Recognition of thalidomide defects.

Smithells, R. W.; Newman, C. G. H.

doi:10.1136/jmg.29.10.716

Cited by 236 publications

(241 citation statements)

References 9 publications

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“…Thalidomide survivors can have shorter stature than average, with the shortness due to shorter leg bones, independent of vertebral defects (Brook et al, 1977; Ruffing, 1977; Newman, 1985; Smithells and Newman, 1992). …”

Section: Thalidomide Embryopathymentioning

confidence: 99%

Thalidomide‐induced teratogenesis: History and mechanisms

Vargesson

2015

Birth Defects Research Pt C

710

557

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Nearly 60 years ago thalidomide was prescribed to treat morning sickness in pregnant women. What followed was the biggest man‐made medical disaster ever, where over 10,000 children were born with a range of severe and debilitating malformations. Despite this, the drug is now used successfully to treat a range of adult conditions, including multiple myeloma and complications of leprosy. Tragically, a new generation of thalidomide damaged children has been identified in Brazil. Yet, how thalidomide caused its devastating effects in the forming embryo remains unclear. However, studies in the past few years have greatly enhanced our understanding of the molecular mechanisms the drug. This review will look at the history of the drug, and the range and type of damage the drug caused, and outline the mechanisms of action the drug uses including recent molecular advances and new findings. Some of the remaining challenges facing thalidomide biologists are also discussed. Birth Defects Research (Part C) 105:140–156, 2015. © 2015 The Authors Birth Defects Research Part C: Embryo Today: Reviews Published by Wiley Periodicals, Inc.

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Section: Thalidomide Embryopathymentioning

confidence: 99%

Thalidomide‐induced teratogenesis: History and mechanisms

Vargesson

2015

Birth Defects Research Pt C

710

557

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“…It caused an increase in miscarriage and still birth rates and a 40% increase in infant mortality, and up to 10,000 children around the world were born with severe limb malformations, as well as other much less common congenital defects (1)(2)(3)(4)(5)(6)(7). Children with such defects are still being born today, particularly in Africa and South America, where thalidomide is now increasingly used in treating leprosy (8,9).…”

mentioning

confidence: 99%

“…Children with such defects are still being born today, particularly in Africa and South America, where thalidomide is now increasingly used in treating leprosy (8,9). Over 80% of children born to mothers who took thalidomide had limb defects (2,3,5,6). These defects ranged from absence of the limb (amelia) or proximal limb elements (phocomelia) to loss of the thumb or digit tip and are induced in a small time-sensitive developmental window (2,3,(6)(7)(8).…”

mentioning

confidence: 99%

“…Over 80% of children born to mothers who took thalidomide had limb defects (2,3,5,6). These defects ranged from absence of the limb (amelia) or proximal limb elements (phocomelia) to loss of the thumb or digit tip and are induced in a small time-sensitive developmental window (2,3,(6)(7)(8). The precise mechanism underlying thalidomide's teratogenic effects, its relative limb specificity, and the range of induced defects have not been established.…”

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confidence: 99%

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Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation

Therapontos

Erskine

Gardner

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

228

319

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Thalidomide is a potent teratogen that induces a range of birth defects, most commonly of the developing limbs. The mechanisms underpinning the teratogenic effects of thalidomide are unclear. 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. These results explain both the timing and relative tissue specificity of thalidomide embryopathy and have significant implications for its use as a therapeutic agent.blood vessels ͉ chick limb development ͉ thalidomide analog ͉ angiogensis ͉ zebrafish

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“…While direct intrastriatal delivery or long-term gene transfer as illustrated above are possibilities, other inhibitors of TNF synthesis may prove useful such as the infamous antiemetic compound thalidomide. Thalidomide is a sedative, immunosuppressive and anti-inflammatory drug that has teratogenic effects (Smithells & Newman, 1992) and inhibits the synthesis of TNF- (Sampaio et al, 1991). Thalidomide was shown to protect nigrostriatal neurons and prevent striatal DA depletion in the early stages of MPTP-induced neurodegeneration (Boireau et al, 1997;Ferger et al, 2004).…”

Section: Immunomodulatory Therapiesmentioning

confidence: 99%