory, had to approve all the drugs prepared by Eichengrün and his associates, it was initially rejected. Apparently, Dreser thought that ASA might "enfeeble" or exhaust the heart, much like salicylic acid. Because these drugs were often given in large doses for the pain and swelling of rheumatic fever, many patients experienced severe reactions, including shortness of breath, panting, and the feeling that their hearts were racing. Thus, Bayer ignored ASA for over a year while the company promoted its successful new drug, Heroin. In 1898, at the Congress of German Naturalists and Physicians, Dreser announced that Heroin was ten times as effective as codeine as a cough medicine and only one-tenth as toxic. Heroin was promoted as a safe, nonhabit-forming drug that could be used to treat colic in babies and to cure morphine addiction.

Eichengrün, who resented Dreser's veto power, tested ASA himself and passed it on to doctors, who reported that it relieved fevers, aching joints, and headaches. When Dreser was finally forced to accept ASA, he wrote a paper on its beneficial properties but neglected to mention either Hoffmann or Eichengrün. Dreser earned royalties on sales of ASA and became wealthy, but Hoffmann and Eichengrün did not share in this wealth because they could only receive royalties for drugs that had been patented. The German patent office refused to patent ASA because it was not a new product nor did its synthesis involve a new process. Bayer fought for patent protection in other nations—with varying success. Notably, Bayer enjoyed both trademark and patent protection on Aspirin only in the United States. In 1899 Bayer began distributing Aspirin to doctors, medical professors, and hospitals. By 1902 about 160 scientific studies had been reported and a voluminous literature on Aspirin had been published. Most reports were very positive. The drug was taken for long periods of time in large doses for inflammation and arthritis. Smaller doses of Aspirin were prescribed for fevers and headaches.

One hundred years after Bayer introduced Aspirin, Walter Sneader, a Scottish scientist and an expert on the history of pharmacology, announced that the man who deserved credit for the discovery of aspirin was not Hoffmann but Eichengrün. Because Eichengrün was Jewish, he had been incarcerated in a concentration camp during World War II and his role in the success of Bayer Aspirin concealed by the Nazis. Although Hoffmann did indeed synthesize and purify acetylsalicylic acid in 1897, the project had been initiated and supervised by Eichengrün. It was not until 1934 that Hoffmann began to assert that he had discovered Aspirin. By that time, however, the Nazis were in power and Eichengrün was unable to challenge Hoffmann's story. After the war, Eichengrün attempted to correct the commonly accepted story of the discovery of aspirin, but he died in 1949, shortly after his account was published. While examining Hoffmann's laboratory notes, Sneader found that Hoffman had adapted methods previously developed by Eichengrün.

Of all the products sold by Bayer in the United States, Aspirin quickly became the most important. By 1909 it accounted for over 31% of Bayer's total sales in the United States. Because Bayer did not have patent protection for Aspirin in Canada, lower-priced Aspirin was smuggled into the United States from Canada, where it sold for about one-third the price. In 1910 the Bayer Company successfully sued a pharmaceutical dealer engaged in smuggling and its American patent was upheld. Bayer, however, estimated that counterfeit Aspirin held about 75% of the American market.

In anticipation of the expiration of patent protection in 1917, Bayer tried to boost sales by bringing the trademarked Bayer Aspirin name to the public. Aspirin tablets were stamped with the Bayer Cross and tablets were enclosed in Bayer packages. The change from powder to tablets had begun in 1914. In 1916 the company began placing ads for Bayer Aspirin in American newspapers. The American Medical Association, which was opposed to the advertising of trademarked or patented products, argued that ASA should be sold under its generic name and that Bayer should not have a monopoly on the drug. At the end of World War I, the U.S. government sold the American assets of Farbenfabriken Bayer to American businesses.

The mechanism by which aspirin works was discovered in the 1970s by the British pharmacologist John Vane (1927- ), a 1982 Nobel laureate, who found that aspirin inhibited the release of the hormone-like substances called prostaglandins. Prostaglandins were discovered in 1935 by the Swedish physiologist and 1970 Nobel laureate Ulf Svante von Euler (1905-1983). Prostaglandins are modified fatty acids that have diverse functions in the body; they affect blood-vessel elasticity, blood platelets and clotting, the functioning of the digestive tract, sensitivity to pain, and inflammation. The studies by these researchers have provided a molecular explanation for using aspirin in the treatment of cardiovascular disease and inflammatory diseases, including rheumatoid arthritis.

Of course, taking aspirin is not without risk. Aspirin can cause allergic reactions and gastrointestinal problems. In children with viral infections such as influenza or chicken pox, the use of aspirin has been linked to the onset of Reye's syndrome, an acute disorder of the liver and central nervous system.

Many other drugs, such as acetaminophen, ibuprofen, naproxyn sodium, and ketoprofen, have challenged aspirin's place as an analgesic. Other pain relievers, however, do not seem to mimic aspirin's beneficial impact on cardiovascular health. Although in the 1920s Bayer's advertisements assured consumers that Aspirin would not affect the heart, clinical studies in the 1940s indicated that men who took aspirin were less likely to suffer heart attacks. Some physicians began to suggest that all their patients should take an aspirin tablet every day to reduce the risk of a heart attack. By the end of the twentieth century, aspirin was being prescribed by physicians as a means of preventing heart attacks. Most of the 80 million aspirin tablets taken by Americans every day in the 1990s were taken to reduce the risk of heart disease and stroke. More medical uses for aspirin are still under study, including the treatment of migraine headaches, the prevention of various cancers, and the improvement of memory and brain function.

LOIS N. MAGNER