Biology 545 Valerie Armijo, Daniel Freeman and Monica Mendoza Thalidomide Biology 545 Valerie Armijo, Daniel Freeman and Monica Mendoza

Introduction Thalidomide is a storied and important toxin which has changed the way we research medicines. After the scandal and mass casualties and deformities there was actual change made for future generations. This presentation will give a glimpse of the change this drug has created and how, despite the adverse handling originally, was able to create some good for the world.

Thalidomide basics Words to know: Angiogenesis – The creation of new blood cells. VEGF (vascular endothelial growth factor) – The major growth factor tied to angiogenesis (causes creation of new blood vessels. Teratogen – A molecule which is transferred from mother to fetus and leads to birth defects in the child or death. Refractory – Often used to describe something that is immune to the effects of (some bacteria are refractory to certain medications meaning they are unaffected by it).

History Around 1953 the drug Thalidomide was discovered by the German pharmaceutical company Chemie Grünenthal. The drug was supposed to be a sedative for people as it was a common request. After rodent testing (as was procedure back then) the drug was released to the public as a sedative in 1956. An Australian Obstetrician then realized it could be a good morning sickness remedy after recognizing its anti-nausea effects. An important note is that drugs were not tested for possible damage to the fetus and teratogenic effects were largely unknown.

History cont. After the incident of many children being born with severe birth defects, multiple countries including the U.S. and the U.K. made stronger regulations on drug research. The FDA required the disclosure of all side effects found during animal testing. Teratogenicity was also a new focus and required information for new drug development.

New history Recently, Thalidomide has been studied and marketed for its antiangiogenic properties. Its original use as a sedative is still applicable when other medications may have failed or in very specific circumstances. These properties can be beneficial for certain cancer treatments or even leprosy as it is used today, albeit with very strict regulations.

Mechanism Although not fully known, Thalidomide has been shown to inhibit angiogenesis through VEGF in some circumstances. VEGF is the major way angiogenesis is mediated so this is thought to be how Thalidomide has its therapeutic properties.

Adverse effects Thalidomide has a wide variety of uses and effects many different bodily mechanisms and therefore has many possible negative effects. Worrisome and very common effects include: Anxiety, chest pain, cough, dizziness, fainting, fast heartbeat, muscle weakness, and troubled breathing. Very common side effects which are not very worrisome: Constipation, diarrhea, drowsiness, nausea, and stomach pain. The teratogenicity of Thalidomide is not just from mother to fetus but can also be transferred through the sperm.

Results Very rough estimates state that somewhere between 10,000 and 100,000 people were affected by thalidomide across the globe. Most of those affected were either still born or died within the first few years of life. Only a small percentage of those affected survived past the age of ten. With these deaths came multiple changes in many countries on how drugs were tested and checked before being released to the public.

Therapeutic/New uses Thalidomide has now begun to be efficaciously utilized in the treatment of both multiple myeloma and leprosy. The strong antiangiogenic effects counteract the angiogenic effects of myeloma and cause it to receive less blood so as it is easier to target. For leprosy, the drug helps by achieving a powerful sedative effect which helps those afflicted to sleep and recover better.

Discussion The fact that we are not quite sure of the actual mechanism behind Thalidomide’s antiangiogenic effects means there is still research to be done. The drug may prove useful for other specific cancers or tumor diseases, especially those refractory to other medications. It is important to find the effect of Thalidomide on VEGF receptors as this may lead to a better understanding of angiogenesis.

Summary In the late 1950’s when Thalidomide was discovered and tested, there were not stringent rules for clinical trials of drugs. Teratogens were also unknown at the time. These factors led to many unforeseen deaths but also to better understanding and more robust research guidelines. Now, after this, Thalidomide has been shown to have positive uses as long as we restrict its use by those who may become or are pregnant.

Conclusion In conclusion, Thalidomide caused much harm but eventually deepened our understanding of possible toxicities and caused some much needed change. If it weren’t for Thalidomide, some other drug would have caused other teratogenic effects and may have been worse. Because of Thalidomide, we can be assured that drugs are rigorously tested and that unborn children will be relatively safe from teratogens.

Resources Thalidomide, Wikipedia, https://en.wikipedia.org/wiki/Thalidomide, 4/10/2019 Thalidomide Side Effects, Drugs.com, https://www.drugs.com/sfx/thalidomide-side-effects.html, 4/10/2019 Calvin J. Kuo M.D. P.H.D., Overview of Angiogenesis Inhibitors, UpToDate, https://www.uptodate.com/contents/overview-of-angiogenesis- inhibitors?search=thalidomide&source=search_result&selectedTitle=3~149&usage_type=default&display_ra nk=2, 4/10/2019 Taraneh Paravar & Delphine J. Lee (2008) Thalidomide: Mechanisms of Action, International Reviews of Immunology, 27:3, 111-135, https://www-tandfonline- com.libproxy.unm.edu/doi/full/10.1080/08830180801911339 https://www.researchgate.net/figure/Tumor-angiogenesis-Notes-A-Tumor-cells-produce-veGF-A-and-other- angiogenic-factors_fig1_269332951