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Painkillers and Prostaglandins editorial april 2003 vol. 10 no. 4 molecular form & function Painkillers and prostaglandins Prostaglandins are powerful signaling agents in the human body. Thus began the world’s current preference for acetaminophen, The two-dozen or so members of this family of small lipid mes- ibuprofen and other related drugs. sengers underpin many profound physiological events — Acetaminophen was identified as a pain reliever in the 1890s, including vasodilation, vasoconstriction, bronchoconstriction, even before aspirin was discovered, but it did not enter wide- platelet activation, inflammation, uterine contractions, pain spread use until the 1950s. A small drug company called McNeil perception and fever. Drugs to counter their less desirable effects Laboratories in Pennsylvania began marketing acetaminophen http://www.nature.com/naturestructuralbiology have become permanent residents in medicine cabinets around under the brand name Tylenol in 1955. Unlike aspirin, aceta- the world, and for a good reason — they are effective, cheap and minophen is strictly an analgesic and antipyretic. It does not reasonably safe. Nevertheless, history has shown that, with new reduce inflammation, but nor does it upset the stomach. information from basic research, a drug can usually be However, acetaminophen at high doses can cause liver failure. improved. For example, the results of a study reported on Clearly, no drug is perfect. page 291 of this issue of Nature Structural Biology shed light on a In the 1960s, scientists at the Boots Pure Drug Company in the particular enzyme involved in prostaglandin metabolism. UK discovered that the phenylalkanoic class of acids, of which Information such as this may eventually lead to even better ibuprofen is a member, are also good pain killers, fever reducers prostaglandin-blocking compounds than those available today. and anti-inflammatory agents. Clinical trials with ibuprofen First discovered in seminal fluid in the early 1930s, were conducted in the 1970s, and in the early 1980s it reached prostaglandins are now known to be important regulators in drugstore shelves under the trade names of Nuprin, Advil and many parts of the body. In 1982, the Nobel Prize in Physiology or Motrin. Related compounds, such as naproxen (known as Aleve) Medicine was presented to three scientists, Sune K. Bergström, and ketoprofen (known as Orudis) are also now available. All of Bengt I. Samuelsson and John R. Vane, for their work on this these can cause stomach upset, but usually less so than aspirin. © Group 2003 Nature Publishing family of hormones. Vane’s contributions include showing that It is now known that all of these drugs block the activities of one of the world’s most widely used drugs — aspirin — acts to cyclooxygenase (COX), enzymes that act early in the pathways of relieve pain, fever and inflammation by blocking the production prostaglandin synthesis. So far, three COX enyzymes have been of prostaglandins. The long history of aspirin and other pain identified: COX-1 is involved in protecting the gastrointestinal relievers emphasizes the importance of this discovery. tract from acid assault; COX-2 is involved in pain, fever, and The ancient Egyptians and Romans were already aware that inflammation; and the role of the newly discovered COX-3, which certain plants could be used to treat pain and fever. Hippocrates is expressed primarily in the brain and heart, remains obscure. also championed the chewing of willow bark for pain relief. In Both aspirin and ibuprofen inhibit COX-1 and COX-2, but England in 1763, the Reverend Edward Stone published a widely acetaminophen appears to inhibit only COX-3. Very read paper promoting the benefits of willow bark extract, and in recently, additional anti-inflammatory agents have been intro- the 1820s salicylic acid was identified as the bark’s active compo- duced, ones that inhibit COX-2 but not COX-1. These com- nent. In 1860, a process for mass-producing salicylic acid was pounds, Celecoxib (known as Celebrex) and rofecoxib (known as discovered. Soon after, many unfortunate patients learned the Vioxx), have become some of the fastest selling drugs on the mar- hard way that the pure form of salicylic acid is not well tolerated, ket. However, they too have their problems, as they promote blood causing diarrhea and vomiting. A search for alternatives ensued, clotting which may lead to heart attack and stroke in rare cases. and in the late 1890s, Felix Hoffman of the Bayer Company in The information from basic research has laid the foundation Germany found that acetylsalicylic acid was a better choice. It for the development of drugs against each of the cyclooxygenase was marketed under the trade name Aspirin, with ‘a’ for the subtypes. However, with each powerful drug, new side effects acetyl group and ‘spir’ for the botanical genus spiraea, from have also emerged. This points to the need to better understand which salicylates can be extracted. the production and function of various prostaglandins in the Aspirin was the main treatment for pain and fever for nearly body. With increased knowledge in this area, perhaps it will 60 years. However, its widespread use highlighted significant eventually be possible to make yet more specific drugs tailored to problems — it could cause peptic ulcers and was linked to each prostaglandin action. One day we may use one drug to dull Reye’s syndrome, a rare but serious problem in children. Once pain, another to reduce blood clotting, yet another to lower again, alternatives to combat pain and fever were sought. fever, and so forth — a pill for every prostaglandin’s purpose. nature structural biology • volume 10 number 4 • april 2003 233.
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