Abnormal Development - Thalidomide: Difference between revisions

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| Pharmacological properties of thalidomide (alpha-phthalimido glutarimide), a new sedative hypnotic drug (1960)<ref name="PMID13832739"><pubmed>13832739</pubmed></ref>  
| Pharmacological properties of thalidomide (alpha-phthalimido glutarimide), a new sedative hypnotic drug (1960)<ref name="PMID13832739"><pubmed>13832739</pubmed></ref>  
:"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."
:"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==
==Historic People==

Revision as of 10:45, 7 April 2016

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Introduction

Thalidomide molecular structure

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. 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".[1]

(More? Historic People)

In Australia, a brief letter by Dr William McBride, linked "Distaval" to newborn abnormalities.[2].

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[3][4] 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 | viral infection | bacterial infection | fungal infection | zoonotic infection | toxoplasmosis | Malaria | maternal diabetes | maternal hypertension | maternal hyperthermia | Maternal Inflammation | Maternal Obesity | hypoxia | biological toxins | chemicals | heavy metals | air pollution | radiation | Prenatal Diagnosis | Neonatal Diagnosis | International Classification of Diseases | Fetal Origins Hypothesis

Some Recent Findings

Frances Oldham Kelsey (1914 - 2015) receives the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy, 1962.
  • 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[5] "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[6] "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[7] "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.[8]"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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Search term: Thalidomide Teratology <pubmed limit=5>Thalidomide Teratology</pubmed>

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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)[9]
"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.[10][1][11]

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"[2]. 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.[12]
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. 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[13]


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

limb structure

Congenital limb reduction.jpg Congenital limb reduction xray.jpg

Text extract below from [14], 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[15]

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 | inner ear | middle ear | outer ear | balance | placode | hearing neural | Science Lecture | Lecture Movie | Medicine Lecture | Stage 22 | hearing abnormalities | hearing test | sensory | Student project

  Categories: Hearing | Outer Ear | Middle Ear | Inner Ear | Balance

Historic Embryology - Hearing 
Historic Embryology: 1880 Platypus cochlea | 1892 Vertebrate Ear | 1902 Development of Hearing | 1906 Membranous Labyrinth | 1910 Auditory Nerve | 1913 Tectorial Membrane | 1918 Human Embryo Otic Capsule | 1918 Cochlea | 1918 Grays Anatomy | 1922 Human Auricle | 1922 Otic Primordia | 1931 Internal Ear Scalae | 1932 Otic Capsule 1 | 1933 Otic Capsule 2 | 1936 Otic Capsule 3 | 1933 Endolymphatic Sac | 1934 Otic Vesicle | 1934 Membranous Labyrinth | 1934 External Ear | 1938 Stapes - 7 to 21 weeks | 1938 Stapes - Term to Adult | 1940 Stapes | 1942 Stapes - Embryo 6.7 to 50 mm | 1943 Stapes - Fetus 75 to 150 mm | 1946 Aquaductus cochleae and periotic (perilymphatic) duct | 1946 aquaeductus cochleae | 1948 Fissula ante fenestram | 1948 Stapes - Fetus 160 mm to term | 1959 Auditory Ossicles | 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.[16]

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:[6]

  1. cereblon dependent process
  2. cereblon independent process (producing reactive oxygen species)[17]

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

Vascular Effect

This recent study[8] 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[8] Thalidomide - CPS49 vascular effect on chicken model[8]

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)[7] "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[18]

It also appears that not all species metabolise thalidomide the same, shown in a study comparing the metabolic breakdown products in mice and man:[19]

"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


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 <pubmed>14464040</pubmed>
  2. 2.0 2.1 <pubmed>331548</pubmed>
  3. <pubmed>16505120</pubmed>
  4. <pubmed>17453375</pubmed>
  5. <pubmed>22348778</pubmed>
  6. 6.0 6.1 <pubmed>20223979 </pubmed>
  7. 7.0 7.1 <pubmed>19751816</pubmed>
  8. 8.0 8.1 8.2 8.3 <pubmed>19433787</pubmed>
  9. <pubmed>13832739</pubmed>
  10. <pubmed>14464041</pubmed>
  11. <pubmed>3991661</pubmed>
  12. <pubmed>6789952</pubmed>
  13. <pubmed>26043938</pubmed>
  14. W. Lenz The History of Thalidomide a lecture given at the 1992 UNITH Congress.
  15. <pubmed>18039390</pubmed>| Orphanet Journal of Rare Diseases
  16. <pubmed>21241746</pubmed>
  17. <pubmed>18418038</pubmed>
  18. <pubmed>17409565</pubmed>| Chem Pharm Bull (Tokyo).PDF
  19. <pubmed>12738721</pubmed>

Reviews

<pubmed>26043938</pubmed> <pubmed>19921660</pubmed> <pubmed>12697909</pubmed> <pubmed>2228814</pubmed> <pubmed>3067416</pubmed> <pubmed>3533365</pubmed> <pubmed>6991189</pubmed>

Articles

<pubmed>17213509</pubmed>"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".

<pubmed>1290446</pubmed>

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. (2024, March 28) Embryology Abnormal Development - Thalidomide. Retrieved from https://embryology.med.unsw.edu.au/embryology/index.php/Abnormal_Development_-_Thalidomide

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© Dr Mark Hill 2024, UNSW Embryology ISBN: 978 0 7334 2609 4 - UNSW CRICOS Provider Code No. 00098G