Abnormal Development - Thalidomide

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Introduction

Thalidomide molecular structure
Thalidomide molecular structure
Thalidomide affected Infant
Thalidomide affected Infant[1]

Thalidomide (Contergan, Distaval) is a drug that was introduced on to the market on October 1, 1957 in West Germany. Thalidomide soon became a drug prescribed to pregnant women to combat symptoms associated with morning sickness. In West Germany, thalidomide could be bought without a prescription. In the United Kingdom, thalidomide was first marketed in April, 1958 (and later withdrawn from sale in December, 1961).[2] When taken during the first trimester of pregnancy, thalidomide prevented the proper growth of the fetus resulting in horrific birth defects ("thalidomide embryopathy") in thousands of children around the world. When taken, mainly in first world countries, between day 20 to 36 after fertilisation (GA 34–50 days LMP) children were born with limb and other defects. In the late 1950's and early 1960's these children became known as "Thalidomide babies".

Dr Widukind Lenz Dr William McBride
Dr Widukind Lenz Dr William McBride
In Germany, a 1961 report by Dr Widukind Lenz described abnormalities with "Contergan".[3]

(More? Historic People)

In Australia, a brief letter by Dr William McBride, linked "Distaval" to newborn abnormalities.[4].

Not all species embryos are affected by the drug in the same way, with human and rabbit being most susceptible to the teratogenic effects. In addition, the effect on human development is also dependent upon the time and dose of the drug exposure, the "critical periods".


More recently there has been a clinical revival for thalidomide use in non-pregnant women, during cancer chemotherapy[5][6] and treatment for multiple myeloma.


Thalidomide Links: Limb Development | Limb Abnormalities | Hearing Abnormalities | Vision Abnormalities | Abnormalities | K12 Thalidomide


Environmental Links: Introduction | Low Folic Acid | Iodine Deficiency | Nutrition | Drugs | Australian Drug Categories | USA Drug Categories | Thalidomide | Herbal Drugs | Illegal Drugs | Smoking | Fetal Alcohol Syndrome | TORCH Infections | Viral Infection | Bacterial Infection | Zoonotic Infection | Toxoplasmosis | Malaria | Maternal Diabetes | Maternal Hypertension | Maternal Hyperthermia | Maternal Inflammation | Maternal Obesity | Hypoxia | Biological Toxins | Chemicals | Heavy Metals | Radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis

Some Recent Findings

Thalidomide destabilises CD147
Thalidomide destabilises CD147[7]
Frances Oldham Kelsey (1914 - 2015) receives the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy, 1962.
  • Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity[7] "Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs." [[Abnormal Development - Thalidomide#CD147 (Basigin)|CD147 (Basigin)]
  • Frances Oldham Kelsey (1914 - 2015) Food and Drug Administration officer who saved U.S. babies from thalidomide dies at 101.The New York Times NIH Biography
  • Deciphering the mystery of thalidomide teratogenicity[8] "Thalidomide was originally developed in 1954 as a sedative that was commonly used to ameliorate morning sickness. However, thalidomide exposure during the first trimester of pregnancy caused multiple birth defects (e.g. phocomelia and amelia), affecting ∼10,000 children worldwide in the late 1950s and early 1960s. Thalidomide is now recognized as a clinically effective, albeit strictly restricted, drug for the treatment of leprosy and multiple myeloma. ...Cereblon forms an E3 ubiquitin ligase complex with DDB1, Cul4A, and Roc1, which is important for the expression of fibroblast growth factor 8, an essential regulator of limb development. Expression of a drug binding-deficient mutant of cereblon suppressed thalidomide-induced effects in zebrafish and chicks. This suggests that thalidomide downregulates fibroblast growth factor 8 expression and induces limb malformation by binding to wild-type cereblon, inhibiting the function of the associated E3 ubiquitin ligase."
  • Australia - Stunning $50m legal coup for ageing thalidomide victims SMH July 29, 2010 "An 86-year-old war hero and one of Australia's leading plaintiff lawyers have negotiated a $50 million windfall payment for 45 Australian and New Zealand victims of the drug thalidomide, which caused birth defects in thousands of children around the world in the early 1960s." Article PDF
  • Identification of a primary target of thalidomide teratogenicity[9] "Here, we identified cereblon (CRBN) as a thalidomide-binding protein. CRBN forms an E3 ubiquitin ligase complex with damaged DNA binding protein 1 (DDB1) and Cul4A that is important for limb outgrowth and expression of the fibroblast growth factor Fgf8 in zebrafish and chicks. Thalidomide initiates its teratogenic effects by binding to CRBN and inhibiting the associated ubiquitin ligase activity. This study reveals a basis for thalidomide teratogenicity and may contribute to the development of new thalidomide derivatives without teratogenic activity."
  • Monkey model[10] "Cynomolgus monkeys were orally administered thalidomide at 15 or 20mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses.'
  • Thalidomide prevents angiogenic outgrowth during early limb formation.[11]"Here we demonstrate that loss of immature blood vessels is the primary cause of thalidomide-induced teratogenesis and provide an explanation for its action at the cell biological level. Antiangiogenic but not antiinflammatory metabolites/analogues of thalidomide induce chick limb defects. Both in vitro and in vivo, outgrowth and remodeling of more mature blood vessels is blocked temporarily, whereas newly formed, rapidly developing, angiogenic vessels are lost. Such vessel loss occurs upstream of changes in limb morphogenesis and gene expression and, depending on the timing of drug application, results in either embryonic death or developmental defects."
More recent papers  
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Links: References | Discussion Page | Pubmed Most Recent | Journal Searches


Search term: Thalidomide Teratology Asher Ornoy, Liza Weinstein-Fudim, Zivanit Ergaz Genetic Syndromes, Maternal Diseases and Antenatal Factors Associated with Autism Spectrum Disorders (ASD). Front Neurosci: 2016, 10;316 PubMed 27458336

A Ornoy, L Weinstein-Fudim, Z Ergaz Prenatal factors associated with Autism Spectrum Disorder (ASD). Reprod. Toxicol.: 2015; PubMed 26021712

Barbara J Hawgood Professor David Poswillo CBE (1927-2003): Skilled oral and maxillofacial surgeon, influential scientist, teacher and adviser. J Med Biogr: 2014, 22(1);47-55 PubMed 24585846

Aryn Martin, Kelly Holloway 'Something there is that doesn't love a wall': histories of the placental barrier. Stud Hist Philos Biol Biomed Sci: 2014, 47 Pt B;300-10 PubMed 24360033

Jason M Hansen, Craig Harris Redox control of teratogenesis. Reprod. Toxicol.: 2013, 35;165-79 PubMed 23089153


Search term: Thalidomide Jianyu Zhu, Degang Yang, Chao Shi, Zhichun Jing Therapeutic Dilemma of Refractory Erythema Nodosum Leprosum. Am. J. Trop. Med. Hyg.: 2017, 96(6);1362-1364 PubMed 28719256

YunShuan Li, Quan Ren, Yali Zhou, Pingping Li, Wanhua Lin, Xiaolin Yin Thalidomide has a significant effect in patients with thalassemia intermedia. Hematology: 2017;1-5 PubMed 28718348

Benjamin J J Seng, Louis L Y Teo, Laura L Chan, David K L Sim, Ka L Kerk, Jia L Soon, Teing E Tan, Cumaraswamy Sivathasan, Choon P Lim Novel use of low-dose thalidomide in refractory gastrointestinal bleeding in left ventricular assist device patients. Int J Artif Organs: 2017; PubMed 28708213

Víctor Manuel Muñoz-Pérez, Eduardo Fernández-Martínez, Héctor Ponce-Monter, Mario I Ortiz Relaxant and anti-inflammatory effect of two thalidomide analogs as PDE-4 inhibitors in pregnant rat uterus. Korean J. Physiol. Pharmacol.: 2017, 21(4);429-437 PubMed 28706457

Yan Guo, Wenwei Xu, Lin Dong, Ning Huang, Kehong Bi Progression of primary myelofibrosis to polycythemia vera: A case report. Medicine (Baltimore): 2017, 96(28);e7464 PubMed 28700486

Nausea and Vomiting of Pregnancy

Around half to two-thirds of all pregnant women will experience nausea and vomiting of pregnancy, typically called "morning sickness". Occurring mainly in the first trimester due to several possible identified causes that include; changed and high levels of hormones, blood pressure fluctuations and changes in carbohydrate metabolism. The more severe prolonged vomiting clinical form is described as hyperemesis gravidarum.


Thalidomide Physical and Chemical Properties

Thalidomide molecular structure

Thalidomide was first synthesised in 1954 by Wilhelm Kunz, a German drug discovery pharmacist for Chemie Grünenthal, searching for new organic compounds. The drug was manufactured as a two enantiomer isomer mix (laevo+ and dextro-). The teratogenic form was laevo+ thalidomide, though rabbits appear to be sensitive to both forms.


  • Molecular Mass: 258.23 Da
  • Color: white crystalline
  • Odor: Odorless
  • Taste: taste-less
  • Melting point: 271°C.
  • Insoluble in ether and benzene
  • Has a low solubility in water, methanol, ethanol and glacial acetic acid

Thalidomide- hydrolyzed metabolites.jpg

Historic 1960 Pharmacology
Pharmacological properties of thalidomide (alpha-phthalimido glutarimide), a new sedative hypnotic drug (1960)[12]
"Thalidomide (alpha-phthalimidoglutarimide, "Distaval," "Contergan") is a new sedative hypnotic drug which produces no toxic effects when administered orally to animals in massive doses. This lack of toxicity may be due to limited absorption. The drug has a quietening effect on the central nervous system, reducing the voluntary activity of laboratory animals and promoting sleep. Unlike the barbiturate drugs it does not cause an initial excitation in mice, incoordination or narcosis. It potentiates the actions of other central nervous system depressants, in particular the barbiturates. Its sedative effects are counteracted by central nervous system stimulants. It has no deleterious side effects and does not affect the heart, respiration or autonomic nervous system."

Study was carried out on mice, rats and anaesthetised cats.

Historic People

Germany

Dr Widukind Lenz Dr Widukind Lenz (1919 - 1995) was a German paediatrician who in 1961 identified the association of thalidomide ("Contergan") with birth abnormalities.[13][3][14]

Contergan tablets.jpg

Dr Lenz was physician-in-chief of the Eppendorfer Kinderklinik (1952), then chair of paediatrics at the University of Hamburg (1961), and director of the Institute of Human Genetics in Münster (1965).

Dr Widukind Lenz

Australia

Dr William McBride A brief letter by an Australian clinician, William McBride, identified "Distaval" as a teratogenic agent, linking of newborn abnormalities with the taking of thalidomide causing a "thalidomide embryopathy"[4]. Later in 1981, Dr McBride attempted to show similar teratogenic effects of a second "Debendox", resulting in a scientific case related to his falsification of data. The second drug has since been shown to not be associated with teratogenic effects.[15]
Dr William McBride

USA

Frances Kelsey Frances Kelsey was at the Food and Drug Administration, where she reviewed of a sleeping pill based on thalidomide already widely used in Europe, but Kelsey was concerned by some data suggesting dangerous side effects in patients who took the drug repeatedly. She continued to withhold drug approval for the U.S.A. leading to less cases in that country. Helen Brooke Taussig Dr Helen Brooke Taussig (1898-1986) was a paediatric cardiologist, who developed a surgical procedure for Tetralogy of Fallot, also campaigned for blocking introduction of thalidomide into the U.S.A.[16] One of her students had drawn her attention to the data on congenital malformations occurring in Germany and England.
Frances Kelsey Dr Helen Brooke Taussig

Thalidomide External Effects

Period approximately covers the developmental stages 11 to 15.

Week: 1 2 3 4 5 6 7 8
Carnegie stage: 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23

Thalidomide external effects timeline.jpg

Thalidomide external effects timeline[17]


Carnegie stage 11 
23 - 26 days

Carnegie stage 11

Carnegie stage 12 
26 - 30 days

Carnegie stage 12

Carnegie stage 13 
28 - 32 days
Stage 13 - Left Ventrolateral View

Stage13 bf4.jpg

 ‎‎Mobile | Desktop | Original

Stage 13 | Embryo Slides

Carnegie stage 13

Carnegie stage 14 
31 - 35 days
Stage 14 - Lateral View

Stage14 bf18.jpg

 ‎‎Mobile | Desktop | Original

Stage 14 | Embryo Slides

Carnegie stage 14

Carnegie stage 15
35 - 38 days

Stage15 bf3.jpg Stage15 bf4.jpg Stage15 bf5.jpg Stage15 bf6.jpg

Limb development after the sensitive period

Stage16-17-limbs01.jpg Stage20-23 limbs b.jpg
Human embryonic limb development (week 6) Human embryonic limb development (week 8)

Limb Reduction

Thalidomide affected Infant
Thalidomide affected Infant limbs[1]
limb structure

Congenital limb reduction.jpg Congenital limb reduction xray.jpg

Text extract below from [18], note that all timings are using the clinical dates of Last Menstrual Period (LMP, GA), which differ by about 14 days more to the developmental date from fertilization.

"It has been suggested that thalidomide does not produce malformations if only taken before the 34th day after the last menstruation (LMP) and usually no malformation if taken only after the 50th day.

Within the sensitive period from day 35 to day 49, there is the following sequence:

35th - 37th day Absence of the ears and deafness
39th - 41st day Absence of arms
43rd - 44th day Phocomelia with three fingers
46th - 48th day Thumbs with three joints

If thalidomide was taken throughout the sensitive period, the consequence may be severe defects of ears, arms and legs and of internal malformations, which often led to early death. About 40% of thalidomide victims died before their first birthday."

These are W. Lenz's historic observations and relate to easily identifiable features.

Hip Dislocation

Congenital dislocation hip.jpg
Also called Developmental Dysplasia of the Hip (information below relates to this condition in general)
  • Normal data - Instability: 1:60 at birth; 1:240 at 1 wk: Dislocation untreated; 1:700
  • congenital instability of hip, later dislocates by muscle pulls or gravity
  • familial predisposition female predominance
  • Growth of femoral head, acetabulum and innominate bone are delayed until the femoral head fits firmly into the acetabulum

Microphthalmia

Microphthalmia.jpg

Microphthalmia clinical image[19]

A clinical description for the presence of a small eye located within the orbit. This condition occurs in up to 11% of blind children.
Links: Anophthalmia and microphthalmia | Anophthalmia | Microphthalmia | Sensory - Vision Abnormalities

Hearing Abnormalities

Hearing loss associated with abnormalities of the inner ear development (otic placode origin) and external ear reduction or deformation (pharyngeal arch origin).


Pharyngeal Arch Development (external ear, stages 14-23 and adult)
External ear stages-14-23-adult.jpg
Pharyngeal Arch Hillock Auricle Component
Arch 1 1 tragus
2 helix
3 cymba concha
Arch 2 4 concha
5 antihelix
6 antitragus
Adult hearing embryonic origins.jpg

Adult hearing embryonic origins

Microtia.jpg

External Ear - Microtia

Newborn hearing test.jpg

Newborn hearing test

Hearing Links: Introduction | Science Lecture | Medicine Lecture | Inner Ear | Middle Ear | Outer Ear | Balance | Hearing - Neural Pathway | Stage 22 | Abnormalities | Neonatal Diagnosis - Hearing | Hearing test | Sensory Introduction | Placodes | Student project | Category:Hearing
Historic Embryology 
Historic Embryology: 1902 Development of Hearing | 1906 Membranous Labyrinth | 1913 Tectorial Membrane | 1918 Human Embryo Otic Capsule | 1918 Cochlea | 1918 Grays Anatomy | 1922 Human Auricle | 1922 Otic Primordia | 1931 Internal Ear Scalae | 1933 Endolymphatic Sac | 1934 Otic Vesicle | 1934 Membranous Labyrinth | 1963 Human Otocyst | Historic Disclaimer

Cereblon Binding

Cereblon (CRBN) was named based on its possible role in cerebral development and the presence of a Lon protease domain. Functionally it had been previously identified as being associated with neural development. Thalidomide specifically binds cereblon, which inhibits the ubiquitin ligase activity of the SCF protein ligase complex, possibly leading to abnormal regulation of the BMP and FGF8 signaling pathways. The SCF complex (Skp, Cullin, F-box containing complex) is a multi-protein E3 ubiquitin ligase complex catalyzing the ubiquitination of proteins destined for proteasomal degradation.

  1. thalidomide binds to CRBN at specific sites.
  2. interaction disrupts the function of the E3 ubiquitin ligase complex (composed by proteins CRBN, DDB1, and Cul4)
  3. down-regulation of fibroblast growth factor genes.


Links: OMIM - Cereblon | UniProt - CRBN

Mouse Neural Cereblon Expression

The following table is from a study of the levels of cereblon messenger RNA (mRNA) in different regions of the adult mouse brain.[20]

Arbitrary signal strength detected by in situ hybridisation from low (+) to high (+++++).

Sortable table
Region Intensity
Infralimbic cortex ++++
Cingulate cortex ++++
Other neocortex; layer V ++++
Other neocortex; other layers +++
Piriform cortex ++++
Accumbens nucleus ++
Caudate putamen ++
Lateral globus pallidus +
Pyramidal layer of the hippocampus +++++
Granular layer of dentate gyrus +++++
Habenular nucleus ++++
Paraventricular hypothalamic nucleus +++
Thalamus ++ ∼ +++
Substantia nigra compacta +++
Red nucleus, magnocellular part ++++
Raphe nuclei +++ ∼ ++++
Trigeminal nucleus +++++
Reticulotegmental nucleus of the pons ++++
Parvicellular reticular nucleus +++
Gigantocellular reticular nucleus ++++
Purkinje layer of the cerebellum +++++
Granular layer of the cerebellum ++++

Signaling Pathway

Two possible mechanisms:[9]

  1. cereblon dependent process
  2. cereblon independent process (producing reactive oxygen species)[21]

Thalidomide shown to:

  • inhibits production of some cytokines (tumor necrosis factor–alpha and vascular endothelial growth factor)
  • inducing apoptosis and producing reactive oxygen species
  • fgf8 is a downstream target


CD147 (Basigin)

Thalidomide destabilises CD147
Thalidomide destabilises CD147[7]

(basigin, BSG, CD147, EMMPRIN) Basigin is a member of the immunoglobulin (Ig) superfamily, with a structure related to the putative primordial form of the family. CD147 has recently been shown[22] to be one of the downstream targets of the cereblon singling pathway and down-regulation can cause similar teratogenic effects in a Zebrafish model.

See also the recent Basigin review[23] "Basigin has isoforms; the common form (basigin or basigin-2) has two immunoglobulin domains, and the extended form (basigin-1) has three. Basigin is the receptor for cyclophilins, S100A9 and platelet glycoprotein VI, whereas basigin-1 serves as the receptor for the rod-derived cone viability factor. Basigin tightly associates with monocarboxylate transporters and is essential for their cell surface translocation and activities. In the same membrane plane, basigin also associates with other proteins including GLUT1, CD44 and CD98."


Model for tumorigenic effect of CD147 action on CD98

Model for tumorigenic effect of CD147 action on CD98[24]

General model for basigin promotes the membrane localization of CD98 and activation of β1-integrin. Basigin could facilitate the membrane localization of newly synthesized CD98 in the ER (blue arrow). Prototypical CIE cargo proteins enter cells through Arf6-positive endocytic vesicles that either fuse with or mature into Rab5a-positive early endosomes (sorting endosomes), where internalized proteins converge and are sorted for recycling (green arrow) or degradation (red arrow). Basigin and CD98 are internalized by a pathway associated with flotillin-1 and the small G protein Arf6. Thereafter, basigin and CD98 could recycle back to the membrane through the fast recycling pathway (green arrow A) mediated by hook1, Rab22a, microtubules and their own cytoplasmic sequences. Other internalized proteins, including integrins, could recycle through the slow recycling pathway (green arrow B). By promoting the membrane redistribution or translocation of CD98, basigin activates β1 integrins and plays a critical role in liver cancer progression.


Links: OMIM - Basigin


Vascular Effect

This recent study[11] has used a chicken limb model system and treatment with a chemical, CPS49 a tetrafluorinated analogue of thalidomide that is chemically and structurally related to thalidomide breakdown products.

Thalidomide - limb signaling.jpg Thalidomide - CPS49 vascular effect.jpg
Chicken limb development signaling[11] Thalidomide - CPS49 vascular effect on chicken model[11]

The researchers identified an antiangiogenic activity, inhibition of blood vessel growth, of CPS49 within the developing limb and in a number of in vitro tissue culture models of vascular growth. The vessel loss was described as the "primary trigger" leading to an increased cell death and impairment in limb signaling pathways, resulting consequently in both limb outgrowth failure and limb truncations. The possibility that fibroblast growth factor levels are altered, may also fit in with the specific thalidomide binding to cereblon.

Primate Model

Cynomolgus monkey

Crab-eating Macaque (Macaca fascicularis, Cynomolgus Monkey, Philippine Monkey, Long-tailed Macaque)[10] "Cynomolgus monkeys were orally administered thalidomide at 15 or 20mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses."


Thalidomide Metabolism in Different Species

Thalidomide hydrolyzed metabolites[25]

It also appears that not all species metabolise thalidomide the same, shown in a study comparing the metabolic breakdown products in mice and man:[26]

"Our results show that thalidomide metabolite profiles in multiple myeloma patients differ considerably from those in mice. The lack of measurable hydroxylated metabolites in urine and in 1 case plasma of these patients suggests that such metabolites are not responsible for the therapeutic effects of thalidomide in multiple myeloma."

Lenalidomide

Lenalidomide molecular structure

(CC-5013, Revlimid) A derivative of thalidomide introduced in 2004, initially intended as a treatment for multiple myeloma. Has also shown efficacy in the hematological disorders, myelodysplastic syndromes. Each year in Australia around 1,500 people are diagnosed with myeloma. Thalidomide can be used in the initial treatment of myeloma and also to control myeloma that has come back (relapsed).

Molecular Formula: C13H13N3O3 Molecular Weight: 259

Australia - Advisory Committee on Prescription Medicines

The Australian Drug Evaluation Committee (ADEC) was established in 1963 following the thalidomide experience and in 2010 this committee was replaced by the Advisory Committee on Prescription Medicines (ACPM). The new ACPM advises and makes recommendations to the Therapeutic Goods Administration (TGA) on prescription medicines listed on the Australian Register of Therapeutic Goods (ARTG), established under the Therapeutic Goods Act 1989. There were approximately 54,000 products on the Australian Register of Therapeutic Goods as at 23 May 2008.

Advisory Committee on Prescription Medicines

  • inclusion of a prescription medicine on the Australian Register of Therapeutic Goods (the Register)
  • changes to an entry of a prescription medicine on the Register
  • removal or retention of a prescription medicine on the Register
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

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.

Regulatory Authorities: 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.


Links: Advisory Committee on Prescription Medicines

Teratology

Now consider how different environmental effects during pregnancy may influence developmental outcomes. The terms listed below are often used to describe these environmental effects

  • Teratogen (Greek, teraton = monster) any agent that causes a structural abnormality (congenital abnormalities) following fetal exposure during pregnancy. The overall effect depends on dosage and time of exposure. (More? Critical Periods of Development)
  • Absolute risk the rate of occurrence of an abnormal phenotype among individuals exposed to the agent. (e.g. fetal alcohol syndrome)
  • Relative risk the ratio of the rate of the condition among the exposed and the nonexposed. (e.g. smokers risk of having a low birth weight baby compared to non-smokers) A high relative risk may indicate a low absolute risk if the condition is rare.
  • Mutagen a chemical or agent that can cause permanent damage to the deoxyribonucleic acid (DNA) in a cell. DNA damage in the human egg or sperm may lead to reduced fertility, spontaneous abortion (miscarriage), birth defects and heritable diseases.
  • Fetotoxicant is a chemical that adversely affects the developing fetus, resulting in low birth weight, symptoms of poisoning at birth or stillbirth (fetus dies before it is born).
  • Synergism when the combined effect of exposure to more than one chemical at one time, or to a chemical in combination with other hazards (heat, radiation, infection) results in effects of such exposure to be greater than the sum of the individual effects of each hazard by itself.
  • Toxicogenomics the interaction between the genome, chemicals in the environment, and disease. Cells exposed to a stress, drug or toxicant respond by altering the pattern of expression of genes within their chromosomes. Based on new genetic and microarray technologies.

References

  1. 1.0 1.1 L GILLIS Thalidomide babies: management of limb defects. Br Med J: 1962, 2(5305);647-51 PubMed 13898662
  2. I M LECK, E L MILLAR Incidence of malformations since the introduction of thalidomide. Br Med J: 1962, 2(5296);16-20 PubMed 14463369
  3. 3.0 3.1 W LENZ, K KNAPP Thalidomide embryopathy. Arch. Environ. Health: 1962, 5;100-5 PubMed 14464040
  4. 4.0 4.1 W G McBride Thalidomide embryopathy. Teratology: 1977, 16(1);79-82 PubMed 331548
  5. Pui-Kai Li, Bulbul Pandit, Dan L Sackett, Zhigen Hu, Jennifer Zink, Jiandong Zhi, Dena Freeman, Robert W Robey, Karl Werbovetz, Andrew Lewis, Chenglong Li A thalidomide analogue with in vitro antiproliferative, antimitotic, and microtubule-stabilizing activities. Mol. Cancer Ther.: 2006, 5(2);450-6 PubMed 16505120
  6. Benjamin Chuah, Robert Lim, Michael Boyer, Ai-Bee Ong, Seng-Weng Wong, Hwai-Loong Kong, Michael Millward, Stephen Clarke, Boon-Cher Goh Multi-centre phase II trial of Thalidomide in the treatment of unresectable hepatocellular carcinoma. Acta Oncol: 2007, 46(2);234-8 PubMed 17453375
  7. 7.0 7.1 7.2 Ruth Eichner, Michael Heider, Vanesa Fernández-Sáiz, Frauke van Bebber, Anne-Kathrin Garz, Simone Lemeer, Martina Rudelius, Bianca-Sabrina Targosz, Laura Jacobs, Anna-Maria Knorn, Jolanta Slawska, Uwe Platzbecker, Ulrich Germing, Christian Langer, Stefan Knop, Herrmann Einsele, Christian Peschel, Christian Haass, Ulrich Keller, Bettina Schmid, Katharina S Götze, Bernhard Kuster, Florian Bassermann Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat. Med.: 2016; PubMed 27294876
  8. Takumi Ito, Hiroshi Handa Deciphering the mystery of thalidomide teratogenicity. Congenit Anom (Kyoto): 2012, 52(1);1-7 PubMed 22348778
  9. 9.0 9.1 Takumi Ito, Hideki Ando, Takayuki Suzuki, Toshihiko Ogura, Kentaro Hotta, Yoshimasa Imamura, Yuki Yamaguchi, Hiroshi Handa Identification of a primary target of thalidomide teratogenicity. Science: 2010, 327(5971);1345-50 PubMed 20223979
  10. 10.0 10.1 Makoto Ema, Ryota Ise, Hirohito Kato, Satoru Oneda, Akihiko Hirose, Mutsuko Hirata-Koizumi, Amar V Singh, Thomas B Knudsen, Toshio Ihara Fetal malformations and early embryonic gene expression response in cynomolgus monkeys maternally exposed to thalidomide. Reprod. Toxicol.: 2010, 29(1);49-56 PubMed 19751816
  11. 11.0 11.1 11.2 11.3 Christina Therapontos, Lynda Erskine, Erin R Gardner, William D Figg, Neil Vargesson Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation. Proc. Natl. Acad. Sci. U.S.A.: 2009, 106(21);8573-8 PubMed 19433787
  12. G F SOMERS Pharmacological properties of thalidomide (alpha-phthalimido glutarimide), a new sedative hypnotic drug. Br J Pharmacol Chemother: 1960, 15;111-6 PubMed 13832739
  13. W LENZ, K KNAPP [Thalidomide embryopathy]. Dtsch. Med. Wochenschr.: 1962, 87;1232-42 PubMed 14464041
  14. W Lenz Thalidomide embryopathy in Germany, 1959-1961. Prog. Clin. Biol. Res.: 1985, 163C;77-83 PubMed 3991661
  15. D M Fleming, J D Knox, D L Crombie Debendox in early pregnancy and fetal malformation. Br Med J (Clin Res Ed): 1981, 283(6284);99-101 PubMed 6789952
  16. H B TAUSSIG The thalidomide syndrome. Sci. Am.: 1962, 207;29-35 PubMed 13919872
  17. Neil Vargesson Thalidomide-induced teratogenesis: History and mechanisms. Birth Defects Res. C Embryo Today: 2015; PubMed 26043938
  18. W. Lenz The History of Thalidomide a lecture given at the 1992 UNITH Congress.
  19. Amit S Verma, David R Fitzpatrick Anophthalmia and microphthalmia. Orphanet J Rare Dis: 2007, 2;47 PubMed 18039390 | Orphanet Journal of Rare Diseases
  20. Miho Aizawa, Yuichi Abe, Takumi Ito, Hiroshi Handa, Hiroyuki Nawa mRNA distribution of the thalidomide binding protein cereblon in adult mouse brain. Neurosci. Res.: 2011, 69(4);343-7 PubMed 21241746
  21. Jürgen Knobloch, Ulrich Rüther Shedding light on an old mystery: thalidomide suppresses survival pathways to induce limb defects. Cell Cycle: 2008, 7(9);1121-7 PubMed 18418038
  22. Ruth Eichner, Michael Heider, Vanesa Fernández-Sáiz, Frauke van Bebber, Anne-Kathrin Garz, Simone Lemeer, Martina Rudelius, Bianca-Sabrina Targosz, Laura Jacobs, Anna-Maria Knorn, Jolanta Slawska, Uwe Platzbecker, Ulrich Germing, Christian Langer, Stefan Knop, Herrmann Einsele, Christian Peschel, Christian Haass, Ulrich Keller, Bettina Schmid, Katharina S Götze, Bernhard Kuster, Florian Bassermann Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity. Nat. Med.: 2016; PubMed 27294876
  23. Takashi Muramatsu Basigin (CD147), a multifunctional transmembrane glycoprotein with various binding partners. J. Biochem.: 2016, 159(5);481-90 PubMed 26684586
  24. Bo Wu, Yi Wang, Xiang-Min Yang, Bao-Qing Xu, Fei Feng, Bin Wang, Qiang Liang, Yu Li, Yang Zhou, Jian-Li Jiang, Zhi-Nan Chen Basigin-mediated redistribution of CD98 promotes cell spreading and tumorigenicity in hepatocellular carcinoma. J. Exp. Clin. Cancer Res.: 2015, 34;110 PubMed 26437640
  25. Takanori Nakamura, Tomomi Noguchi, Hiroyuki Miyachi, Yuichi Hashimoto Hydrolyzed metabolites of thalidomide: synthesis and TNF-alpha production-inhibitory activity. Chem. Pharm. Bull.: 2007, 55(4);651-4 PubMed 17409565 | Chem Pharm Bull (Tokyo).PDF
  26. Jun Lu, Brian D Palmer, Phillip Kestell, Peter Browett, Bruce C Baguley, George Muller, Lai-Ming Ching Thalidomide metabolites in mice and patients with multiple myeloma. Clin. Cancer Res.: 2003, 9(5);1680-8 PubMed 12738721

Reviews

Neil Vargesson Thalidomide-induced teratogenesis: History and mechanisms. Birth Defects Res. C Embryo Today: 2015; PubMed 26043938

Neil Vargesson Thalidomide-induced limb defects: resolving a 50-year-old puzzle. Bioessays: 2009, 31(12);1327-36 PubMed 19921660

J N Gordon, P M Goggin Thalidomide and its derivatives: emerging from the wilderness. Postgrad Med J: 2003, 79(929);127-32 PubMed 12697909

E J Saunders, J A Saunders Drug therapy in pregnancy: the lessons of diethylstilbestrol, thalidomide, and bendectin. Health Care Women Int: 1990, 11(4);423-32 PubMed 2228814

T D Stephens Proposed mechanisms of action in thalidomide embryopathy. Teratology: 1988, 38(3);229-39 PubMed 3067416

C G Newman The thalidomide syndrome: risks of exposure and spectrum of malformations. Clin Perinatol: 1986, 13(3);555-73 PubMed 3533365

I Fletcher Review of the treatment of thalidomide children with limb defeciency in Great Britain. Clin. Orthop. Relat. Res.: 1980, (148);18-25 PubMed 6991189


Articles

Mercédes Benegbi 45 years later...where do we stand? Can J Clin Pharmacol: 2007, 14(1);e37-9 PubMed 17213509

"The Thalidomide Victims Association of Canada (TVAC) was founded in 1988 and is the only organization in North America to work with and for Thalidomide victims. Our mission is to empower our members and to improve their quality of life through various programs and customized services. With the return of Thalidomide on the market, TVAC also took on the mandate of informing the public on the devastating effects of this medication and to promote awareness and caution when using any teratogenic products currently available". H SAUNDERS, R WRIGHT, K HODGKIN Thalidomide and congenital deformities. Br Med J: 1962, 2(5307);796 PubMed 14497528

I M LECK, E L MILLAR Incidence of malformations since the introduction of thalidomide. Br Med J: 1962, 2(5296);16-20 PubMed 14463369

W G McBride Prescription drugs in the first trimester and congenital malformations. Aust N Z J Obstet Gynaecol: 1992, 32(4);386 PubMed 1290446


Books on Thalidomide

A selection of recent general public information books on Thalidomide, available from various internet commercial suppliers (search using the book title). Please note that this listing does not reflect an endorsement of the book or its content and is provided for educational purposes only.

  • Thalidomide Kid (Paperback) by Kate, Rigby (Author)
  • Thalidomide - A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References (Paperback) by ICON Health Publications (Author) Internet supplier link: Amazon

Search Pubmed

June 2010 "thalidomide teratogenicity" All (147) Review (57) Free Full Text (11)


Search Pubmed: thalidomide teratogenicity | Thalidomide | McBride WG |

External Links

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Cite this page: Hill, M.A. 2017 Embryology Abnormal Development - Thalidomide. Retrieved July 22, 2017, from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Thalidomide

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