thalidomide and the thalidomide disaster are firmly riveted together in the minds of the population, and it is worth considering how such a tragedy could occur and whether a similar occurence might be repeated with another new and promising drug. Thalidomide was introduced around 1957 as a safe hypnotic and sedative. In an immediate sense it was safe, massive doses producing no acute toxicity in animals. It was considered that the drug was far safer than the barbiturates, which were at that time the commonly used hypnotic, and often used by people committing suicide. It was impossible to commit suicide using thalidomide.

The drug became popular in Germany and because of the lack of acute toxicity it became available over the counter without prescription. Around 1960 a number of cases of phocomelia (meaning ‘seal-like limbs’), in which long limb bones failed to develop, appeared in new-born babies both in Germany and Australia. It took a long time before the connection was made between thalidomide and birth defects. The reasons for this are clear in retrospect. First, only a small proportion of the population taking the drug were pregnant, and even women who were pregnant needed to take the drug between the thirty-seventh and fifty-fourth day following the last menstruation for the teratogenic effects (drug-induced fetal abnormalities) to be manifest. Finally, not all women who took the drug during the crucial period produced babies with teratogenic abnormalities. Other candidates considered to be responsible were radioactive fallout from atomic testing, X-rays, hormones, food additives, and contraceptive pills. The correlation between those taking thalidomide in the crucial period and the incidence of phocomelia became more evident, and the drug was withdrawn in 1961. It must be noted that correlation and causation are not the same, although there can now be no doubt that thalidomide was the cause.

At the time questions were asked why tests for teratogenic potential of the drug had not been made before it was released. First, the effects produced by thalidomide in pregnant women had not occurred before with other drugs and secondly, it was not easy to replicate the effects seen in humans in animal species. Altogether there were some 10 000 cases of babies with phocomelia, mostly in Europe, with some in Australia and a few in the US, of whom about 50% survived with deformed limbs, eyes, hearts, alimentary, and urinary tracts. All of these have required long term care and treatment, only partially ameliorated by the settlement made by the manufacturer. Another question asked was why there were so many cases before the cause of the teratogenic effects was identified. It was unlikely that any medical practitioner would have seen more than one case, and while the incidence of fetal abnormalities of the thalidomide type in normal pregnancy are very rare, the incidence is not zero. It was a German paediatrician who had encountered more than one case, and noted that thalidomide had been taken in all instances, who suggested the connection which was eventually verified.

While the human misery that resulted from the introduction of this seemingly harmless drug is incalculable, an important new development was introduced. To make it less likely that other, yet unknown, bizarre effects from the introduction of new drugs can ever occur on the same scale, most countries have introduced a monitoring system. In the UK, practitioners record any effect a patient reports, or signs which become obvious upon examination, together with the drugs prescribed. This data is entered immediately onto a national database. Of course, most of the reported effects will be nothing at all to do with drug treatment, but as the data will come from an entire country, or group of countries, correlations of effects with drug usage will be quickly spotted and sound the alarm before thousands of people are affected. The thalidomide story also illustrates another problem in regard to the introduction of new drugs: the public demand the unattainable — that all drugs should be perfectly safe under all conditions — but ultimate answers can be provided only by the consequences of general release.

Alan W. Cuthbert

Thalidomide

Definition

Thalidomide, which is also known as Thalomid, is a drug used to fight aggressive cancers, particularly those that have metastasized, or spread.

Purpose

There are many studies, either in progress or recently completed, that suggest thalidomide can slow or stop the spread of cancer of the brain, breast, colon and prostate, as well as multiple myeloma (a cancer of the marrow of the bone). Research studies that consider the benefit of thalidomide in treating other cancers are multiplying rapidly. The use of the drug in cancer therapy is likely to increase.

Description

Thalidomide was first introduced in 1957 primarily as a tranquilizer, a medication prescribed particularly for imparting drowsiness and sleep. Then, it was given to pregnant women to provide them with relief from morning sickness. Soon after being prescribed to pregnant women, thalidomide was linked to death or severe disabilities in newborns. Some children who had been exposed to thalidomide while in the womb (in utero) failed to develop limbs or had very short limbs. Others were born blind or deaf or with other physical problems.

The same action of thalidomide that harms babies, may make it useful as a powerful cancer fighter. Thalidomide interferes with the formation of blood vessels. It is called an antiangiogenic drug because angiogenesis refers to the formation of blood vessels.

Cancers that spread have a lot of blood vessels (are highly vascularized). Thus, when cancer cells are not nourished by a blood supply, they die. One way to stop the spread of cancer is to stop the formation of the blood vessels that carry nourishment to the cancer cells, and that is what thalidomide is thought to do. (Researchers are also interested in other activities of thalidomide, particularly the ones that make it capable of eliminating skin eruptions, such as sores, or ulcers, in the mouths of patients with AIDS and leprosy.)

Recommended dosage

Dosages being used depend on the type of cancer being attacked. For example, in one study, to treat multiple myeloma, a starting dose of 200 milligrams per day was increased to 800 milligrams per day over a two-week period.

In a colon cancer study, 400 milligrams per day of thalidomide were given in combination with the anti-cancer drug irinotecan . The dose of irinotecan was between 300 and 350 milligrams per day. Used in combination with irinotecan, thalidomide contributed its own cancer-fighting properties and it also seemed to reduce the side effects of irinotecan.

In a trial using thalidomide to treat prostate cancer , both low doses (as low as 200 milligrams per day) and high doses (as high as 1200 milligrams per day) were tried. The patients taking high doses fared somewhat better.

Precautions

The serious threat thalidomide poses to fetuses cannot be overstated. No pregnant woman and no woman who has any chance of becoming pregnant should take thalidomide. (Only women who have had a hysterectomy or who are at the age of menopause and have been in a menopausal state, which is no menses, or periods, for 24 consecutive months, can be considered as having no chance of becoming pregnant.)

Patients taking thalidomide must meet strict criteria for use. Pharmacies that dispense thalidomide must have special registration.

Side effects

Besides the extreme risk thalidomide poses to fetuses, it also produces side effects in the person taking the drug. The side effects of thalidomide are much milder than many other anticancer drugs, and because the drug poses less discomfort than other cancer-fighting drugs, it is particularly attractive to oncologists, or physicians who treat cancer patients.

Among the side effects are erratic heartbeat, swelling (edema), digestive upsets of all sorts, including both constipation and diarrhea , pain in muscles in the back and neck, and skin problems.

Interactions

Both barbiturates, salts and esters used to encourage sleep, and alcohol increase the effect of thalidomide's power of sedation. They should not be taken with the drug. Food interferes with the absorption of thalidomide, and it should be taken when the stomach is empty.

Diane M. Calabrese

KEY TERMS

Angiogenesis

—The process by which tumors gain access to a blood supply, allowing tumor growth.

Fetus

—Human embryo.

Kilogram

—Metric measure that equals 2.2 pounds.

Milligram

—One-thousandth of a gram, and there are one thousand grams in a kilogram. A gram is the metric measure that equals about 0.035 ounces.

Sedation

—Process of reducing a particularly excited or agitated state.

Thalidomide

Thalidomide is a drug that was marketed in the late 1950s and early 1960s in Great Britain and Europe . It was used both as a sleeping pill and as an antidote to morning sickness in pregnant women.

In 1962, a host of usually rare limb abnormalities suddenly became much more common. About 10,000 babies were born displaying, in particular, a shortening of the arms and/or legs called phocomelia. In phocomelia, for example, the baby may be born with the upper arm and forearm completely absent, and the hand attached to the trunk of the body by a short little bone. This same situation can occur with the legs, so that the majority of the leg is totally absent, and the foot is attached to the trunk of the body. Other babies were born with amelia, the complete absence of one or more limbs. Other birth defects involving the eyes, teeth, heart , intestine, and anus were similarly noted to be significantly more common.

These birth defects were soon traced to the drug thalidomide, which was proven to be a potent teratogen (substance which interferes with normal development in the embryo). In fact, studies showed that fully 20% of all babies exposed to thalidomide during their first eight weeks in the uterus were born with the characteristic abnormalities described above. Because the skeletal system begins to be formed as early as the third week of development, and small buds which will become the limbs appear around week five, anything which interferes with development at this very early stage has devastating effects. Once the marketing of thalidomide was halted, these birth defects again became rare occurrences.

Currently, thalidomide has been shown to have some use in the treatment of two different illnesses. In leprosy , also known as Hansen's disease, a bacterial disease causing both skin and nervous system problems, thalidomide has some effect against inflammation and pain . The FDA approved thalidomide for use in certain forms of leprosy, with very strict safeguards in place against use of the drug in pregnant women. A special program, called System for Thalidomide Education and Prescribing Safety (STEPS) approves only specified practitioners to prescribe thalidomide. Mandatory monthly pregnancy tests for all women of childbearing age taking the drug, as well as a requirement that two reliable forms of birth control be used by such women who are given thalidomide, are part of the STEPS program. Men are required to sign a statement that they will use a latex condom during all sexual encounters, even if they have previously undergone a vasectomy. Required video education, strict patient registeries, small prescription amounts (thalidomide is only to be prescribed for one month at a time), and careful monitoring are also part of the STEPS program. Studies are also underway to explore using thalidomide to help guard against immune system rejection of bone marrow transplants, ulcers and severe weight loss in AIDS , systemic lupus erythematosus, breast cancer , and Kaposi's sarcoma, multiple myeloma, kidney cancer, brain tumors, and prostate cancer.

See also Embryo and embryonic development.

Resources

books

Behrman, Richard E., et al. Nelson Textbook of Pediatrics. Philadelphia: W.B. Saunders Company, 1992.

Berkow, Robert, and Andrew J. Fletcher. The Merck Manual ofDiagnosis and Therapy. Rahway, NJ: Merck Research Laboratories, 1992.

Fanaroff, Avroy A,. and Richard J. Martin. Neonatal-PerinatalMedicine. St Louis: Mosby Year Book, Inc., 1992.

Sadler, T.W. Langman's Medical Embryology. Baltimore: Williams & Wilkins, 1985.

Sanford, Louis, and Alfred Gilman. Goodman and Gilman'sPharmacological Basis of Therapeutics. New York: Pergamon Press, Inc., 1990.

Taeusch, H. William, et al. Schaffer and Avery's Diseases of theNewborn. 6th ed. Philadelphia: W.B. Saunders Company, 1991.

Thalidomide

Resources

Thalidomide is a drug that was first marketed in the late 1950s and early 1960s in Great Britain and Europe as a sleeping pill and as an antidote to morning sickness in pregnant women. However, thalidomide is a teratogen (substance that interferes with normal development in the embryo), and use of the drug caused many birth defects, leading to it being banned from use. As of 2006, however, there was a renewed interest in thalidomide for the treatment of inflammation-related diseases such as Crohn’s disease and some cancers.

After thalidomide was introduced on the market, a host of usually rare limb abnormalities suddenly became much more common in the early 1960s. About 10,000 babies were born displaying, in particular, a shortening of the arms and/or legs called phocomelia. In phocomelia, for example, the baby may be born with the upper arm and forearm completely absent, and the hand attached to the trunk of the body by a short bone. This same situation can occur with the legs, so that the majority of the leg is totally absent, and the foot is attached to the trunk of the body. Other babies were born with amelia, the complete absence of one or more limbs. Other birth defects involving the eyes, teeth, heart, intestines, and anus were similarly noted to be significantly more common.

These birth defects were soon traced to the use of thalidomide, which was proven to be potent. In fact, studies showed that fully 20% of all babies exposed to thalidomide during their first eight weeks in the uterus were born with the characteristic abnormalities described earlier. Because the skeletal system begins to be formed as early as the third week of development, and small buds that will become the limbs appear around week five, anything that interferes with development at this very early stage has devastating effects. Once the marketing of thalidomide was halted, these birth defects again became rare occurrences.

Currently, thalidomide has been shown to have some use in the treatment of two different illnesses. In leprosy, also known as Hansen’s disease, a bacterial disease causing both skin and nervous-system problems, thalidomide has some effect against inflammation and pain. The U.S. Food and Drug Administration has approved thalidomide for use in certain forms of leprosy, with very strict safeguards in place against use of the drug in pregnant women. A special program, called System for Thalidomide Education and Prescribing Safety approves only specified practitioners to prescribe thalidomide. Monthly pregnancy tests are mandatory for all women of childbearing age taking the drug, as is a requirement that two reliable forms of birth control be used by such women who are given thalidomide. As of 2006, studies are focusing on the use of thalidomide to help guard against immune system rejection of bone marrow transplants, ulcers and severe weight loss in AIDS, systemic lupus erythematosus, breast cancer, and Kaposi’s sarcoma, multiple myeloma, kidney cancer, brain tumors, and prostate cancer.

Resources

BOOKS

Marieb, Elaine. Essentials of Human Anatomy and Physiology. New York: Prentice Hall College Division, 2005.

Stephens, Trent D., and Rock Brynner. Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine. New York: Perseus Publishing, 2001.

PERIODICALS

Moon, Mary A. “HIV-linked multiple myeloma responds to thalidomide.” Internal Medicine News. 35 (2002): 54.

thalidomide Drug originally developed as a mild hypnotic, but whose use by women in early pregnancy until the early 1960s came to be associated with serious birth deformities. It is still manufactured for occasional use in the treatment of leprosy and acquired immune deficiency syndrome (AIDS).