Thalidomide: a Teratogen of the 1960s - Research Paper Example

Thalidomide: A Teratogen of the 1960s Thalidomide is a teratogen that was administered to women across the globe in late 1950s and caused thousands of malformed babies. Now the drug is proving useful in treating some types of cancer. This paper traces the story of thalidomide — from its origin to growth to ban to revival as a cancer treatment drug. Introduction No drug has gained the level of notoriety that thalidomide had in the last century. Banned as the cause of one of the biggest tragedies in the human history, the drug rose like a phoenix, to prove that some good can come out of it after all. The FDA owes its powers to the drug. Lawyers use this drug to teach how action can be taken against negligent companies. Journalists use this drug as an example of disaster control through effective communication of research findings. A bestselling author made the story of this drug the plot of his book. For the victims, it is an ongoing nightmare that has caused untold anguish and heartbreak. For the medical communities it is turning out to be a panacea to fight AIDS, cancer, and many other diseases. Thalidomide had become popular among pregnant women as a sleep inducer and anti-emetic before its teratogenicity was discovered and it was banned. However, recent research found it effective in the treatment of diseases such as cancer. In this paper, we aim to review the havoc it created in the 1960s and the current efforts being made in using this drug for cancer treatment. Origin and growth to fame Thalidomide or α-[N-phthalmido]-glutarimide is an odorless, white crystalline compound with low solubility in water (McBride, 1977; Stirling et al., 1997; cited in Miller & Strömland, 1999). Switzerland-based CIBA synthesized it in 1953, while the former West Germany based Chemie Grünenthal synthesized it in 1954 (Rajkumar, 2004). Clinical tests on the compound revealed central nervous system depression as the most prominent pharmacological effect, and so it was introduced as a sedative–hypnotic (Schardein, 2000). Other uses found were in prevention of pregnancy-related morning sickness. Animal testing in rodents revealed it was nontoxic (Brent and Holmes, 1988; cited in Miller & Strömland, 1999). In 1957, Chemie Grünenthal, who patented the drug, introduced thalidomide with brand name Contergan as a prescription-free, over-the-counter drug (Schardein, 2000). Advertisements claimed that the drug could cure anxiety, tension, sleeplessness, and gastritis, without causing any side effects, even in pregnant women who could use it to stop morning sickness (Lenz 1988, McBride 1977; cited in Miller & Strömland, 1999). By 1960, Chemie Grünenthal and its licensees were selling the drug in 46 different countries under different brand names (Carlson, 2006) and production in Germany alone had reached 14.58 tons (Miller & Strömland, 1999). Discovery of teratogenicity As early as 1959, pediatricians in Germany started reporting cases of children born deformed. The first scientific paper bringing to light the increase in number of children with birth defects was published by a German Scientist Wiedemann in 1961 (Schardein, 2000). A couple of months later, 34 children with long-bone defects were reported at a pediatricians meeting in Dusseldorf, and Hamburg based geneticist–physician Dr. Widukind Lenz asked whether the mothers in these cases had taken some drug (Schardein, 2000). In December 1961, in two separate reports by Australian-physician Dr. McBride (McBride, 1961, cited in Rajkumar, 2004) and Dr. Lenz indicated that thalidomide is associated with these malformations (Lenz, 1962; cited in Rajkumar, 2004). Ever-increasing cases of malformed babies in mothers who took thalidomide resulted in its withdrawal from the market in West Germany, the United Kingdom, and many other countries. By then, lasting damage had already been done and thousands of children were born with malformations in arms, limbs, and reproductory organs, as well as hearing, eyesight, and behavioral problems (see Table 1). Table 1. Cases of thalidomide teratogenicity reported. Source: Briggs, Freeman &Yaffe, 2008 Country Cases Country Cases Australia 26 Mexico 4 Austria 7 Netherlands 34 Belgium 35 Norway 11 Brazil 99 Portugal 8 Canada 122 Spain 5 Denmark 20 Sweden 153 Finland 8 Switzerland 12 Ireland 51 Taiwan 36 Italy 86 UK 271 Japan 299 West Germany 3049 In the US, the Food and Drug administration (FDA) had not approved the use of thalidomide because of concerns of safety raised by an FDA physician Francis Kelsey, so the number of thalidomide associated teratogenicity were limited (Kelsey 1988; cited in Miller & Strömland, 1999). However, soon after the medical community became aware of the tragedy, the US government passed a new legislation in 1962 to regulate the pharmaceutical industry (Rajkumar, 2004). Explaining Thalidomide Teratogenicity The term teratogenicity refers to malformations in the fetus. Studies comparing period of exposure to thalidomide and the resultant fetal anomalies revealed that the drug is teratogenic 20–36 days after fertilization or 34–50 days after last menstrual period (Lenz and Knapp, 1962; cited in Miller & Strömland, 1999). The human embryonic mass embeds to the uterine wall on the seventh day of fertilization and organs are formed in the next seven weeks. It is during this time that teratogens cause harm to the fetus by affecting cell division, stopping fetal chemical signals, or by blocking supply of blood to new tissues (Carlson, 2006). Many theories exist regarding how thalidomide works. However, all scientists agree that a single dose of thalidomide during the sensitive period could harm the fetus. Research over a period of time revealed that defects include (Carlson, 2006): Malformations of limbs (including amelia or missing limbs, phocomelia or flipper-like limbs, and bone distortions), eyes, ears, and face Malformations of kidneys, bladders, intestines, and ureters Malformed or missing genitals, uterus, and oviducts Defects in heart, spine and chest structure, and central nervous system (Miller & Strömland, 1999) Mental retardation Miscarriages early in the pregnancy (Carlson, 2006) Nearly 40% of the infants died before age of one (Rajkumar, 2004) Based on the literature available, Miller & Strömland (1999) designed a timetable chart for effects of thalidomide on fetal development, as shown in Figure 1. Figure 1 Summary timetable of thalidomide embryopathy. Source: Miller & Strömland, 1999. Attempts at revival of thalidomide as a cancer cure Following reports of thalidomide teratogenicity, research began on the possibility of using it to cure cancer — a drug that could harm fetal organs that grow in a few weeks is likely to stop growth of malignant tumors too (Burley, 1962, and Rogerson, 1962; cited in Rajkumar, 2004). In the United States, studies were conducted on the use of thalidomide in fighting cancer; however, no remarkable results were achieved and the idea of using thalidomide to cure cancer was abandoned (Rajkumar, 2004). Meanwhile, other uses of thalidomide such as treatment of erythema nodosum leprosum, Behçet syndrome, graft-versus-host-disease, oral ulcers, and HIV associated wasting were discovered (Rajkumar, 2004). Following these discoveries, the US FDA approved restricted use of thalidomide for treating erythema nodosum leprosum and developed a stringent program to avoid teratogenicity due to thalidomide (Rajkumar, 2004). Cancer research on agents that stop growth of tumors by preventing generation of blood vessels in the region again sparked interest in using thalidomide. Studies on animal corneal models showed that thalidomide could stop blood vessel generation in tumors (Rajkumar, 2004). A 1997 University of Arkansas study on patients with relapsed and refractory myeloma revealed that 32% of 84 patients responded to thalidomide therapy (Singhal, et al. 1999; cited in Rajkumar, 2004). The results were confirmed by other organizations, and the drug was found to be effective in treating myeloma in the early stages (Rajkumar, 2004). Today, research is on to study the effect of thalidomide in treatment of different types of malignant tumors discovered in the early stages. Conclusion and lessons learnt Thalidomide was introduced in 1957 as a sedative-hypnotic and cure for morning sickness, but was withdrawn from the markets over evidence of teratogenicity. However, the drug has re-emerged as a treatment option for many conditions including cancer, especially in the early stages. However, the most important lesson learnt form the 1960s tragedy is the importance of safety data and tests before approving a drug for use. While the onus of investigating probable side effects of a drug is on the pharmaceutical industry, doctors have the responsibility of informing patients about any drug prescribed, and every individual should consider the possible side effects of popping a pill. It is up to the citizens, medical practitioners, and the pharmaceutical industry to avoid another such tragedy. Works Cited Brent, RL & Holmes, LB. Clinical and basic science from the thalidomide tragedy: what have we learned about the causes of limb defects? Teratology 38 (1988): 241–251. Briggs, Gerald G, Freeman, Rroger K, & Yaffe, Sumner J. Drugs in Pregnancy and Lactation: A Reference Guide to Fetal and Neonatal Risk. Baltimore: Lippincott Williams & Wilkins, 2008. Retrieved April 25, 2009 from Burley DM. Thalidomide and congenital abnormalities [letter]. Lancet. 1 (1962): 100-101. Carlson, Elof A. Times of triumph, times of doubt: science and the battle for public trust. CSHL Press, 2006. Retrieved April 26, 2009 from Kelsey, Francis O. Thalidomide update: regulatory aspects. Teratology. 38 (1988): 221–226. Lenz W. Thalidomide and congenital abnormalities [letter]. Lancet. 1 (1962): 45. Lenz, W. A short history of thalidomide embryopathy. Teratology. 38 (1988): 203–215. Lenz, W & Knapp, K. Die thalidomide-embryopathie. Dtsch Med Wochenschr 87 (1962): 1232–1242. McBride WG. Thalidomide and congenital abnormalities [letter]. Lancet. 2 (1961): 1358. McBride, WG. Thalidomide embryopathy. Teratology 16 (1977): 79–82. Miller, Marilyn T, & Strömland, Kerstin. Teratogen update: thalidomide: a review, with a focus on ocular findings and new potential uses. Teratology. 60 (1999): 306–321. Rajkumar, Vincent S. Thalidomide: Tragic Past and Promising Future. Mayo Clin Proc. 79.7 (2004): 899–903 Rogerson G. Thalidomide and congenital abnormalities [letter]. Lancet. 1 (1962): 691. Schardein, James L. Chemically induced birth defects. MA: Informa Health Care, 2000. Retrieved April 25, 2009 from < http://books.google.co.in/books?id=KZcOqBM-wVMC> Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 341 (1999): 1565-1571. Stirling, DI, Sherman, M, & Strauss, S. Thalidomide: a surprising recovery. JAm Pharmacol Assoc. NS37 (1997): 307–313. Read More