Abnormal Development - Thalidomide - Revision history

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	==Advisory Committee on Medicines==		==Advisory Committee on Medicines==

	* 1963 - Australian Drug Evaluation Committee (ADEC) was established in 1963 following the thalidomide experience.		* '''1963''' - Australian Drug Evaluation Committee (ADEC) was established in 1963 following the thalidomide experience.
	* 2010 - the ADEC committee was replaced by the Advisory Committee on Prescription Medicines (ACPM)		* '''2010''' - the ADEC committee was replaced by the Advisory Committee on Prescription Medicines (ACPM)
	* 2017 ACPM committee was replaced by the Advisory Committee on Medicines (ACM).		* '''2017''' - ACPM committee was replaced by the Advisory Committee on Medicines (ACM).

	:''The ACM provides independent medical and scientific advice to the Minister for Health and the Therapeutic Goods Administration (TGA) on issues relating to the safety, quality and efficacy of medicines supplied in Australia including issues relating to pre-market and post-market functions for medicines.''		:''The ACM provides independent medical and scientific advice to the Minister for Health and the Therapeutic Goods Administration (TGA) on issues relating to the safety, quality and efficacy of medicines supplied in Australia including issues relating to pre-market and post-market functions for medicines.''

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	* 2017 ACPM committee was replaced by the Advisory Committee on Medicines (ACM).		* 2017 ACPM committee was replaced by the Advisory Committee on Medicines (ACM).

			:''The ACM provides independent medical and scientific advice to the Minister for Health and the Therapeutic Goods Administration (TGA) on issues relating to the safety, quality and efficacy of medicines supplied in Australia including issues relating to pre-market and post-market functions for medicines.''

	{{Australian Drug Categories}}		{{Australian Drug Categories}}

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	Molecular Formula: C<sub>13</sub>H<sub>13</sub>N<sub>3</sub>O<sub>3</sub> Molecular Weight: 259		Molecular Formula: C<sub>13</sub>H<sub>13</sub>N<sub>3</sub>O<sub>3</sub> 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 ~~[http://www.tga.gov.au/committee/acpm.htm~~ 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 Medicines==

			* 1963 - Australian Drug Evaluation Committee (ADEC) was established in 1963 following the thalidomide experience.
			* 2010 - the ADEC committee was replaced by the Advisory Committee on Prescription Medicines (ACPM)
			* 2017 ACPM committee was replaced by the Advisory Committee on Medicines (ACM).

	~~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}}		{{Australian Drug Categories}}
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	:'''Links:''' [~~http~~://www.tga.gov.au/committee/~~acpm.htm~~ Advisory Committee on ~~Prescription~~ Medicines]		:'''Links:''' [https://www.tga.gov.au/committee/advisory-committee-medicines-acm Advisory Committee on Medicines]

	== Teratology ==		== Teratology ==
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	* [http://www.npsu.unsw.edu.au/PRERUWeb.nsf/page/CADC Australian Congenital Anomalies Monitoring System (ACAMS)]		* [http://www.npsu.unsw.edu.au/PRERUWeb.nsf/page/CADC Australian Congenital Anomalies Monitoring System (ACAMS)]
	* [http://www.thalidomide.org/default_eng.asp? The Swedish Thalidomide Society]		* [http://www.thalidomide.org/default_eng.asp? The Swedish Thalidomide Society]
			* [https://www.tga.gov.au/committee/advisory-committee-medicines-acm Australia TGA - Advisory Committee on Medicines]

	{{Glossary}}		{{Glossary}}

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	\|}		\|}
	<br>		<br>
	In Germany it is estimated that between 1957 and 1962, approximately 5000 children were born with severe birth defects due to maternal thalidomide use as a sedative and as effective relief from morning sickness.{{#pmid:30887894\|PMID30887894}}		In Germany it is estimated that between 1957 and 1962, approximately 5000 children were born with severe birth defects due to maternal thalidomide use as a sedative and as effective relief from morning sickness.{{#pmid:30887894\|PMID30887894}} A recent study by researchers of this German population, has attempted to generate reference tables of limb to body height ratios of healthy human adults for assessing potential thalidomide embryopathy.{{#pmid:30869735\|PMID30869735}}


	===Australia===		===Australia===

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	More recently there has been a clinical revival for thalidomide use in non-pregnant women, during cancer chemotherapy{{#pmid:16505120\|PMID16505120}}{{#pmid:17453375\|PMID17453375}} ~~and~~ treatment for multiple myeloma.		More recently there has been a clinical revival for thalidomide use in non-pregnant women, during cancer chemotherapy{{#pmid:16505120\|PMID16505120}}{{#pmid:17453375\|PMID17453375}}, treatment for multiple myeloma and graft rejection.{{#pmid:30877871\|PMID30877871}}.

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	\|}		\|}
	<br>		<br>
	It is estimated that between ~~the period of~~ 1957 and 1962, approximately 5000 children were born ~~in Germany~~ with severe birth defects due to maternal thalidomide as a sedative and effective relief from morning sickness.{{#pmid:30887894\|PMID30887894}}		In Germany it is estimated that between 1957 and 1962, approximately 5000 children were born with severe birth defects due to maternal thalidomide use as a sedative and as effective relief from morning sickness.{{#pmid:30887894\|PMID30887894}}

	===Australia===		===Australia===

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	\| Dr Widukind Lenz		\| Dr Widukind Lenz
	\|}		\|}
			<br>
			It is estimated that between the period of 1957 and 1962, approximately 5000 children were born in Germany with severe birth defects due to maternal thalidomide as a sedative and effective relief from morning sickness.{{#pmid:30887894\|PMID30887894}}

	===Australia===		===Australia===
	{\|		{\|

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	===USA===		===USA===

	====Helen Brooke Taussig====		====Helen Brooke Taussig====
	[[File:Helen Brooke Taussig.jpg\|thumb\|\|alt=Helen Brooke Taussig\|Helen Brooke Taussig]]		[[File:Helen Brooke Taussig.jpg\|thumb\|150px\|alt=Helen Brooke Taussig\|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.{{#pmid:13919872\|PMID13919872}} One of her students had drawn her attention to the data on congenital malformations occurring in Germany and England.		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.{{#pmid:13919872\|PMID13919872}} One of her students had drawn her attention to the data on congenital malformations occurring in Germany and England.


			:'''Links:''' [https://cfmedicine.nlm.nih.gov/physicians/biography_316.html NLM]

	====Frances Oldham Kelsey====		====Frances Oldham Kelsey====
	[[File:Frances Kelsey.jpg\|thumb\|alt=Frances Oldham Kelsey\|Frances Oldham Kelsey (1914 - 2015) receives the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy, 1962.]]		[[File:Frances Kelsey.jpg\|thumb\|150px\|alt=Frances Oldham Kelsey\|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) 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.		Frances Oldham Kelsey (1914 - 2015) 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.
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	Frances Oldham Kelsey (1914 - 2015) Food and Drug Administration officer who saved U.S. babies from thalidomide dies at 101.		Frances Oldham Kelsey (1914 - 2015) Food and Drug Administration officer who saved U.S. babies from thalidomide dies at 101.


	:'''Links:''' [http://www.nytimes.com/2015/08/08/science/frances-oldham-kelsey-fda-doctor-who-exposed-danger-of-thalidomide-dies-at-101.html?smid=nytcore-ipad-share&smprod=nytcore-ipad&_r=0 The New York Times] [http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_182.html NIH Biography]		:'''Links:''' [http://www.nytimes.com/2015/08/08/science/frances-oldham-kelsey-fda-doctor-who-exposed-danger-of-thalidomide-dies-at-101.html?smid=nytcore-ipad-share&smprod=nytcore-ipad&_r=0 The New York Times] [http://www.nlm.nih.gov/changingthefaceofmedicine/physicians/biography_182.html NIH Biography]
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	==Thalidomide External Effects==		==Thalidomide External Effects==
	Period approximately covers the developmental stages 11 to 15.		Period approximately covers the developmental stages 11 to 15.

	{{Carnegie_stage_table_1}}		{{Carnegie_stage_table_1}}

	[[File:Thalidomide external effects timeline.jpg\|600px]]		[[File:Thalidomide external effects timeline.jpg\|600px]]

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	{{Hearing Links}}		{{Hearing Links}}
	==Cereblon==		==Cereblon==
			[[File:Murine Cereblon in complex with Thalidomide.jpg\|thumb\|alt=Murine Cereblon in complex with Thalidomide\|Murine Cereblon in complex with Thalidomide]]
	Cereblon ({{CRBN}}) was named based on its possible role in '''cereb'''ral 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.		Cereblon ({{CRBN}}) was named based on its possible role in '''cereb'''ral 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.

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	* '''A new mammalian model system for thalidomide teratogenesis: Monodelphis domestica''' {{#pmid:28130151\|PMID28130151}} "From 1957 to 1962, thalidomide caused birth defects in >10,000 children. While the drug was pulled from the market, thalidomide is currently prescribed to treat conditions including leprosy. As a result, a new generation of babies with thalidomide defects is being born in the developing world. This represents a serious problem, as the mechanisms by which thalidomide disrupts development remain unresolved. This lack of resolution is due, in part, to the absence of an appropriate mammalian model for thalidomide teratogenesis. We test the hypothesis that opossum (Monodelphis domestica) is well suited to model human thalidomide defects. Results suggest that {{opossum}} embryos exposed to thalidomide display a range of phenotypes (e.g., heart, craniofacial, limb defects) and penetrance similar to humans. Furthermore, all opossums with thalidomide defects exhibit vascular disruptions. Results therefore support the hypotheses that opossums make a good mammalian model for thalidomide teratogenesis, and that thalidomide can severely disrupt angiogenesis in mammals." {{opossum}}		* '''A new mammalian model system for thalidomide teratogenesis: Monodelphis domestica''' {{#pmid:28130151\|PMID28130151}} "From 1957 to 1962, thalidomide caused birth defects in >10,000 children. While the drug was pulled from the market, thalidomide is currently prescribed to treat conditions including leprosy. As a result, a new generation of babies with thalidomide defects is being born in the developing world. This represents a serious problem, as the mechanisms by which thalidomide disrupts development remain unresolved. This lack of resolution is due, in part, to the absence of an appropriate mammalian model for thalidomide teratogenesis. We test the hypothesis that opossum (Monodelphis domestica) is well suited to model human thalidomide defects. Results suggest that {{opossum}} embryos exposed to thalidomide display a range of phenotypes (e.g., heart, craniofacial, limb defects) and penetrance similar to humans. Furthermore, all opossums with thalidomide defects exhibit vascular disruptions. Results therefore support the hypotheses that opossums make a good mammalian model for thalidomide teratogenesis, and that thalidomide can severely disrupt angiogenesis in mammals." {{opossum}}

	* '''Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity'''{{#pmid:27294876\|PMID27294876}} "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 ([[Abnormal Development - Thalidomide#CD147 (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)]

	* '''Australia - Stunning $50m legal coup for ageing thalidomide victims''' [http://www.smh.com.au/national/stunning-50m-legal-coup-for-ageing-thalidomide-victims-20100728-10vus.html 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." [[Media:SMH_July_29,_2010-Stunning_$50m_legal_coup_for_ageing_thalidomide_victims.pdf\|Article PDF]]		* '''Australia - Stunning $50m legal coup for ageing thalidomide victims''' [http://www.smh.com.au/national/stunning-50m-legal-coup-for-ageing-thalidomide-victims-20100728-10vus.html 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." [[Media:SMH_July_29,_2010-Stunning_$50m_legal_coup_for_ageing_thalidomide_victims.pdf\|Article PDF]]
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	\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}		\| [[File:Mark_Hill.jpg\|90px\|left]] {{Most_Recent_Refs}}

	Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Thalidomide+Teratology ''Thalidomide Teratology''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Thalidomide ''Thalidomide'']		Search term: [http://www.ncbi.nlm.nih.gov/pubmed/?term=Thalidomide+Teratology ''Thalidomide Teratology''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Thalidomide ''Thalidomide''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Cereblon ''Cereblon''] \| [http://www.ncbi.nlm.nih.gov/pubmed/?term=Tbx5 ''Tbx5'']

	\|}		\|}
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	# interaction disrupts the function of the E3 ubiquitin ligase complex (composed by proteins CRBN, DDB1, and Cul4)		# interaction disrupts the function of the E3 ubiquitin ligase complex (composed by proteins CRBN, DDB1, and Cul4)
	# down-regulation of fibroblast growth factor genes.		# down-regulation of fibroblast growth factor genes.


			'''Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity'''{{#pmid:27294876\|PMID27294876}} "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 ([[Abnormal Development - Thalidomide#CD147 (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)]