For example, taking aspirin may actually double your risk of gastric bleeding, and as a June 2011 editorial in American Family Physician notes, it has been clear for nearly twenty years that enteric-coated or buffered aspirin does not necessarily decrease the risk of gastrointestinal problems. As we grow older and the stomach lining thins, the risk is even higher, which is why the prescription for long-term aspirin therapy to reduce the risk of heart attack is a daily “baby aspirin,” 75 or 81 milligrams rather than the standard 325 milligrams tablet. True, aspirin’s ability to “thin” blood, that is, to prevent platelets from sticking together to build artery-clogging clots, certainly reduces the risk of heart attack and stroke in some patients, but which patients and by how much?
How do you let this new drug, aspirin, go on sale if you can’t answer those questions? And if the drug, aspirin, has been used for decades or even centuries without the requisite tests, how do you allow it to stay on the market?
The answer to the first question is, you don’t. The answer to the second is that you may choose to leave it in place and catch up when you can, perhaps when a new use is proposed.
Obviously, the FDA was not around to evaluate colchicine when Alexander of Tralles first prescribed it, or to say yes or no to Thomas Sydenham’s argument that it might be too dangerous for human beings. The 1938 Food, Drug, and Cosmetic Act did require all new drugs to be approved by the FDA for safety, but it also permitted drugs already on the market, such as generic colchicine, to remain available. In 1976, when Merck & Company created Col-Probenecid, a pill containing colchicine and the drug probenecid, which lowers uric acid, the FDA did test and approve the combination as a “new” drug. But it was considered unlikely that any drug company would invest the millions of dollars required to prove safety and effectiveness for plain colchicine, a natural substance that had been used for centuries and was available to anyone who wanted to go out, gather meadow saffron, and extract the active ingredient for which an effective dose had already been established.
Unlikely, that is, until one company did. In 2007, URL Pharma, a division of Takeda Pharmaceuticals U.S.A., in turn a subsidiary of Takeda Pharmaceuticals Company Limited of Japan, began testing a lower-dose colchicine product called Colcrys and discovered that it worked as well as the customary higher-dose, longer-term regimen. This was, as The New England Journal of Medicine explained, “technically a new indication for the drug.” In 1984, Congress had passed the Waxman-Hatch Act (1984) that contained provisions to increase the availability of less-expensive generic drugs. Under this law, the FDA was required to award URL Pharma three years of “market exclusivity” for its “new” generic colchicine, meaning the company would be the only one permitted to sell the drug.
URL Pharma also proposed to market Colcrys as a treatment for familial Mediterranean fever (FMF), a genetic disorder that worldwide affects perhaps 100,000 people of Armenian, Arabic, Turkish, and Jewish ancestry. Although colchicine was already known to help control the pain and fever of FMF, URL Pharma provided more safety information based on the trials for the low-dose colchicine gout product. The company’s intention to propose Colcrys as treatment for FMF put the medicine under the protection of yet another law: The Orphan Drug Act. This law, passed in 1983, encourages research on drugs for diseases such a FMF that affect relatively small numbers of people; therefore, they do not guarantee the immense profits that will accrue to, say, a new antibiotic that can treat millions. The incentive in the law is a second guarantee of exclusivity, this time for seven years.
In July 2009, the FDA officially announced what doctors and patients had known since Alexander’s day: Colchicine effectively treats acute flares of gouty arthritis.
No surprise there.
What did surprise many patients and physicians was the FDA-approved double dose of exclusivity, which immediately produced one of those moments best described as proof of the Doctrine of Unintended Consequences. As the New England Journal of Medicine reported, “Once the FDA approved Colcrys, the manufacturer brought a lawsuit seeking to remove any other versions of colchicine from the market and raised the price by a factor of more than fifty, from $0.09 per pill to $4.85 per pill [and the average 23-day prescription from $6.72 to $185.53]. According to the Centers for Medicare and Medicaid Services, state Medicaid programs filled about 100,000 prescriptions of colchicine in 2007 and paid approximately $1 million for the drug. Use of the new brand-name colchicine could add as much as $50 million per year to these insurance ad programs’ budgets at a time when they are addressing the rising costs of health care by reducing some services or raising eligibility thresholds.”
There may be another such issue on the horizon. Colchicine interrupts mitosis, the process by which cells divide their chromosomes to reproduce themselves. As a result, some of the resulting new cells may have more than the normal amount of genetic material. This is useful for breeding new and unusual plants, but not so good for human beings—unless the cells whose division colchicine interrupts are malignant.
As early as 1939, colchicine had been put through trials to evaluate its effects on patients suffering from leukemia; today is it sometimes used together with more conventional anti-tumor medication. In September 2011, researchers from the Institute for Cancer Therapeutics (ICT) at the University of Bradford (England) reported that a “smart bomb” using colchicine, chemically modified to make it inactive in the body until it reaches the tumor, had been able to slow the growth of five types of cancer—breast, colon, lung, sarcoma, and prostate—in laboratory mice without appearing to cause adverse effects. In some cases, it killed the tumor outright by destroying the blood vessels that keep the malignancy alive. And it worked fast. In one study, 50 percent of the mice were in complete remission, no tumor evident, after only one dose. If such results continue to be replicated in animal studies and the drug is approved for trials on humans and the results are positive, there is the possibility of a new approval (and more exclusivity) for even a very old drug.
But not just any very old drug. Colchicine, the meadow saffron plant’s remedy for the king of diseases may now join the anti-tumor drugs vinblastine (Velban) and vincristine (Oncovin) from the Madagascar periwinkle in the biggest, baddest battle of them all, the war on cancer. And, given the toxicity of virtually all the drugs used to treat the Big C, you just have to think that in the end even Thomas Sydenham—the man who developed laudanum, but feared colchicum—would have approved this newest effect of our big toe on our lives.
In the beginning, when we were not yet first among primates, our feet were still hands and that toe was still a finger, special in its opposability, but a finger nonetheless. As it evolved, moving into line with the other four, our third and fourth hominin hands became feet. We gained a platform on which to stand, but along with it came a site for the pain of gout. Podagra, now defined by Stedman’s Medical Dictionary as “Severe pain in the foot, especially that of gout in the great toe,” has been with us since the Ebers papyrus. It was in the Greek pantheon in the person of its namesake goddess; in the pipes that leeched lead into Roman homes and human bodies; in the British, French, and American dance around the Revolution; in our discovery of the chemistry of proteins and purines; and finally in our modern drug laws and regulations, one more example—if one were needed—of how our special human foot has drawn its outline on the canvas of our lives.
Notes
(1)Chaplin was serious about film and movement, but not about gout. He included comical gouty characters in two films, His New Profession (1912) and The Cure (1917).
(2)If you are hearing impaired, your newly grafted toe will also restore your ability to communicate fully with sign language, a system that connects you to the Celts. American sign language is generally believed to have been invented by Laurent Clerc and Thomas Hopkins Gallaudet, but the pair, who set up the first American school for the deaf in 1817, were certainly not the first to codify hand signals. For example, ogham is an ancient Celtic alphabet based on indenta
tions and lines for vowels and lines for consonants that may still be seen on very old monuments in Ireland; positioning the fingers to imitate the written letters gave the Celts a secret language invaders could not understand.
(3)The list of the arthritides (singular: arthritis from the Greek word arthron meaning joint) includes, but is not limited to:
Ankylosing spondylitis
Aseptic necrosis
Avascular necrosis
Basal joint arthritis
Behçet disease
Bursitis
Carpo-metacarpal arthritis
Calcium pyrophosphate dihydrate deposition disease
Carpal tunnel syndrome
Celiac disease
Costochondritis
Crohn disease
Degenerative joint disease
Dermatomyositis
Discoid lupus erythematosus
Ehlers-Danlos syndrome
Eosinophilic fasciitis
Felty syndrome
Fibromyalgia
Fifth disease
Forestier disease
Fungal arthritis
Gaucher disease
Giant cell arteritis
Gonococcal arthritis
Henoch-Schönlein purpura
Infectious arthritis
Inflammatory bowel disease
Joint hypermobility
Juvenile arthritis
Kawasaki disease
Legg-Calve-Perthes disease
Lupus arthritis
Lyme disease
Pseudogout
Psoriatic arthritis
Raynaud phenomenon
Reiter syndrome
Restless legs syndrome
Rheumatic fever
Rheumatoid arthritis
Scleroderma
Septic arthritis
Sjögren syndrome
Somatotroph adenoma
Spinal stenosis
Temporomandibular joint disorder
Mixed or undifferentiated connective disease
Marfan syndrome
Mycotic arthritis
Osgood-Schlatter disease
Osteitis deformans
Osteoarthritis
Osteonecrosis
Osteoporosis
Page disease
Palindromic rheumatism
Polyarteritis nodosa
Polymyalgia rheumatica
Polymyositis
Temporal arteritis
Tietze syndrome
Tuberculous arthritis
Ulcerative colitis
Vasculitis
Viral arthritis
(4)Bocking and de Wyche served an authentic architectural treasure, the Chichester Cathedral. The building was begun in 1078, consecrated in 1108, rebuilt in 1178, given a new Christopher Wren spire in 1721 to replace one destroyed by a lightning strike, and rebuilt again in 1861 after the original stone walls collapsed. Today the Cathedral is famous not only for its history, but also for its art, a modern collection commissioned by Walter Hussey (1909–1985), Dean at Chichester from 1955 to 1977. Hussey was clearly a man of catholic taste, embracing arts and artists of many persuasions. His collection includes Leonard Bernstein whose Chichester Psalms (1965) had music from West Side Story and Hebrew text from the Old Testament; Mark Chagall whose stained glass window (1978) was based on Psalm 150 (“… let everything that hath breath praise the Lord”); John Piper, whose tapestry of the Holy Trinity was woven in France in 1966; and neo-romantic British artist Graham Sutherland, known for his Welsh landscapes but represented here by an altarpiece, Noli Me Tangere (1961), with Christ holding out his hand to Mary Magdalene.
(5)To convert degrees Celsius to degrees Fahrenheit, multiply the Celsius number by 1.8 and add 32. To convert Fahrenehit to Celsius, subtract 32 from the Fahrenheit number and divide the result by 1.8.
(6)As William Safire explained in The New York Times in 1997, the sobriquet came from “white ‘bucks,’ the casual, carefully scuffed buckskin shoes with red rubber soles and heels worn by generations of college men at Ivy League schools. Many of these kids, supposedly never changing their beloved footgear, went on to become masters of the universe on Wall Street and in the best-known law firms.”
5
DESIRE
‘They are not wise, then, who stand forth to buffet against Love; for Love rules the gods as he will, and me.”
Sophocles, Trachiniae (The Women of Trachis, c. 430 BCE)
IF THE Vitruvian Man’s is the ideal masculine form, with every part, private and otherwise, exquisitely detailed, then Cinderella’s is the perfect female foot. Generations of women may have wondered how the girl managed to get around without cutting a toe on that glass slipper, but not a single one has ever doubted the sublime femininity of the foot that fit the shoe too small for the nasty stepsisters whose loathsome nature is captured in the size of their own unfortunate extremities.
The Aarne-Thompson-Uther (ATU) Index is a system that classifies traditional folk tales by plot. Created by Finnish folklorist Antti Aarne (1867–1925) in 1910, it was expanded and translated into English in 1928 by Stith Thompson (1885–1976), professor of English and folklore at Indiana University, and then updated in 2004 by Hans-Jorg Uther, professor of German literature at the University of Duisburg-Essen. In all three versions, Cinderella is listed as ATU 510 A, a subtype of the category ATU 501 (persecuted heroine), one section of Supernatural Helpers 500–559.
East, west, north, and south virtually every culture on earth has its own version of this Mistreated-Motherless-Girl-Finds-Prince story. Some estimates put the number of such tales at more than 1,000, some with shoes, some without, some with cinders, some without, but all with a motherless, orphaned, or abandoned heroine, an animal guardian, a magic gown, and a handsome prince.
One very early example is Rhodopis (Rosy Cheek), the fictionalized sixth century BCE tale of a real woman variously described as a Thracian courtesan or a slave, but either way a stranger and alone in Egypt. As recorded by the Roman historian Strabo, this girl gets her prince when a bird picks up one of her sandals, flies to the palace, and drops the shoe in the lap of the Pharaoh, Amasis, who immediately orders a search for its owner whom he soon finds and makes his queen.
The Chinese Cinderella girl, Yah Shen/Yeh-Hsein, has a magic fish carry her shoe to her prince. The no-shoes Katie Woodencloak (Norway) has a friendly bull; the heroine of Ashey Pelt (Ireland), a black ewe; in Rashin-Coatie (or Rashiecoat, a Scottish king’s daughter made to dress in a rashin coat, a garment made of grasses), a red calf; in Conkiajgharuna (The Little Rag Girl, Georgia), a cow. Nomi, the Zula Cinderella, follows a talking fish’s instructions to eat him and then toss his bones into the garden of the chief, who then seeks to choose a wife for his son by asking the women of the village to pick up the bones—which slip out of everyone’s hands but Nomi’s who, thanks to her finny friend, walks off with the prince.
After years of making do only with helpful animals or an occasional older woman, the Cinderella girl—in this case, the Parisian Cendrillon—finally got her fairy godmother in 1697 courtesy of Charles Perrault (1628–1703), a member of the Academie FranÇaise who also introduced the pumpkin that turned into a carriage attended by mice that turned into men … and the wonderful glass slipper. Some histories of the Cinderella shoe story suggest this last may have been an accident of language, that when Perrault first heard the tale he confused the word vair (French for squirrel fur) with verre (French for glass). Others dismiss this as a literary urban legend.
Perrault’s typically frothy Parisian romance was followed by Aschenputtel (Ash Girl), the Grimms’ typically grim German version. Jacob and Wilhelm’s persecuted heroine plants a tree on her mother’s grave. The tree attracts a white dove who grants all the girl’s material wishes including an increasingly lovely wardrobe of gold and silver dresses and gold and silver shoes for an increasingly important series of royal balls. Eventually, Aschenputtel gets her man and her gorgeous wedding, but it doesn’t end pleasantly.
The girl and the prince have barely said, “I do,” when the Grimms, ever true to their name, conjure up an entire avian air force—white pigeons, turtle-doves, and “all the birds beneath the sky”—that, like creatures from a Hitchcock movie, dive-bomb the stepsisters and peck out their eyes.
After that, the only thing left to do was to liberate Cinderella from her need to find a protective Prince, a task addressed by therapist Colette Dowling in The Cinderella Complex, a treatise urging women to forget the prince and take control of their own lives. The book, published in 1981 at the height of the feminist awakening, has been translated into twenty languages, but the emergence of Chick Lit as a major category suggests that not all that much has changed. Around the world, little girls still fight with their mothers and sisters, consider themselves strangers in their own homes, and dream of escaping into an ending where the Girl still gets her Prince and the Prince still gets the Right Girl.
But is it the girl that he wants? Or simply her foot?
The heart wants what the nose knows
Like the palm of your hand, the sole of your foot is an erogenous zone, highly innervated and exquisitely sensitive to touch. It is also perfumed by friendly bacteria that digest and then excrete the produce of 250 thousand sweat glands per foot, bathing your feet in a salty sweat that carries messengers called pheromones (from the Greek words pherein meaning to carry and hormon meaning to impel).
Pheromones were isolated and identified in 1959 by Nobel laureate Adolf Butenandt (Chemistry; 1939) and named by German biochemist Peter Karlson and Swiss entomologist Martin Lüscher. These chemicals, first found in silkworms, come in two broad categories: releaser pheromones and primer pheromones. The releasers initiate a behavioral response in another individual, such as causing him or her to move closer to the source of the delicious odor. The primers set off a physical response, such as an increase in another’s blood pressure or heartbeat or the secretion of sex hormones. Together, the two molecules may explain the mysterious phenomenon of love at first sight that some suggest might more accurately be labeled, “love at first scent”—the caveat being that you can see across a crowded room, but you have to be pretty much nose to nose to catch the scent.
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