K12 Thalidomide

Embryology - 2 Dec 2023 Expand to Translate
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K12 Professional Development 2016

Teacher Note
50px\|left]] This is currently only a draft designed to help K12 students understand the drug thalidomide. Below are links to more detailed pages that are designed for university level students, that would also be valuable for teacher reference. These collapsible tables are additional information and the pages can also be printed out with these sections collapsed, so students do not see the contents. Note that this is currently a draft page still under development. Links: Thalidomide \| Australian Drug Categories K12 Professional Development 2016 \| K12 Professional Development 2014

What is the history of thalidomide?

Thalidomide is a drug that was introduced on to the market on October 1, 1957 in West Germany as "contergan". When taken, mainly in first world countries, early in a pregnancy children were born with limb and other defects. In the late 1950's and early 1960's these children became known as "thalidomide babies".

Originally intended to be prescribed as a general "sleeping pill", once its effects on suppressing sickness (nausea) were identified, it soon became a drug also prescribed to pregnant women to combat the symptoms associated with morning sickness.

Teacher Note
Thalidomide is the "chemical name" of the drug, and like many other drugs released today was known by doctors and patients by its "commercial\| or "trade". This commercial name can also differ between countries, even though the active chemical remains the same. Thalidomide Commercial (trade) names Germany - Contergan UK/Australia - Distaval Here is an example of another chemical drug, ibuprofen (isobutylphenylpropanoic acid) a nonsteroidal anti-inflammatory drug (NSAID) used for treating pain, fever, and inflammation. Its trade names in different countries include - Advil, Motrin, and Nurofen. Note this is not as dangerous as thalidomide, but has its own cautions as to its use.

Morning sickness

Around half to two-thirds of all pregnant women will experience nausea and vomiting of pregnancy, typically called "morning sickness". This occurs mainly in the first trimester of pregnancy (the first 3 months) due to pregnancy changes in hormone levels, blood pressure fluctuations, and changes in carbohydrate metabolism.

This feeling unwell can be ongoing (day after day) and may also be severely weakening for the woman. Some women also experience this for a longer period of time.

Therefore drugs which could "suppress" this feeling of nausea were, and still are, in high demand.

<html5media width="352" height="240">https://www.youtube.com/embed/https://youtu.be/xg3zhW-4_B0</html5media>

What does thalidomide look like?

The molecular structure of thalidomide.

Thalidomide was first synthesised in 1954 by Wilhelm Kunz, a German drug discovery pharmacist for Chemie Grünenthal, searching for new organic compounds.

C₁₃H₁₀N₂O₄

It has a small mass (Molecular Mass 258.23 Da) and appears as a white crystalline powder with no smell or taste.

The drug was manufactured as a mix of two forms that have the same chemical structure, only one of them was dangerous!

<html5media width="240" height="300">File:Thalidomide 3 model.mp4</html5media>

Teacher Note
Thalidomide two chemical format with the same molecular structure are called an "enantiomer isomer mix" (laevo+ and dextro-). Both have the physical properties, but are non-superimposable mirror images of each other and rotate plane-polarized light (+/−) by equal amounts but in the opposite directions (laevo+ and dextro-).

Who discovered the danger of this drug?

It was identified initially as dangerous by two doctors who saw serious abnormalities appearing more frequently in newborn children.


Dr Widukind Lenz	Dr William McBride
In Germany, a 1961 report by Dr Widukind Lenz described abnormalities with "Contergan".	In Australia, a brief letter by Dr William McBride, linked "Distaval" to newborn abnormalities.

Teacher Note
This is an example for students of inadequate drug testing and a lack of understanding of environmental effects on human development. This is often cited today as a reason to have significant testing of drugs before release and classification of drugs based upon their affects on development.

Why do you think that this drug affected 1000's of children in mainly first word countries?

Why did this drug affect development?

The drug generally affected the growth of blood vessels. It was also time specific in its effects.

Carnegie stage 11 23 - 26 days
Human Embryo (stage 11) dorsolateral whole embryo dorsolateral label dorsal embryo lateral embryo lateral head lateral head with overlay embryo cross-section ventrolateral head ventrolateral head with overlay ventral head buccopharyngeal membrane neural crest posterior neuropore anterior neuropore Carnegie stage 11

Carnegie stage 12 26 - 30 days
Carnegie stage 12

Carnegie stage 13
28 - 32 days

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Carnegie stage 13

Carnegie stage 14
31 - 35 days

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Carnegie stage 14

Carnegie stage 15
35 - 38 days

How do we test drugs today?

Problems associated with the historic introduction of drugs, like thalidomide, that a strict and lengthy process is required for each new drug.

Drug Testing
Typical testing of new drug compound today involves a lengthy series of animal and human studies. Animal studies Usually tested in at least two mammalian species (rats and guinea pigs) using both single and repeated doses. For determining reproductive effects, tests on both male and female animals with dosing begins 4 weeks prior to mating are conducted to determine effects on fertility in both sexes, on embryogenesis, and on fetal malformation. Human Clinical trials Following animal studies to determine dose, efficacy and apparent safety, human studies can commence. Clinical trials are carried out under very strict conditions, set by international regulatory bodies in agreement with the principles espoused in the Declaration of Helsinki. There are four phases to the trials. Phase I trials - conducted in small groups of 10 to 20 healthy young male volunteers. Designed to examine how the drug is absorbed, distributed, metabolised and excreted by the body and to establish the safe dose for phase II trials. Phase II trials - conducted in 50 to 100 patients with the disease rather than healthy volunteers as in phase I. Designed to examine what effect the drug has on the body (heart rate, blood pressure and cognitive effects) depending on the disease the drug is being developed to treat. Phase III trials - conducted in 100’s of patients (larger numbers) with a particular disease or condition and are generally randomised comparative double-blinded studies. Using a comparator of either placebo, another active drug already used, or both. Several phase III trials are usually required by the regulatory authorities. Note that even these studies may not identify uncommon adverse effects, until used widely in the community. Phase IV trials - (post-registration) conducted in 1000’s of patients over several years, these trials are randomised controlled trials undertaken after the drug has been registered. After phase I to III the pharmaceutical company compiles all study data for independent assessment by government regulatory authorities in each country: FDA in the USA, Therapeutic Goods Administration (TGA) in Australia, Medsafe in New Zealand, Medicines & Healthcare products Regulatory Agency (MHRA) in the UK, and Health Products and Food Branch (HPFB) in Canada.

Declaration of Helsinki
The Declaration of Helsinki was developed by The World Medical Association (WMA) as a statement of ethical principles for medical research involving human subjects, including research on identifiable human material and data. The Declaration is intended to be read as a whole and each of its constituent paragraphs should not be applied without consideration of all other relevant paragraphs. It is widely regarded as the cornerstone document on human research ethics. It is named after the location of its initial adoption in Helsinki, Finland, in June 1964.

How do we classify drugs?

Read the Australian Drug Categories, and then think about how would you classify thalidomide?

Australian Drug Categories
Legal drugs are classified, usually by each country's appropriate regulatory body, on the safety of drugs during pregnancy. In Australia, the Therapeutic Goods Authority has classes (A, B1, B2, B3, C, D and X) to define their safety. In the USA, drugs are classified by the Food and Drug Administration (FDA) into classes (A, B, C, D, and X) to define their safety. (More? Australian Drug Categories) Pregnancy Category A - Have been taken by a large number of pregnant women and women of childbearing age without an increase in the frequency of malformations or other direct or indirect harmful effects on the fetus having been observed. Pregnancy Category B1 - Drugs which have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have not shown evidence of an increased occurrence of fetal damage. Pregnancy Category B2 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals are inadequate or may be lacking, but available data show no evidence of an increased occurrence of fetal damage. Pregnancy Category B3 - Have been taken by only a limited number of pregnant women and women of childbearing age, without an increase in the frequency of malformation or other direct or indirect harmful effects on the human fetus having been observed. Studies in animals have shown evidence of an increased occurrence of fetal damage, the significance of which is considered uncertain in humans. Pregnancy Category C - Have caused or may be suspected of causing, harmful effects on the human fetus or neonate without causing malformations. These effects may be reversible. Pregnancy Category D - Have caused, are suspected to have caused or may be expected to cause, an increased incidence of human fetal malformations or irreversible damage. These drugs may also have adverse pharmacological effects. Pregnancy Category X - Have such a high risk of causing permanent damage to the fetus that they should NOT be used in pregnancy or when there is a possibility of pregnancy. Abnormal Development - Drugs

Is thalidomide still being used?

Lenalidomide molecular structure

(CC-5013, Revlimid) A derivative of thalidomide introduced in 2004, initially intended as a treatment for a cancer of blood plasma cells (multiple myeloma). Myeloma cells are made in the bone marrow. Each year in Australia around 1,500 people are diagnosed with myeloma.

Has also shown efficacy in the haematological disorders, myelodysplastic syndromes.

Cite this page: Hill, M.A. (2023, December 2) Embryology K12 Thalidomide. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/K12_Thalidomide

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