Thalidomide

Question 1

What was the purpose of thalidomide in the late 1950s

Answer 1

Treat nausea in pregnant women

Question 2

Symptoms of phocomelia syndrome

Answer 2

Limb reduction abnormalities
Malformations of the inner and outer ears - hearing impairment
Ocular abnormalities
Kidney malformations
Gastrointestinal deformities
Autism
Mental retardation
Death (30-40%)

Question 3

Problems with thalidomide testing

Answer 3

Tested in rodent models - only 1
no pregnancy tests done
Modes of action

Question 4

Thalidomide problems - window of exposure

Answer 4

Women were taking it at different stages in their pregnancies - differing effects
Sensitive period (20-34 days after fertilisation)
- Upper limb (day 24-32)
- External ear (day 20-24)

Question 5

How does Thalidomide act?

Answer 5

Oxidative stress
Formation of ROS
Reduction in glutathione levels
Oxidative DNA damage
Cell death
Anti-agiogenesis
Inhibits blood vessel formation - crucial for limb development
Interferes with FGF signalling

Question 6

Importance of thalidomide in toxicology? Why was it a fundamental time point in history?

Answer 6

thalidomide drove the change in toxicology and the way drug safety was measurement due to its effects
Changed the OECD guidelines

Question 7

What did the thalidomide episode highlight?

Answer 7

• before thalidomide it was believed the placenta was an almost impenetrable barrier
• the need for systematic testing of pharmaceutics and other chemical for developmental toxicity.
• that differences in sensitivity between species must be taken into account

Question 8

What is a teratogen?

Answer 8

an agent that causes congenital malformations or defects

Question 9

What is a congenital malformation?

Answer 9

refers to anatomical abnormalities present at birth

Question 10

Define taratogenesis

Answer 10

the formation of an abnormal embryo

Question 11

Important. characteristics of teratogens

Answer 11

during first 2 weeks of gestations, teratogens usually kill the embryo
Organs most vulnerable during embryonic stage
Each organ has a critical period of vulnerability

Question 12

What are the causes of CD in humans?

Answer 12

Infectious agents
Radiation
Chemical or pharmacological
Chromosomal and genetic factors

Question 13

Modes of action of teratogens

Answer 13

Interferes with nucleic acids
Deficiency of energy supply inhibition of enzymes
Inhibition of growth factor signalling cascades
Oxidative stress

Question 14

Testing for teratogens

Answer 14

OECD guideline 414 - prenatal development toxicity study

• prenatal exposure
• preferentially 2 species
• number of animals - minimum 20 pregnant females
• treatment with test chemical from implantation to the expected day of delivery
• one control and at least 3 dose levels