Thalidomide
 The most famous example of the importance of chirality in pharmaceuticals is probably also the most tragic. The pharmaceutical company Chemie Grunenthal developed the drug Thalidomide as an anti-nausea agent in 1954. Thalidomide was thought to be safe and was used widely. Doctors in Europe prescribed thalidomide to quell morning sickness in pregnant women in the late 1950s and early 1960s. It was also used as an additive in some cold and flu medications during the same period. However, Thalidomide is a chiral compound and while one of its molecular geometries possessed the desired therapeutic effect, its mirror image was tetragenic in nature, causing fetal deformities. It is projected that approximately 10,000 babies were affected, but the exact number is not known because of a high fetal and infant mortality rate associated with the drug.
The story of Thalidomide in the United States is much different. Despite heavy lobbying by the manufacturers of Thalidomide the Food and Drug Administration would not allow the drug to be sold in the US without further clinical tests. During the course of these tests the relationship between Thalidomide and birth defects was reported in Germany. So in all there were only 20 cases of birth defects caused by Thalidomide in the US. In 1962 the head of the FDA, Dr. Francis Kelsey, received the President's Award for Distinguished Federal Civilian Service for preventing a Thalidomide tragedy in the US.
It is worthy of note that the two forms of Thalidomide interconvert in the body. So even if a geometrically pure form was initially produced it would readily convert to a mixture containing both forms of the drug once taken internally.
More information about Thalidomide can be found at: www.thalidomidesociety.co.uk |
In 1985, Seldane became the first available antihistamine for treating allergies that was unlikely to cause drowsiness. At the time Seldane was known to be chiral in nature with one molecular geometry containing the antihistamine affect while the other was believed to simply be inert ballast. However, this belief proved to be false as it was discovered that the "inactive" molecular geometry of Seldane actually caused a potentially fatal heart condition in some patients. At the same time a little known company named Sepracor was developing a process for producing a geometrically pure formulation of Seldane that contained only the therapeutic form of the drug. Sepracor was eventually awarded a patent for this formulation. In 1997 this geometrically pure form was approved by the FDA and is currently marketed as Allegra. Subsequently, in 1998, the FDA forced Seldane's manufacturers (Hoescht Marion Roussel and Baker Norton Pharmaceuticals) to remove their product from the market. Sepracor currently licenses the patent for Allegra to Aventis and Allegra is considered a blockbuster drug with sales of approximately $1.2 billion worldwide.
Another example of the effects of chirallity in the pharmaceutical industry is Albuterol. Albuterol is an anti-asthmatic drug that was marketed as an equal mixture of the two possible geometrical forms under the name Proventil®. However, one of the geometrical forms was found to actually cause airway constriction, in addition to being responsible for other side effects. Once again Sepracor developed a process through which only the desirable geometrical form was produced. However, instead of licensing the technology to an established pharmaceutical company Sepracor now sells the pure form as Xopenex® and has used its success to transform itself into a full-fledged pharmaceutical producer.
