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{{Short description|Immunomodulatory drug known for its ability to cause birth defects}}
{{About|the drug|the musical about a person with thalidomide disability|Thalidomide!! A Musical}}
{{About|the drug|the thalidomide scandal and birth defect crisis|Thalidomide scandal}}
{{drugbox | verifiedrevid = 418982755
{{Use dmy dates|date=October 2022}}
| drug_name = Thalidomide
{{cs1 config|name-list-style=vanc|display-authors=6}}
| IUPAC_name = (''RS'')-2-(2,6-dioxopiperidin-3-yl)-1''H''-isoindole-1,3(2''H'')-dione
{{infobox drug
| image = Thalidomide-2D-skeletal-wavy.svg
| Verifiedfields = changed
| imagename = 1 : 1 mixture (racemate)
| Watchedfields = changed
| width = 200px
| verifiedrevid = 420478187
| CASNo_Ref = {{cascite|correct|CAS}}
| image = Thalidomide enantiomers.svg
| width = 200
| alt =
| caption =
| chirality = Racemic mixture

<!-- Clinical data -->
| pronounce = {{IPAc-en|θ|ə|ˈ|l|ɪ|d|ə|m|aɪ|d}}<ref>{{OED|Thalidomide}}</ref>
| tradename = Contergan, Thalomid, others
| Drugs.com = {{drugs.com|monograph|thalidomide}}
| MedlinePlus = a699032
| licence_EU = yes
| DailyMedID = Thalidomide
| licence_US = Thalidomide
| pregnancy_AU = X
| pregnancy_category =
| routes_of_administration = ]
| class =
| ATC_prefix = L04
| ATC_suffix = AX02
| ATC_supplemental =

<!-- Legal status -->
| legal_AU = S4
| legal_AU_comment =
| legal_BR = C3<!-- OTC, A1, A2, A3, B1, B2, C1, C2, C3, C4, C5, D1, D2, E, F -->
| legal_BR_comment =
| legal_CA = Rx-only
| legal_CA_comment =
| legal_DE = <!-- Anlage I, II, III or Unscheduled -->
| legal_DE_comment =
| legal_NZ = <!-- Class A, B, C -->
| legal_NZ_comment =
| legal_UK = POM
| legal_UK_comment =
| legal_US = Rx-only
| legal_US_comment = <ref name="Thalomid FDA label">{{cite web | title=Thalomid- thalidomide capsule | website=DailyMed | date=11 March 2021 | url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2eda833b-1357-4ed4-a093-194524fcb061 | access-date=21 October 2022 | archive-date=21 October 2022 | archive-url=https://web.archive.org/web/20221021205855/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2eda833b-1357-4ed4-a093-194524fcb061 | url-status=live }}</ref>
| legal_EU = Rx-only
| legal_EU_comment = <ref>{{cite web | title=Thalidomide BMS EPAR | website=European Medicines Agency | date=17 September 2018 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-celgene | access-date=21 October 2022 | archive-date=21 October 2022 | archive-url=https://web.archive.org/web/20221021205855/https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-celgene | url-status=live }}</ref><ref>{{cite web | title=Thalidomide Lipomed EPAR | website=European Medicines Agency | date=18 July 2022 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-lipomed | access-date=21 October 2022 | archive-date=21 October 2022 | archive-url=https://web.archive.org/web/20221021205902/https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-lipomed | url-status=live }}</ref>
| legal_UN = <!-- N I, II, III, IV / P I, II, III, IV -->
| legal_UN_comment =
| legal_status = <!-- For countries not listed above -->

<!-- Pharmacokinetic data -->
| bioavailability = 90%
| protein_bound = 55% and 66% for the (''R'')-(+)- and (''S'')-(−)-enantiomers, respectively<ref name = clinp>{{cite journal | vauthors = Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL | title = Clinical pharmacokinetics of thalidomide | journal = Clinical Pharmacokinetics | volume = 43 | issue = 5 | pages = 311–27 | year = 2004 | pmid = 15080764 | doi = 10.2165/00003088-200443050-00004 | s2cid = 37728304 }}</ref>
| metabolism = ] (minimally via ]-mediated 5-hydroxylation; mostly via non-enzymatic hydrolysis at the four amide sites)<ref name = clinp/>
| elimination_half-life = 5–7.5 hours (dose-dependent)<ref name = clinp/>
| excretion = Urine, feces and semen<ref name = clinp/>

<!-- Identifiers -->
| CAS_number_Ref = {{cascite|correct|??}}
| CAS_number = 50-35-1
| PubChem = 5426
| IUPHAR_ligand = 7327
| DrugBank_Ref = {{drugbankcite|correct|drugbank}}
| DrugBank = DB01041
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| ChemSpiderID = 5233
| UNII_Ref = {{fdacite|correct|FDA}} | UNII_Ref = {{fdacite|correct|FDA}}
| UNII = 4Z8R6ORS6L | UNII = 4Z8R6ORS6L
| KEGG_Ref = {{keggcite|correct|kegg}}
| InChI = 1/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)
| KEGG = D00754
| InChIKey = UEJJHQNACJXSKW-UHFFFAOYAZ
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 9513
| ChEMBL_Ref = {{ebicite|correct|EBI}} | ChEMBL_Ref = {{ebicite|correct|EBI}}
| ChEMBL = 468 | ChEMBL = 468
| NIAID_ChemDB =
| PDB_ligand =
| synonyms = α-Phthalimidoglutarimide

<!-- Chemical and physical data -->
| C=13 | H=10 | N=2 | O=4
| SMILES =
O=C1c2ccccc2C(=O)N1C3CCC(=O)NC3=O
| StdInChI_Ref = {{stdinchicite|correct|chemspider}} | StdInChI_Ref = {{stdinchicite|correct|chemspider}}
| StdInChI = 1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17) | StdInChI = 1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)
| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}} | StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}
| StdInChIKey = UEJJHQNACJXSKW-UHFFFAOYSA-N | StdInChIKey = UEJJHQNACJXSKW-UHFFFAOYSA-N
| density =
| CAS_number = 50-35-1
| density_notes =
| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}
| melting_point =
| ChemSpiderID = 5233
| melting_high =
| ATC_prefix = L04
| melting_notes =
| ATC_suffix = AX02
| ATC_supplemental = | boiling_point =
| boiling_notes =
| PubChem = 5426
| solubility =
| DrugBank = DB01041
| sol_units =
| KEGG_Ref = {{keggcite|correct|kegg}}
| specific_rotation =
| KEGG = D00754
| smiles = c1ccc2c(c1)C(=O)N(C2=O)C3CCC(=O)NC3=O
| C=13 | H=10 | N=2 | O=4
| molecular_weight = 258.23 g/mol
| bioavailability =
| protein_bound = 55% and 66% for the (+)-''R'' and (–)-''S'' enantiomers, respectively
| metabolism = Hepatic (])<ref>{{cite journal
| author = Ando Y, Fuse E, Figg WD
| title = Thalidomide metabolism by the CYP2C subfamily
| journal = Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
| volume = 8
| issue = 6
| pages = 1964–73
| pmid = 12060642
| url = http://clincancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=12060642
| accessdate = 2009-06-18
| date = June 1, 2002 }}</ref>
| elimination_half-life = mean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses
| excretion =
| pregnancy_AU = X
| pregnancy_US = X
| pregnancy_category =
| legal_AU = <!-- Unscheduled / S2 / S4 / S8 -->
| legal_UK = <!-- GSL / P / POM / CD -->
| legal_US = <!-- Rx-only -->
| legal_status = Rx-only
| routes_of_administration = oral
}} }}
'''Thalidomide''' ({{pron-en|θəˈlɪdəmaɪd}}) was introduced as a ] drug in the late 1950s. In 1961, it was withdrawn due to ] and ]. There is now a growing clinical interest in thalidomide, and it is introduced as an immunomodulatory agent used primarily, combined with ], to treat ]. The drug is a potent teratogen in ], ]s,<ref>Ito, T., Ando, H., Suzuki, T., Ogura, T., Hotta, K., Imamura, Y., Yamaguchi, Y. and Handa, H. (2010). Identification of a Primary Target of Thalidomide Teratogenicity. Science 327, 1345-1350.</ref> ]s and ]s including humans: severe birth defects may result if the drug is taken during pregnancy.<ref></ref>


<!-- Definition and medical uses -->
Thalidomide was sold in a number of countries across the world from 1957 until 1961 when it was withdrawn from the market after being found to be a cause of birth defects in what has been called "one of the biggest medical tragedies of modern times".<ref>{{cite web|url=http://www.bbc.co.uk/science/horizon/2004/thalidomide.shtml|title=Thalidomide - A Second Chance? - programme summary|last=Anon|publisher=BBC|accessdate=2009-05-01}}</ref> It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000.<ref name="Born freak">{{cite web |url= http://www.channel4.com/life/microsites/B/bornfreak/birthday.html
'''Thalidomide''', sold under the brand names '''Contergan''' and '''Thalomid''' among others, is an ] medication used to treat a number of cancers (e.g., ]), ], and many ]s (e.g., complications of ] such as ]s).<ref name=AHFS>{{cite web |title=Thalidomide Monograph for Professionals |url=https://www.drugs.com/monograph/thalidomide.html |website=Drugs.com|date=7 April 2023}} Updated as required.</ref><ref name="pubchem">{{cite web |title=Thalidomide {{!}} C13H10N2O4 |id=CID 5426 |url=https://pubchem.ncbi.nlm.nih.gov/compound/Thalidomide |website=PubChem |publisher=], ] |access-date=13 February 2023 |archive-date=13 February 2023 |archive-url=https://web.archive.org/web/20230213133343/https://pubchem.ncbi.nlm.nih.gov/compound/Thalidomide |url-status=live }}</ref> Thalidomide has been used to treat conditions associated with ]: ], HIV-associated ], diarrhea, and ], but increases in HIV viral load have been reported.<ref name=AHFS/>
| title=Born Freak | last=Anon | work=Happy Birthday Thalidomide
| publisher=Channel 4 | accessdate=2009-05-01
}}</ref>
Since then thalidomide has been found to be a valuable treatment for a number of medical conditions and it is being prescribed again in a number of countries, although its use remains controversial, including its testing in the developing world.<ref>{{cite web
| title=Prudence and the Pill: Testing Thalidomide in the Global South
| url=http://www.biopoliticaltimes.org/article.php?id=5504
| last=Washington, Harriet A. | date=January 14, 2011
}}</ref><ref>{{cite web
| url=http://www.healthyforms.com/health-news/2006/03/thalidomide-controversial-treatment.php | date=March 10, 2006
| title=Thalidomide:controversial treatment for multiple myeloma
| last=Anon | work=Health news|accessdate=2009-05-01\
}} {{Dead link|date=September 2010|bot=H3llBot}}</ref><ref>{{cite news
| url= http://www.timesonline.co.uk/tol/news/uk/scotland/article695193.ece?token=null&offset=0&page=1
| title=Can thalidomide ever be trusted? | last=Bowditch
| first=Gillian | date=March 26, 2006 | work=The Sunday Times
| publisher=News International Limited | accessdate=2009-05-01
| location=London}}</ref> The thalidomide tragedy led to much stricter testing being required for drugs and pesticides before they can be licensed.<ref name="The chemical industry">{{cite book
| last=Heaton | first=C. A. | title=The Chemical Industry
| publisher=Springer | year=1994 |pages=40 | isbn=0751400181
}}</ref>


<!-- Side effects and mechanism -->
==History==
Common side effects include ], ], and ].<ref name=AHFS/> Severe side effects include ], ], and ].<ref name=BNF76>{{cite book|title=British national formulary: BNF 76|date=2018|publisher=Pharmaceutical Press|isbn=9780857113382|pages=936|edition=76}}</ref> Thalidomide is a known human ] and carries an extremely high risk of severe, life-threatening birth defects if administered or taken during pregnancy.<ref name="AHFS" /> It causes skeletal deformities such as ] (absence of legs and/or arms), absence of bones, and ] (malformation of the limbs). A single dose of thalidomide, regardless of dosage, is enough to cause ] effects.<ref name=AHFS/>
===Development===
Thalidomide was developed by German pharmaceutical company ] in ] near ], although this claim has recently been challenged. A report published by Martin W. Johnson, director of the Thalidomide Trust in the United Kingdom, mentioned evidence found by Argentinian author Carlos De Napoli that suggested the drug had been first developed as a possible antidote to nerve toxins, such as ], by Otto Ambros, a ] scientist who joined Grünenthal after the war. Correspondence between various drug companies, French firm ], which was under Nazi control during the war years, ], which held the Swedish licence to distribute thalidomide, and ], the German pharmaceutical firm, seem to confirm the existence of the product years before Grünenthal secured a patent in 1954. Furthermore, a relation has been suggested between testing thalidomide and the Nazi ].
Grünenthal has reacted to these claims by stating: “To our knowledge there was no collaboration between Grünenthal and Rhône-Poulenc for the development of Contergan/thalidomide. Three Grünenthal employees discovered thalidomide and Grünenthal is the sole inventor on the patent.” According to Grünenthal, Dr. Heinrich Mückter was one of those responsible for inventing Thalidomide. Other sources mark Dr. Mückter as a fledgling pharmacologist who carried out wartime experiments on Polish prisoners to find a cure for typhus. He caused the death of hundreds in the process.
<ref>{{cite news
| title = Thalidomide 'was created by the Nazis'
| first = Daniel
| last = Foggo
| url = http://www.timesonline.co.uk/tol/life_and_style/health/article5683577.ece
| publisher = The Times
| location = London
| date = 2009-02-08
| accessdate = 2009-06-18
}}
</ref>


<!-- Early history -->
De Napoli suggested elsewhere that thalidomide may have been first ] by British scientists at the ] in 1949.<ref>{{cite news|url=http://www.timesonline.co.uk/tol/life_and_style/health/article6832320.ece|title=Thalidomide victim Gary Syner to go on hunger strike|last=Foggo|first=Daniel|date=13 September 2009|work=The Sunday Times|publisher=Times Newspapers Ltd.|accessdate=2009-09-28 | location=London}}</ref>
Thalidomide was first marketed in 1957 in West Germany, where it was available ].<ref name=OUP2003>{{cite book | title = The Oxford Companion to the Body | vauthors = Cuthbert A | year = 2003 | publisher = Oxford University Press | url = https://archive.org/details/oxfordcompaniont0000unse_z0k4/page/682 | doi = 10.1093/acref/9780198524038.001.0001 | isbn = 9780198524038 | url-access = registration | page = }}</ref><ref name=Mill1991/> When first released, thalidomide was promoted for ], ], "tension", and ].<ref name=Mill1991>{{cite journal | vauthors = Miller MT | title = Thalidomide embryopathy: a model for the study of congenital incomitant horizontal strabismus | journal = Transactions of the American Ophthalmological Society | volume = 89 | pages = 623–74 | year = 1991 | pmid = 1808819 | pmc = 1298636 }}</ref><ref name=Lou2004>{{cite book | vauthors = Loue S, Sajatovic M |title=Encyclopedia of Women's Health |date=2004 |publisher=Springer Science & Business Media |isbn=9780306480737 |page=644 |url=https://books.google.com/books?id=LbHWgd-mDbsC&pg=PA644 |language=en |access-date=25 August 2020 |archive-date=15 November 2021 |archive-url=https://web.archive.org/web/20211115114232/https://books.google.com/books?id=LbHWgd-mDbsC&pg=PA644 |url-status=live }}</ref> While it was initially thought to be safe in pregnancy, ] arose, resulting in its removal from the market in Europe in 1961.<ref name=OUP2003/><ref name=Mill1991/> The total number of infants severely harmed by thalidomide use during pregnancy is estimated at over 10,000, possibly 20,000, of whom about 40% died around the time of birth.<ref name=AHFS/><ref name=Mill1991/> Those who survived had limb, eye, urinary tract, and heart problems.<ref name=OUP2003/> Its initial entry into the US market was prevented by ], a reviewer at the FDA.<ref name=Lou2004/> The birth defects caused by thalidomide led to the development of greater ] and monitoring in many countries.<ref name=OUP2003/><ref name=Lou2004/>
Thalidomide, launched by Grünenthal on 1 October 1957,<ref name="Bombay">{{cite journal|last=Moghe|first=Vijay V|coauthors=Ujjwala Kulkarni, Urvashi I Parmar|year=2008|title=Thalidomide|journal=Bombay Hospital Journal|publisher=Bombay Hospital |location=Bombay|volume=50|issue=3|pages=446|url=http://www.bhj.org/journal/2008_5003_july/download/page-472-476.pdf|format=PDF|accessdate=25 October 2009}}</ref> was found to act as an effective tranquiliser and painkiller and was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches. It was also found to be an effective ] which had an inhibitory effect on ], and so thousands of pregnant women took the drug to relieve their symptoms.<ref name="Born freak" /> At the time of the drug's development it was thought unlikely that any drug could pass from the mother across the ] and harm the developing ].<ref name="The chemical industry"/>


<!-- Current use -->
===Birth defects===
It was approved in the United States in 1998 for use as a treatment for cancer.<ref name=AHFS/> It is on the ].<ref name="WHO22nd">{{cite book | title = Model list of essential medicines: 22nd list| year = 2021 | hdl = 10665/345533| publisher = ] | location = Geneva | id = WHO/MHP/HPS/EML/2021.02 | hdl-access=free | vauthors = Organization WH }}</ref> It is available as a ].<ref name=BNF76/><ref>{{cite web | title=First Generic Drug Approvals | website=U.S. ]| date=30 May 2023 | url=https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-url=https://web.archive.org/web/20230630003621/https://www.fda.gov/drugs/drug-and-biologic-approval-and-ind-activity-reports/first-generic-drug-approvals | archive-date=30 June 2023 | url-status=live | access-date=30 June 2023}}</ref>
]
In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with ] such as ], as a consequence of thalidomide use.<ref name="Bren">{{cite news | first =Linda | last =Bren | author = | coauthors = | title =Frances Oldham Kelsey: FDA Medical Reviewer Leaves Her Mark on History | url =http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2001/201_kelsey.html | work =FDA Consumer | publisher =US ] | date =2001-02-28 | accessdate =2009-12-23 }}</ref> The Australian obstetrician ] and the German ] ] suspected a link between birth defects and the drug, and this was proved by Lenz in 1961.<ref>{{cite web|url=http://www.whonamedit.com/doctor.cfm/1002.html|title=Widukind Lenz|last=Anon|work=who name it?|publisher= Ole Daniel Enersen|accessdate=2009-05-01}}</ref><ref name="40 years on">{{cite news|url=http://news.bbc.co.uk/1/hi/uk/2031459.stm|title=Thalidomide:40 years on|last=Anon|work=BBC news|publisher=BBC|accessdate=2009-05-01 | date=2002-06-07}}</ref> McBride was later awarded a number of honours including a medal and prize money by the prestigious L'Institut de la Vie in Paris.<ref> See also main ] article.</ref>


{{TOC limit}}
In the United Kingdom the drug was licensed in 1958 and, of the approximately 2000 babies born with defects, 466 survived.<ref>{{cite news|url=http://news.bbc.co.uk/1/hi/health/8458855.stm|title=Apology for thalidomide survivors|date=14 January 2010|work=BBC News:Health|publisher=BBC News|accessdate=2010-01-14}}</ref> The drug was withdrawn in 1961 and in 1968, after a long campaign by '']'' newspaper, a compensation settlement for the UK victims was reached with ].<ref name="they didn't know">{{cite news|url=http://news.bbc.co.uk/1/hi/health/3589173.stm|title=They just didn't know what it would do|last=Ryan|first=Caroline|date=1 April 2004|work=BBC News:Health|publisher=BBC news|accessdate=2009-05-01}}</ref><ref>{{cite news|url=http://www.timesonline.co.uk/tol/life_and_style/health/article3602694.ece|title=Thalidomide: the battle for compensation goes on|last=Flintoff|first=John-Paul|date=March 23, 2008|work=The Sunday Times|publisher=Times Newspapers Ltd.|accessdate=2009-05-01 | location=London}}</ref> In Germany approximately 2,500 thalidomide babies were born.<ref name="40 years on"/> In some extreme cases, it could kill the patient if there were other diseases or drugs in the body.


==Medical uses==
] receives an award from President ] for blocking sale of thalidomide in the United States]]
]
The impact in the United States was minimized when ] and ] ] refused ] approval for an application from the ] company to market thalidomide, saying further studies were needed. And although thalidomide was never approved for sale in the United States, millions of tablets had been distributed to physicians during a clinical testing program. It was impossible to know how many pregnant women had been given the drug to help alleviate morning sickness or as a sedative.<ref>{{cite web|url=http://www.birthdefects.org/research/bendectin_1.php|title=How a Commonly Used Drug Caused Birth Defects|last=Mekdeci|first=Betty}}</ref>


Thalidomide is used as a first-line treatment for ] in combination with ] or with ] and ] to treat acute episodes of ], as well as for maintenance therapy.<ref name=UKlabel2017>{{cite web |title=Thalidomide Celgene 50 mg Hard Capsules - Summary of Product Characteristics |url=https://www.medicines.org.uk/emc/medicine/21005 |publisher=UK Electronic Medicines Compendium |access-date=26 June 2017 |date=January 2017 |archive-date=30 August 2018 |archive-url=https://web.archive.org/web/20180830210156/https://www.medicines.org.uk/emc/medicine/21005 |url-status=live }}</ref><ref name=USlabel2017>{{cite web |title=US Thalomid label |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020785s061lbl.pdf |publisher=FDA |date=January 2017 |access-date=26 June 2017 |archive-date=10 July 2017 |archive-url=https://web.archive.org/web/20170710160759/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020785s061lbl.pdf |url-status=live }} For label updates see {{cite web | url = https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020785 | title = FDA index page for NDA 020785 | archive-url = https://web.archive.org/web/20170629110300/https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&ApplNo=020785 | archive-date=29 June 2017 }}</ref>
Canada was the last country to stop the sales of the drug, in early 1962.<ref>{{cite web|url=http://www.history.ca/ontv/titledetails.aspx?titleid=21267|title=Turning Points of History - Prescription for Disaster|publisher=History Television|accessdate=24 February 2010}}</ref>


The bacterium that causes ] (TB) is related to ]. Thalidomide may be helpful in some cases where ] and ]s are not sufficient to resolve severe inflammation in the brain.<ref>{{cite journal | vauthors = Buonsenso D, Serranti D, Valentini P | title = Management of central nervous system tuberculosis in children: light and shade | journal = European Review for Medical and Pharmacological Sciences | volume = 14 | issue = 10 | pages = 845–53 | date = October 2010 | pmid = 21222370 | url = http://www.europeanreview.org/wp/wp-content/uploads/827.pdf | archive-url = https://web.archive.org/web/20160818223324/http://www.europeanreview.org/wp/wp-content/uploads/827.pdf | archive-date = 18 August 2016 }}</ref><ref>{{cite journal | vauthors = van Toorn R, Solomons R | title = Update on the diagnosis and management of tuberculous meningitis in children | journal = Seminars in Pediatric Neurology | volume = 21 | issue = 1 | pages = 12–8 | date = March 2014 | pmid = 24655399 | doi = 10.1016/j.spen.2014.01.006 }}</ref>
In 1962, the ] enacted laws requiring tests for safety during pregnancy before a drug can receive approval for sale in the U.S.<ref name =Burkholz>{{cite news | first =Herbert | last =Burkholz | title = Giving Thalidomide a Second Chance | url =http://www.fda.gov/fdac/features/1997/697_thal.html | work =FDA Consumer | publisher =US ] | date =1997-09-01 | accessdate =2006-09-21 }}</ref> Other countries enacted similar legislation, and thalidomide was not prescribed or sold for decades.


It is used as a second-line treatment to manage ] and ] in children and has been prescribed for other conditions in children, including ] and ]; the evidence for these uses is weak.<ref>{{cite journal | vauthors = Yang CS, Kim C, Antaya RJ | title = Review of thalidomide use in the pediatric population | journal = Journal of the American Academy of Dermatology | volume = 72 | issue = 4 | pages = 703–11 | date = April 2015 | pmid = 25617013 | doi = 10.1016/j.jaad.2015.01.002 }}</ref> It is recommended only as a third line treatment in graft-versus-host-disease in adults because of lack of efficacy and side effects observed in clinical trials.<ref>{{cite journal | vauthors = Wolff D, Gerbitz A, Ayuk F, Kiani A, Hildebrandt GC, Vogelsang GB, Elad S, Lawitschka A, Socie G, Pavletic SZ, Holler E, Greinix H | title = Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD | journal = Biology of Blood and Marrow Transplantation | volume = 16 | issue = 12 | pages = 1611–28 | date = December 2010 | pmid = 20601036 | doi = 10.1016/j.bbmt.2010.06.015 | url = http://www.bbmt.org/article/S1083-8791(10)00275-2/fulltext | doi-access = free | access-date = 26 June 2017 | archive-date = 29 August 2021 | archive-url = https://web.archive.org/web/20210829083423/https://www.astctjournal.org/article/S1083-8791%2810%2900275-2/fulltext | url-status = live }}</ref><ref>{{cite journal | vauthors = Wolff D, Schleuning M, von Harsdorf S, Bacher U, Gerbitz A, Stadler M, Ayuk F, Kiani A, Schwerdtfeger R, Vogelsang GB, Kobbe G, Gramatzki M, Lawitschka A, Mohty M, Pavletic SZ, Greinix H, Holler E | title = Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease | journal = Biology of Blood and Marrow Transplantation | volume = 17 | issue = 1 | pages = 1–17 | date = January 2011 | pmid = 20685255 | doi = 10.1016/j.bbmt.2010.05.011 | url = http://www.bbmt.org/article/S1083-8791(10)00223-5/fulltext | doi-access = free | access-date = 26 June 2017 | archive-date = 29 August 2021 | archive-url = https://web.archive.org/web/20210829083352/https://www.astctjournal.org/article/S1083-8791%2810%2900223-5/fulltext | url-status = live }}</ref>
September 2010, as noted in an article titled "The Public’s Quiet Savior From Harmful Medicine", the FDA honored Dr. Kelsey with the first Kelsey award. It will be given to an FDA staff member annually. The award came 50 years after Dr. Kelsey, then a new medical officer at the agency, first reviewed the application from the William S. Merrell Company of Cincinnati.<ref>{{cite web|url=http://www.nytimes.com/2010/09/14/health/14kelsey.html?_r=1&8dpc|title=The Public’s Quiet Savior From Harmful Medicines|date=September 13, 2010|work=The New York Times}}</ref>


==Contraindications==
===Mechanism===
Prescriptions of thalidomide are accompanied by strict measures to avoid any possibility of use during pregnancy, and thalidomide should be avoided in women wanting to conceive.<ref name="bermas2019a">{{cite journal | vauthors = Bermas BL | title = Paternal safety of anti-rheumatic medications | journal = Best Practice & Research. Clinical Obstetrics & Gynaecology | volume = 64 | pages = 77–84 | date = April 2020 | pmid = 31727565 | doi = 10.1016/j.bpobgyn.2019.09.004 | s2cid = 208034967 }}</ref> In the United States, the prescribing doctor is required to ensure that ] is being used and that regular pregnancy tests are taken.<ref name=USlabel2017/><ref name=UKlabel2017/>
It was soon discovered that only one particular ] of thalidomide caused the teratogenicity. The pair of ], while mirror images of each other, cause different effects,<ref>{{cite book
| author = Eccles H; Ratcliff B
| title = Chemistry 2
| publisher = Cambridge University Press
| year = 2001
| pages = 170
| isbn = 978-0-521-79882-2
}}</ref> although it is now known that the "safe" isomer can be converted to the teratogenic isomer once in the human body.<ref name="40 years on"/><ref>{{cite web|url=http://www.chm.bris.ac.uk/motm/thalidomide/optical2iso.html|title=Optical Isomerism In Thalidomide|last=Ligham|first=Alex|month=April | year=2000|work=Thalidomide|accessdate=2009-05-02}}</ref>(see ]).


===Revived interest=== ==Adverse effects==
{{See also|List of thalidomide side effects}}
In 1964 ], Professor at the ] at Hadassah University Hospital (he was also the chief staff and manager of Hansen Leper Hospital in Jerusalem), administered thalidomide to a critically ill patient with ], a painful complication of ], in an attempt to relieve his pain in spite of the ban. The patient slept for hours, and was able to get out of bed without aid upon awakening. The result was followed by more favorable experiences and then by a clinical trial.<ref name =Silverman>{{cite journal |last= Silverman, MD |first= William |authorlink= |coauthors= |date= 2002-04-22|title=The Schizophrenic Career of a "Monster Drug" |journal=Pediatrics |volume= 110 |issue= 2 |pages= 404–406 |id= |url=http://pediatrics.aappublications.org/cgi/content/full/110/2/404 |accessdate= 2006-09-21|doi=10.1542/peds.110.2.404|pmid=12165600 }}</ref> He found that patients with ] leprosum, a painful skin condition, experienced relief of their pain by taking thalidomide.
Thalidomide ].<ref name=UKlabel2017/><ref name=USlabel2017/><ref name=toxmech2009>{{cite journal | vauthors = Smith SW | title = Chiral toxicology: it's the same thing...only different | journal = Toxicological Sciences | volume = 110 | issue = 1 | pages = 4–30 | date = July 2009 | pmid = 19414517 | doi = 10.1093/toxsci/kfp097 | doi-access = free }}</ref><ref>Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, p3</ref> The U.S. ] (FDA) and other regulatory agencies have approved marketing of the drug only with an auditable ] that ensures that people using the drug are aware of the risks and avoid pregnancy; this applies to both men and women, as the drug can be transmitted in ].<ref name=toxmech2009/>{{Failed verification|date=September 2022|reason=source does not appear to say drug is transmitted in semen}}<ref name="bermas2019a"/>


There is a high risk that thalidomide can cause excessive ]. There is also a high risk that thalidomide can interfere with the production of several types of new blood cells, creating a risk of infection via ], ], and ], and risks that blood will not clot via ]. There is also a risk of ] via lack of red blood cells. The drug can also damage nerves, causing potentially irreversible ].<ref name=UKlabel2017/><ref name=USlabel2017/>
Further work conducted in 1991 by Dr. Gilla Kaplan at Rockefeller University in New York City showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha and believed it would be an effective treatment for AIDS. Kaplan partnered with Celgene Corporation to further develop the potential for thalidomide in AIDS and tuberculosis. However, clinical trials for AIDS proved disappointing.


Thalidomide has several adverse cardiovascular effects, including risk of ]s, ], and changes in heart rhythm, such as ], ], and ].<ref name=UKlabel2017/><ref name=USlabel2017/>
In 1994, Dr. Robert D'Amato at Harvard Medical School discovered that thalidomide was a potent inhibitor of new blood vessel growth (known as angiogenesis). Numerous cancer clinical trials were initiated with thalidomide based upon this finding and subsequently in 1997 Dr. Bart Barlogie’s reported thalidomide’s initial effectiveness against ] and it was later approved in the United States by the FDA for use in this ]. The FDA has also approved the drug's use in the treatment of ] leprosum. There are studies underway to determine the drug's effects on ] and several types of ]s. However, ] and patients alike must go through a special process to prescribe and receive thalidomide (S.T.E.P.S.) to ensure no more children are born with birth defects traceable to the medication. Celgene Corporation has also developed analogues to thalidomide, such as ], that are substantially more powerful and have fewer side effects&nbsp;— except for greater ].<ref>{{cite journal
| author = Rao KV
| title = Lenalidomide in the treatment of multiple myeloma
| journal = American Journal of Health-system Pharmacy : AJHP : Official Journal of the American Society of Health-System Pharmacists
| volume = 64
| issue = 17
| pages = 1799–807
| year = 2007
| month = September
| pmid = 17724360
| doi = 10.2146/ajhp070029
| accessdate = 2009-06-18
}}</ref>


Thalidomide can cause ] and severe skin reactions like ]. It tends to make people sleepy, which creates risk when driving and operating other machinery. As it kills cancer cells, it can cause ]. Thalidomide can ].<ref name=UKlabel2017/><ref name=USlabel2017/>
More recently the ] has stated that:


In addition, very common (reported in more than 10% of people) adverse effects include ], dizziness, tingling, numbness, constipation, and ].<ref name=UKlabel2017/><ref name=USlabel2017/>
<blockquote>


Common adverse effects (reported by 1–10% of people) include confusion, depressed mood, reduced coordination, heart failure, difficulty breathing, interstitial lung disease, lung inflammation, vomiting, dry mouth, rashes, dry skin, fever, weakness, and a sense of unwellness.<ref name=UKlabel2017/><ref name=USlabel2017/>
"The WHO does not recommend the use of thalidomide in leprosy as experience has shown that it is virtually impossible to develop and implement a fool-proof surveillance mechanism to combat misuse of the drug. The drug ] is now a component of the multidrug therapy (MDT), introduced by WHO in 1981 as the standard treatment for leprosy and now supplied free of charge to all patients worldwide."<ref>{{cite web|url=http://www.who.int/lep/research/thalidomide/en/index.html|title=Use of thalidomide in leprosy|last=Anon|work=WHO:leprosy elimination|publisher=WHO|accessdate=22 April 2010}}</ref>
</blockquote>


===United States=== === Interactions ===
There are no expected ] interactions between thalidomide and other medicines due to its neutral effects on ] and the ] family. It may interact with sedatives due to its sedative action and bradycardic agents, like beta-blockers, due to its bradycardia-inducing effects. The risk of ] may be increased by concomitant treatment of thalidomide with other agents known to cause peripheral neuropathy.<ref name = TGA>{{cite web|title=THALOMID® CAPSULES|work=TGA eBusiness Services|publisher=Celgene Pty Limited|date=21 June 2013|access-date=17 January 2014|url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03581-3|format=PDF|archive-date=4 September 2015|archive-url=https://web.archive.org/web/20150904052354/https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03581-3|url-status=live}}</ref> The risk of ]s with thalidomide seems to be increased when patients are treated with ] or other cytotoxic agents (including ] and ]) concurrently. Thalidomide may interfere with various contraceptives, and hence it is advised that women of reproductive age use at least two different means of contraception to ensure that no child will be conceived while they are taking thalidomide.<ref name=UKlabel2017/><ref name=USlabel2017/><ref name = TGA/>
On July 16, 1998, the FDA approved the use of thalidomide for the treatment of lesions associated with Erythema Nodosum Leprosum (ENL). Because of thalidomide’s potential for causing birth defects, the distribution of the drug was permitted only under tightly controlled conditions. The FDA required that ], which planned to market thalidomide under the brand name ''Thalomid'', establish a System for Thalidomide Education and Prescribing Safety (S.T.E.P.S.) oversight program. The conditions required under the program include; limiting prescription and dispensing rights only to authorized prescribers and pharmacies, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug and providing periodic pregnancy tests for women who are prescribed it.<ref></ref>
On May 26, 2006, the U.S. Food and Drug Administration granted accelerated approval for thalidomide (Thalomid, Celgene Corporation) in combination with dexamethasone for the treatment of newly diagnosed ] (MM) patients.<ref></ref> The FDA approval came seven years after the first reports of efficacy in the medical literature<ref name=Desikan>{{cite journal | last = Desikan | first = R | coauthors = N. Munsi, J. Zeldis et al.| title = Activity of thalidomide (THAL) in multiple myeloma (MM) confirmed in 180 patients with advanced disease | journal = Blood | volume = 94 | issue = Suppl. 1 | pages = 603a-603a | publisher = | year = 1999 | url = | doi = | id = | accessdate = }}</ref> and Celgene took advantage of "off-label" marketing opportunities to promote the drug in advance of its FDA approval for the myeloma indication. Thalomid, as the drug is commercially known, sold over $300 million per year, while only approved for leprosy.<ref>{{cite web
|first = MA
|last = Ismail
|title = FDA: A Shell of its Former Self
|url = http://projects.publicintegrity.org/rx//report.aspx?aid=722
|work = Pushing Prescriptions
|publisher = The Centre for Public Integrity
|date = 2005-07-07
}}
</ref>


===United Kingdom=== ===Overdose===
As of 2013, eighteen cases of overdoses had been reported with doses of up to 14.4&nbsp;grams, none of them fatal.<ref name = TGA/> No specific antidote for overdose exists and treatment is purely ].<ref name = TGA/>
Thalidomide is available to only a small number of patients in the UK, generally in specialist cancer treatment centres where research trials are taking place and specialist doctors have experience in its use.<ref>{{cite web|url=http://www.cancerbackup.org.uk/Treatments/Biologicaltherapies/Angiogenesisinhibitors/Thalidomide|title=Thalidomide|last=Anon|work=Cancer treatments|publisher=Cancerbackup|accessdate=2009-05-01}}</ref>


===Brazil=== ==Pharmacology==
The precise mechanism of action for thalidomide was not known until the twenty-first century,<ref name="Yamamoto">{{cite journal | vauthors = Yamamoto J, Ito T, Yamaguchi Y, Handa H | title = Discovery of CRBN as a target of thalidomide: a breakthrough for progress in the development of protein degraders | journal = Chemical Society Reviews | volume = 51 | issue = 15 | pages = 6234–6250 | date = August 2022 | pmid = 35796627 | doi = 10.1039/D2CS00116K | s2cid = 250337170 | doi-access = free }}</ref> although efforts to identify thalidomide's ] action generated more than 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000.<ref name=Stephens2000>{{cite journal | vauthors = Stephens TD, Bunde CJ, Fillmore BJ | title = Mechanism of action in thalidomide teratogenesis | journal = Biochemical Pharmacology | volume = 59 | issue = 12 | pages = 1489–1499 | date = June 2000 | pmid = 10799645 | doi = 10.1016/S0006-2952(99)00388-3 }}</ref> The primary mechanism of action of thalidomide and its analogs in both their anti-cancer and teratogenic effects is now known to be as ] ] modulators.<ref name="Yamamoto"/><ref>{{cite journal | vauthors = Ito T, Handa H | title = Molecular mechanisms of thalidomide and its derivatives | journal = Proceedings of the Japan Academy. Series B, Physical and Biological Sciences | volume = 96 | issue = 6 | pages = 189–203 | date = 11 June 2020 | pmid = 32522938 | pmc = 7298168 | doi = 10.2183/pjab.96.016 | bibcode = 2020PJAB...96..189I }}</ref><ref>{{cite journal | vauthors = Asatsuma-Okumura T, Ando H, De Simone M, Yamamoto J, Sato T, Shimizu N, Asakawa K, Yamaguchi Y, Ito T, Guerrini L, Handa H | title = p63 is a cereblon substrate involved in thalidomide teratogenicity | journal = Nature Chemical Biology | volume = 15 | issue = 11 | pages = 1077–1084 | date = November 2019 | pmid = 31591562 | doi = 10.1038/s41589-019-0366-7 | s2cid = 203853198 }}</ref><ref>{{cite journal | vauthors = Gao S, Wang S, Song Y | title = Novel immunomodulatory drugs and neo-substrates | journal = Biomarker Research | volume = 8 | issue = 1 | pages = 2 | date = December 2020 | pmid = 31938543 | pmc = 6953231 | doi = 10.1186/s40364-020-0182-y | doi-access = free }}</ref>


Thalidomide also binds to and acts as an ] of the ] and hence is a ] of some capacity.<ref name="LiuSu2010">{{cite journal | vauthors = Liu B, Su L, Geng J, Liu J, Zhao G | title = Developments in nonsteroidal antiandrogens targeting the androgen receptor | journal = ChemMedChem | volume = 5 | issue = 10 | pages = 1651–61 | date = October 2010 | pmid = 20853390 | doi = 10.1002/cmdc.201000259 | s2cid = 23228778 }}</ref> In accordance, it can produce ] and ] as side effects in men.<ref name="NuttallWarrier2015">{{cite journal | vauthors = Nuttall FQ, Warrier RS, Gannon MC | title = Gynecomastia and drugs: a critical evaluation of the literature | journal = European Journal of Clinical Pharmacology | volume = 71 | issue = 5 | pages = 569–78 | date = May 2015 | pmid = 25827472 | pmc = 4412434 | doi = 10.1007/s00228-015-1835-x }}</ref>
Brazil has the second highest prevalence rate of ] in the world and thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965. A study published in 1994 found 61 people born after 1965 whose limb defects and exposure history were compatible with thalidomide embryopathy. In 63.6% of these cases, thalidomide had been prescribed without the physician informing the patient about the drug's teratogenicity. Since then production, dispensing and prescription of thalidomide have been strictly controlled, but cases of thalidomide embryopathy are thought to have occurred until today.<ref>{{cite journal|last=Paumgartten|first=J.R.|coauthors=Chahoud, Ibrahim|month=July | year=2006|title=Thalidomide embryopathy cases in Brazil after 1965|journal=Reproductive Toxicology|publisher=Elselvier|volume=22|issue=1|pages=1, 2|url=http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6TC0-4J2W0DX-1&_user=899537&_rdoc=1&_fmt=&_orig=search&_sort=d&view=c&_acct=C000047642&_version=1&_urlVersion=0&_userid=899537&md5=064ddf875924b5b116f6ed8d82049b07|doi=10.1016/j.reprotox.2005.11.007|pmid=16427249|last1=Paumgartten|first1=FJ|last2=Chahoud|first2=I}}</ref><ref>{{cite journal|last=Correio Braziliense|month=January | year=2006|title=Talidomida volta a assustar|url=http://www.saude.df.gov.br/003/00301009.asp?ttCD_CHAVE=31041}}</ref>


=== Chirality and biological activity ===
==Possible indications==
Thalidomide is provided as a ] of two ]s; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood.<ref name=toxmech2009/> The (R)-enantiomer has the desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effects. Attempting to extract solely ''R''-thalidomide does not remove the risk of birth defects, as it was demonstrated that the "safe" ''R''-thalidomide undergoes an ''in vivo'' ] to the "teratogenic" ''S''-thalidomide. &nbsp; Under biological conditions, the enantiomers interconvert (''bidirectional chiral inversion'' – (R)- to (S)- and vice versa).<ref>{{Cite book |url=https://www.worldcat.org/oclc/52515592 |title=Stereochemical aspects of drug action and disposition |date=2003 |publisher=Springer | vauthors = Branch SK, Eichelbaum M, Testa B, Somogyi A |isbn=978-3-540-41593-0 |location=Berlin |oclc=52515592}}</ref><ref>{{Cite web |title=Thalidomide |website=Chiralpedia |date=20 August 2022 |url=https://chiralpedia.com/blog/thalidomide/ |access-date=27 August 2022 |language=en-US |archive-date=27 August 2022 |archive-url=https://web.archive.org/web/20220827093228/https://chiralpedia.com/blog/thalidomide/ |url-status=live }}</ref>
Serious infections including ] and ] cause the level of ] (TNFα) to rise. TNFα is a chemical mediator in the body, and it may enhance the wasting process in cancer patients as well. Thalidomide may reduce the levels of TNFα, and it is possible that the drug's effect on ENL is caused by this mechanism.<ref name =Burkholz />


== Chemistry ==
Thalidomide also has potent anti-inflammatory effects that may help ENL patients. In July 1998, the FDA approved the application of ] to distribute thalidomide under the brand name Thalomid for treatment of ENL. Pharmion Corporation, who licensed the rights to market thalidomide in Europe, Australia and various other territories from Celgene, received approval for its use against ] in ] and ] in 2003.<ref name =Chem>{{cite web|url =http://pubs.acs.org/cen/coverstory/83/8325/8325thalidomide.html |title=Thalidomide |accessdate =2006-09-21 |last =Rouhi |first =Maureen |work=Chemical & Engineering News |publisher=] }}</ref> Thalomid, in conjunction with ], is now standard therapy for multiple myeloma.
] of thalidomide:<br />Left: (''S'')-(−)-thalidomide<br />Right: (''R'')-(+)-thalidomide]]


Thalidomide is ]; while ''S''-thalidomide is the bioactive form of the molecule, the individual enantiomers can ] to each other due to the acidic hydrogen at the ], which is the carbon of the ] ring bonded to the ] ]. The racemization process can occur '']''.<ref name = clinp/><ref name="stereospecific44">{{cite journal | vauthors = Eriksson T, Björkman S, Roth B, Fyge A, Höglund P | title = Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide | journal = Chirality | volume = 7 | issue = 1 | pages = 44–52 | year = 1995 | pmid = 7702998 | doi = 10.1002/chir.530070109 }}</ref><ref name="pmid14505639">{{cite journal | vauthors = Man HW, Corral LG, Stirling DI, Muller GW | title = Alpha-fluoro-substituted thalidomide analogues | journal = Bioorganic & Medicinal Chemistry Letters | volume = 13 | issue = 20 | pages = 3415–7 | date = October 2003 | pmid = 14505639 | doi = 10.1016/S0960-894X(03)00778-9 }}</ref><ref name="Bartlett2004">{{cite journal | vauthors = Bartlett JB, Dredge K, Dalgleish AG | title = The evolution of thalidomide and its IMiD derivatives as anticancer agents | journal = Nature Reviews. Cancer | volume = 4 | issue = 4 | pages = 314–22 | date = April 2004 | pmid = 15057291 | doi = 10.1038/nrc1323 | s2cid = 7293027 }}</ref> The process of conversion of one enantiomer to its mirror-image version with no other change in the molecule is called chiral inversion.<ref>{{cite journal | vauthors = Wsól V, Skálová L, Szotáková B | title = Chiral inversion of drugs: coincidence or principle? | journal = Current Drug Metabolism | volume = 5 | issue = 6 | pages = 517–533 | date = December 2004 | pmid = 15578945 | doi = 10.2174/1389200043335360 }}</ref>
Thalidomide is also prescribed for its anti-inflammatory effects in ], an autoimmune skin disease.
Thalidomide has been used in chronic bullous dermatosis of childhood (CBDC) with encouraging results.<ref>http://www.ijdvl.com/text.asp?2010/76/4/427/66601</ref> Although, peripheral neuritis may be a limiting factor for long term use of thalidomide.


] originally synthesized thalidomide using a three-step sequence starting with ] treatment, but this has since been reformed by the use of ].<ref name="synth">{{cite journal| vauthors = Muller GW, Konnecke WE, Smith AM, Khetani VD | date=19 March 1999|title=A Concise Two-Step Synthesis of Thalidomide | journal=Organic Process Research & Development|volume=3|issue=2|pages=139–140|doi=10.1021/op980201b }}</ref> As shown in the image below, ''N''-carbethoxyphthalimide (1) can react with <small>L</small>-glutamine to yield ''N''-phthaloyl-<small>L</small>-glutamine (2). Cyclization of ''N''-phthaloyl-<small>L</small>-glutamine occurs using ], which then yields thalidomide (3).<ref name="synth" /> Celgene Corporation's original method resulted in a 31% yield of ''S''-thalidomide, whereas the two-step synthesis yields 85–93% product that is 99% pure.
Thalidomide also inhibits the growth of new blood vessels (]), which may be useful in treating ] and other diseases. This effect helps ] patients with ], although there are better and cheaper drugs to treat the condition. Thalidomide may be able to fight painful, debilitating ] lesions in the mouth and ] of AIDS patients which prevent them from eating. The FDA formed a Thalidomide Working Group in 1994 to provide consistency between its divisions, with particular emphasis on safety monitoring. The agency also imposed severe restrictions on the distribution of Thalomid through the System for Thalidomide Education and Prescribing Safety (STEPS) program.<ref name =Burkholz />


In 2023, it is reported that ] and ] under suitable conditions can react directly to form thalidomide. In the procedure, phthalic anhydride and <small>L</small>-glutamine are grounded and added into ] solvent. The solution, along with ] and ], is refluxed at ~110°C for 9 hours; after that the solution goes through a simple ] procedure to obtain the product.<ref>{{Cite journal | vauthors = Savini EB, Bandieri E |date=2023 |title=One step synthesis of thalidomide |url=https://cssp.chemspider.com/Article.aspx?id=964 |journal=] |language=en}}</ref>
Thalidomide is also being investigated for treating symptoms of ], ], ], ], ], and ]. In a small trial, Australian researchers found thalidomide sparked a doubling of the number of ]s in patients, allowing the patients' own ] to attack cancer cells.


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==History ==
Studies carried out in animal models have suggested that the use of combined therapy with thalidomide and
In 1952, thalidomide was synthesised by ], but was found "to have no effect on animals" and was discarded on that basis.<ref name=themee>{{cite web|author1=Royal Pharmaceutical Society|title=The evolution of pharmacy, Theme E, Level 3 Thalidomide and its aftermath|url=https://www.rpharms.com/museum-pdfs/e3a-thalidomide-and-its-aftermath-2011.pdf|date=2011|archive-url=https://web.archive.org/web/20141009110927/https://www.rpharms.com/museum-pdfs/e3a-thalidomide-and-its-aftermath-2011.pdf |archive-date=9 October 2014}}</ref> In 1957, it was acquired by ] in Germany.<ref name=themee/> The German company had been established as a soap maker after World War II ended, to address the urgent market need for antibiotics.<ref>{{cite book | vauthors = Rosett CM, Hagerty A | chapter = What History Can Teach us About Using Machine Learning Well |date=2021 | veditors = Rosett CM, Hagerty A | title = Introducing HR Analytics with Machine Learning: Empowering Practitioners, Psychologists, and Organizations |pages=171–189 |place=Cham |publisher=Springer International Publishing |language=en |doi=10.1007/978-3-030-67626-1_10 |isbn=978-3-030-67626-1 | s2cid = 236710887 }}</ref> ]<ref name=ktnyt>{{Cite news| vauthors = Thomas K |url=https://www.nytimes.com/2020/03/23/health/thalidomide-survivors-usa.html|title=The Unseen Survivors of Thalidomide Want to Be Heard|date=23 March 2020|work=The New York Times|access-date=23 March 2020|language=en-US|issn=0362-4331|archive-date=23 March 2020|archive-url=https://web.archive.org/web/20200323154020/https://www.nytimes.com/2020/03/23/health/thalidomide-survivors-usa.html|url-status=live}}</ref> was appointed to head the discovery program based on his experience working with the German army's antiviral research. While preparing ] for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of ], a ]. The medicinal chemistry work turned to improving the lead compound into a suitable drug: the result was thalidomide. The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative, but it was never tested on pregnant women.<ref>{{cite book| vauthors = Sneader W |title=Drug discovery: a history|url=https://archive.org/details/drugdiscoveryhis00snea|url-access=limited|date=2005|publisher=Wiley|location=Chichester|isbn=978-0-471-89979-2|page=|edition=Rev. and updated}}</ref>
] could have a therapeutic benefit in the treatment of *Visceral Leshmaniasis.<ref>{{cite journal|last=Ghassem|first=Solgi|coauthors=KARIMINIA A., ABDI K, DARABI M, GHAREGHOZLOO B.|month=March | year=2006|title=Effects of combined therapy with thalidomide and glucantime on leishmaniasis induced by Leishmania major in BALB/c mice|journal=Korean Journal of Parasitology|volume=44|issue=1|pages=55–61|url=http://synapse.koreamed.org/Synapse/Data/PDFData/0066KJP/kjp-44-55.pdf|format=PDF|doi=10.3347/kjp.2006.44.1.55|pmid=16514283|pmc=2532651}}</ref>


Researchers at Chemie Grünenthal found that thalidomide was a particularly effective ] that had an inhibitory effect on ].<ref name=pmid15172781>{{cite journal | vauthors = Franks ME, Macpherson GR, Figg WD | title = Thalidomide | journal = Lancet | volume = 363 | issue = 9423 | pages = 1802–11 | date = May 2004 | pmid = 15172781 | doi = 10.1016/S0140-6736(04)16308-3 | s2cid = 208789946 | url = https://zenodo.org/record/1259793 | access-date = 30 June 2019 | archive-date = 21 August 2019 | archive-url = https://web.archive.org/web/20190821212125/https://zenodo.org/record/1259793 | url-status = live }}</ref> On 1 October 1957, the company launched thalidomide and began marketing it under the trade name Contergan.<ref>{{cite web | url = https://www.grunenthal.com/about-us/history | title = Grünenthal: Where we come from | archive-url = https://web.archive.org/web/20180702093114/https://www.grunenthal.com/about-us/history | archive-date=2 July 2018 | access-date = 2 July 2018 }} See also {{cite web | url = http://www.contergan.grunenthal.info/thalidomid/Home_/351300028.jsp;jsessionid=D8966B9045A2EDE78D5AC41F85C93424.drp1?naviLocale=en_EN | title = Developments regarding thalidomide | archive-url = https://web.archive.org/web/20180702064501/http://www.contergan.grunenthal.info/thalidomid/Home_/351300028.jsp;jsessionid=D8966B9045A2EDE78D5AC41F85C93424.drp1?naviLocale=en_EN | archive-date=2 July 2018 }}</ref><ref name="Bombay">{{cite journal | vauthors = Moghe VV, Kulkarni U, Parmar UI |year=2008 |title=Thalidomide |journal=Bombay Hospital Journal |publisher=Bombay Hospital |location=Bombay |volume=50 |issue=3 |pages=472–6 |url=http://www.bhj.org.in/journal/2008_5003_july/download/page-472-476.pdf |access-date=8 August 2016 |archive-date=20 August 2016 |archive-url=https://web.archive.org/web/20160820114658/http://www.bhj.org.in/journal/2008_5003_july/download/page-472-476.pdf |url-status=live }}</ref> It was proclaimed a "wonder drug" for ], coughs, colds and headaches.<ref>Campbell, Denis. "'Wonder drug' left babies with deformed limbs." ''The Guardian''. 29 July 2009.</ref>
A study published in April 2010 discusses the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations. The research was conducted in an experimental model of the genetic disease ].<ref>{{cite journal|unused_data=Published online: 4 April 2010|last=Lebrin|first=Franck|coauthors=Srun S., Raymond2] K, Martin S., van den Brink S, Freitas C., Bréant C., Mathivet T., Larrivée B., Thomas J., Arthur H., Westermann C., Disch F., Mager J., Snijder R., Eichmann A., Mummery C.|month=April | year=2010|title=Thalidomide stimulates vessel maturation and reduces epistaxis in individuals with hereditary hemorrhagic telangiectasia|journal=Nature Medicine|pmid=20364125|volume=16|issue=4|pages=420–428|url=http://www.nature.com/nm/journal/v16/n4/full/nm.2131.html|doi=10.1038/nm.2131}}</ref>


During that period, the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the ].<ref name=pmid15172781/> Thousands of pregnant women took the drug to relieve their symptoms. At the time of the drug's development, scientists did not believe any drug taken by a pregnant woman could pass across the ] and harm the developing fetus.<ref name=Chem1994>{{cite book | vauthors = Heaton CA | title = The Chemical Industry | publisher = Springer | year = 1994 | isbn = 978-0-7514-0018-2 }}</ref> There soon appeared reports of abnormalities in children being born to mothers using thalidomide. In late 1959, it was noticed that ] developed in patients who took the drug over a period of time, and it was only after this point that thalidomide ceased to be provided over the counter.<ref>{{cite journal | vauthors = Kelsey FO | title = Events after thalidomide | journal = Journal of Dental Research | volume = 46 | issue = 6 | pages = 1201–5 | year = 1967 | pmid = 5235007 | doi = 10.1177/00220345670460061201 | s2cid = 11175347 }}</ref>
===Thalidomide and multiple myeloma===
Thalidomide was first tested in humans as a single agent for the treatment of ] in 1996 due to its antiangiogenic activity and the full study published in 1999.<ref>{{cite journal
| author = Singhal S, Mehta J, Desikan R, ''et al.''
| title = Antitumor activity of thalidomide in refractory multiple myeloma
| journal = The New England Journal of Medicine
| volume = 341
| issue = 21
| pages = 1565–71
| year = 1999
| month = November
| pmid = 10564685
| url = http://content.nejm.org/cgi/pmidlookup?view=short&pmid=10564685&promo=ONFLNS19
| accessdate = 2009-06-18
| doi = 10.1056/NEJM199911183412102
| last12 = Barlogie
| first12 = B
}}</ref> Since then many studies have shown that thalidomide in combination with ] has increased the survival of multiple myeloma patients. The combination of thalidomide and dexamethasone, often in combination with ], is now one of the most common regimens for patients with newly diagnosed multiple myeloma, with an improved response rate of up to 60-70%.<ref>{{cite journal
| author = Gieseler F
| title = Pathophysiological considerations to thrombophilia in the treatment of multiple myeloma with thalidomide and derivates
| journal = Thrombosis and Haemostasis
| volume = 99
| issue = 6
| pages = 1001–7
| year = 2008
| month = June
| pmid = 18521500
| doi = 10.1160/TH08-01-0009
| accessdate = 2009-06-18
}}</ref><ref>{{cite journal
| author = Denz U, Haas PS, Wäsch R, Einsele H, Engelhardt M
| title = State of the art therapy in multiple myeloma and future perspectives
| journal = European Journal of Cancer (Oxford, England : 1990)
| volume = 42
| issue = 11
| pages = 1591–600
| year = 2006
| month = July
| pmid = 16815703
| doi = 10.1016/j.ejca.2005.11.040
| accessdate = 2009-06-18
}}</ref> Thalidomide may also cause side effects such as ], fatigue, skin rash, and ], or blood clots, which could lead to ] or ].<ref name="pmid18182082">{{cite journal |author=Haas PS, Denz U, Ihorst G, Engelhardt M |title=Thalidomide in consecutive multiple myeloma patients: single-center analysis on practical aspects, efficacy, side effects and prognostic factors with lower thalidomide doses |journal=Eur. J. Haematol. |volume=80 |issue=4 |pages=303–9 |year=2008 |month=April |pmid=18182082 |doi=10.1111/j.1600-0609.2007.01022.x |url=}}</ref> Bennett et al. have conducted a systematic review of VTE associated with thalidomide in multiple myeloma patients.<ref>{{cite journal
| author = Bennett CL, Angelotta C, Yarnold PR, ''et al.''
| title = Thalidomide- and lenalidomide-associated thromboembolism among patients with cancer
| journal = JAMA : the Journal of the American Medical Association
| volume = 296
| issue = 21
| pages = 2558–60
| year = 2006
| month = December
| pmid = 17148721
| doi = 10.1001/jama.296.21.2558-c
| accessdate = 2009-06-18
}}</ref> They have found that when thalidomide was administered without ], VTE rates reached as high as 26%. Owing to the high rates of VTE associated with thalidomide in combination with dexamethasone or ], a ] was added in the US in 2006 to the package insert for thalidomide, indicating that patients with multiple myeloma who receive thalidomide-dexamethasone may benefit from concurrent thromboembolism prophylaxis or ]. In addition, owing to these side effects, newer drugs, such as ] (marketed as Velcade) and a thalidomide derivative, ] (marketed as Revlimid), have increased in popularity.{{Citation needed|date=May 2009}}


While initially considered safe, the drug was responsible for ] deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public.<ref>{{cite journal | vauthors = Vargesson N, Stephens T | title = Thalidomide: history, withdrawal, renaissance, and safety concerns | journal = Expert Opinion on Drug Safety | volume = 20 | issue = 12 | pages = 1455–1457 | date = December 2021 | pmid = 34623196 | doi = 10.1080/14740338.2021.1991307 | s2cid = 238476677 | hdl = 2164/19455 | hdl-access = free }}</ref> Experts estimate that thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, with over half of them in West Germany.<ref name="Thalidomide-induced teratogenesis">{{cite journal | vauthors = Vargesson N | title = Thalidomide-induced teratogenesis: history and mechanisms | journal = Birth Defects Research. Part C, Embryo Today | volume = 105 | issue = 2 | pages = 140–156 | date = June 2015 | pmid = 26043938 | pmc = 4737249 | doi = 10.1002/bdrc.21096 }}</ref> The regulatory authorities in ] never approved thalidomide.<ref name="oncozine.com">{{cite web | vauthors = Hofland P |url = https://oncozine.com/reversal-of-fortune-how-a-vilified-drug-became-a-life-saving-agent-in-the-war-against-cancer/ |title = Reversal of Fortune: How a Vilified Drug Became a Life-saving Agent in the "War" Against Cancer |work = Onco'Zine |date = December 2013 |access-date = 10 February 2018 |archive-date = 11 February 2018 |archive-url = https://web.archive.org/web/20180211072029/https://oncozine.com/reversal-of-fortune-how-a-vilified-drug-became-a-life-saving-agent-in-the-war-against-cancer/ |url-status = live }}</ref> One reason for the initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They were tested for toxicity on rodents only, as was usual at the time.<ref name="VFA">{{cite web | url = http://www.vfa.de/de/arzneimittel-forschung/artikel-arzneimittel-forschung/teratogenitaet.html | title = VFA: teratogenic effects | archive-url = https://web.archive.org/web/20140104022807/http://www.vfa.de/de/arzneimittel-forschung/artikel-arzneimittel-forschung/teratogenitaet.html | archive-date= 4 January 2014| date = 6 July 2011 }}</ref>
==Teratogenic mechanism==
]
Thalidomide is ]&nbsp;– it contains both left- and right-handed ]s in equal amounts. The (''R'') ] is effective against morning sickness but the (''S'') is ]. The enantiomers can interconvert (]) '']''<ref>{{cite journal |journal= Clin Pharmacokinet. |year= 2004 |volume= 43 |issue= 5 |pages= 311–327 |title= Clinical pharmacokinetics of thalidomide |pmid= 15080764 |author= Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL |doi= 10.2165/00003088-200443050-00004 }}</ref>&nbsp;– that is, if a human is given pure (''R'')-thalidomide or (''S'')-thalidomide, both isomers will later be found in the ]&nbsp;– therefore, administering only one enantiomer will not prevent the teratogenic effect.


In the UK, the British pharmaceutical company ] (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of ]), marketed thalidomide throughout the UK, Australia, and New Zealand, under the brand name Distaval, as a remedy for ]. Their advertisement claimed that "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child ... Outstandingly safe Distaval has been prescribed for nearly three years in this country."<ref name="oncozine.com"/> Globally, more pharmaceutical companies started to produce and market the drug under license from Chemie Grünenthal. By the mid-1950s, 14 pharmaceutical companies were marketing thalidomide in 46 countries under at least 37 different trade names.
The mechanism of thalidomide's teratogenic action has led to over 2000 research papers and the proposal of fifteen or sixteen plausible mechanisms.<ref name="Stephens">{{cite journal
| author = Stephens TD, Bunde CJ, Fillmore BJ
| title = Mechanism of action in thalidomide teratogenesis
| journal = Biochemical Pharmacology
| volume = 59
| issue = 12
| pages = 1489–99
| year = 2000
| month = June
| pmid = 10799645
| doi = 10.1016/S0006-2952(99)00388-3
}}</ref> A theoretical synthesis in 2000<ref name="Stephens"/> suggested the following mechanism: thalidomide ] (inserts itself) into ] in G-C (]-]) rich regions.<ref>Koch HP, Czejka MJ. (1986). Evidence for the intercalation of thalidomide into DNA: clue to the molecular mechanism of thalidomide teratogenicity? Z Naturforsch . 41(11-12):1057-61. PMID 2953123</ref><ref>{{cite journal
| author = Huang PH, McBride WG
| title = Interaction of -thalidomide with rat embryonic DNA in vivo
| journal = Teratogenesis, Carcinogenesis, and Mutagenesis
| volume = 17
| issue = 1
| pages = 1–5
| year = 1997
| pmid = 9249925
| doi = 10.1002/(SICI)1520-6866(1997)17:1<1::AID-TCM2>3.0.CO;2-L
}}</ref> Owing to its glutarimide part, (S) thalidomide fits neatly into the major groove of DNA at purine sites.<ref name="Stephens"/> Such intercalation impacts upon the promoter regions of the genes controlling the development of limbs, ears, and eyes such as ] and ]. These normally activate the production of the cell surface attachment ] αvβ3 with the resulting αvβ3 integrin dimer stimulating ] in developing limb buds. This then promotes the outgrowth of the bud (IGF-I and FGF-2 are also both known to stimulate angiogenesis). Therefore, by inhibiting the chain of events, thalidomide causes the truncation of limb development. In 2009 this theory<ref name="Stephens"/> received strong support, with research showing "conclusively that loss of newly formed blood vessels is the primary cause of thalidomide teratogenesis, and developing limbs are particularly susceptible because of their relatively immature, highly angiogenic vessel network."<ref>{{cite journal
| author = Therapontos C, Erskine L, Gardner ER, Figg WD, Vargesson N
| title = Thalidomide induces limb defects by preventing angiogenic outgrowth during early limb formation
| journal = Proceedings of the National Academy of Sciences of the United States of America
| volume = 106
| issue = 21
| pages = 8573–8
| year = 2009
| month = May
| pmid = 19433787
| doi = 10.1073/pnas.0901505106
| accessdate = 2009-06-18
| pmc = 2688998
}}</ref>


In the US, representatives from Chemie Grünenthal approached ] (SKF), now ], with a request to market and distribute the drug in North America. A memorandum, rediscovered in 2010 in the archives of the FDA, shows that in 1956–57, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women.<ref>{{Cite web |title=Lawsuit Blames Thalidomide for More Birth Defects |url=https://www.scientificamerican.com/article/lawsuit-blames-thalidomide-for-more/ |access-date=2023-02-04 |website=Scientific American |language=en |archive-date=4 February 2023 |archive-url=https://web.archive.org/web/20230204035126/https://www.scientificamerican.com/article/lawsuit-blames-thalidomide-for-more/ |url-status=live }}</ref> In 1956, researchers involved in clinical trials at SKF noted that, even when used in very high doses, thalidomide could not induce sleep in mice.{{citation needed|date=October 2015}} When administered at doses 50 to 650 times larger than that claimed by Chemie Grünenthal to be "sleep-inducing", the researchers could still not achieve the hypnotic effect in animals that it had on humans.{{citation needed|date=October 2015}} After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. In 1958, Chemie Grünenthal reached an agreement with the William S. Merrell Company in Cincinnati, Ohio (], now part of ]), to market and distribute thalidomide throughout the US.<ref name="oncozine.com"/>
===Inactivation of the protein cereblon===


The US FDA refused to approve thalidomide for marketing and distribution. However, the drug was distributed in large quantities for testing purposes, after the American distributor and manufacturer ] had applied for its approval in September 1960.{{citation needed|date=October 2015}} The official in charge of the FDA review, ], did not rely on information from the company, which did not include any test results. Richardson-Merrell was called on to perform tests and report the results. The company demanded approval six times and was refused each time. The distribution for "testing" resulted in 17 children born in the US with thalidomide-induced malformations. Oldham Kelsey was awarded the ] by President Kennedy in 1962 for not allowing thalidomide to be approved for sale in the US. She was also inducted into the ] in 2000.<ref>{{cite web | url = https://www.fda.gov/fdac/features/2001/201_kelsey.html | title = Report | publisher = U.S. Food and Drug Administration | archive-url = https://web.archive.org/web/20090512235601/https://www.fda.gov/fdac/features/2001/201_kelsey.html | archive-date = 12 May 2009 | date = 12 May 2009 }}</ref>
Thalidomide binds to and inactivates the protein ], which is important in limb formation.<ref>{{cite news |author=] |coauthors= |title=Answers Begin to Emerge on How Thalidomide Caused Defects |url=http://www.nytimes.com/2010/03/16/science/16limb.html?ref=science&pagewanted=all |quote=As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide.|work=] |date= March 15, 2010 |accessdate=2010-03-21 }}</ref> The inactivation, thus, leads to a ] effect on ]. This was confirmed when the scientists, using genetic techniques, reduced the production of ] in developing chick embryo and zebrafish embryo. These embryos had defects similar to those treated with thalidomide. Thus the mechanism that causes teratogenicity has been established but the mechanism for other therapeutic effects remains unclear.<ref name="Ito_2010">{{cite journal | author = Ito T, Ando H, Suzuki T, Ogura T, Hotta K, Imamura Y, Yamaguchi Y, Handa H | title = Identification of a primary target of thalidomide teratogenicity | journal = Science | volume = 327 | issue = 5971 | pages = 1345–1350 | year = 2010 | month = | pmid = 20223979 | pmc = | doi = 10.1126/science.1177319 | url = http://www.sciencemag.org/cgi/content/abstract/327/5971/1345 | laysummary = http://news.bbc.co.uk/1/hi/sci/tech/8562998.stm | laysource = BBC News }}</ref>


Canada's Food and Drug Directorate approved the sale of thalidomide by prescription in November 1960.<ref name="Peritz2014">{{cite news | vauthors = Peritz I |title=The fight of their lives: After years of neglect, Canadian thalidomide survivors make a plea for help |url=https://www.theglobeandmail.com/news/national/the-aftermath-of-thalidomide/article21689771/ |access-date=5 February 2023 |work=] |date=November 21, 2014 |archive-date=5 February 2023 |archive-url=https://web.archive.org/web/20230205215237/https://www.theglobeandmail.com/news/national/the-aftermath-of-thalidomide/article21689771/ |url-status=live }}</ref> There were many different forms sold: Kevadon, produced by the William S. Merrell Company seeking approval for its thalidomide product, was released on the market in April 1961, and the most common variant (Horner's Talimol) was put on the market on October 23 of the same year.<ref name=pmid14076167>{{cite journal | vauthors = Webb JF | title = Canadian Thalidomide Experience | journal = Canadian Medical Association Journal | volume = 89 | pages = 987–92 | date = November 1963 | issue = 19 | pmid = 14076167 | pmc = 1921912 }}</ref> Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects.<ref name=pmid14076167/> It was not until March 1962 that both drugs were banned from the Canadian market by the directorate, and soon afterward physicians were warned to destroy their supplies.<ref name=pmid14076167/>
==Thalidomide analogs==


===Leprosy treatment===
The exploration of the ] and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide ]s. In 2005, Celgene received FDA approval for ] (Revlimid) as the first commercially useful derivative. Revlimid is only available in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another analog, ], is in the clinical trial phase.<ref></ref> These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.<ref>Raghupathy R., Billett H.H. ' Promising therapies in sickle cell disease Cardiovascular and Hematological Disorders - Drug Targets 2009 9:1 (1-8)</ref>
In 1964, Israeli physician ] administered thalidomide to a patient critically ill with ]. The patient exhibited ] (ENL), a painful skin condition, one of the complications of leprosy. The treatment was attempted despite the ban on thalidomide's use, and the results were favourable: the patient slept for hours and was able to get out of bed without aid upon awakening. A clinical trial studying the use of thalidomide in leprosy soon followed.<ref name="Silverman">{{cite journal | vauthors = Silverman WA | title = The schizophrenic career of a "monster drug" | journal = Pediatrics | volume = 110 | issue = 2 Pt 1 | pages = 404–6 | date = August 2002 | pmid = 12165600 | doi = 10.1542/peds.110.2.404 }}</ref>


Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965, and by 1996, at least 33 cases of thalidomide embryopathy were recorded in people born in Brazil after 1965.<ref>{{cite journal | vauthors = Castilla EE, Ashton-Prolla P, Barreda-Mejia E, Brunoni D, Cavalcanti DP, Correa-Neto J, Delgadillo JL, Dutra MG, Felix T, Giraldo A, Juarez N, Lopez-Camelo JS, Nazer J, Orioli IM, Paz JE, Pessoto MA, Pina-Neto JM, Quadrelli R, Rittler M, Rueda S, Saltos M, Sánchez O, Schüler L | title = Thalidomide, a current teratogen in South America | journal = Teratology | volume = 54 | issue = 6 | pages = 273–7 | date = December 1996 | pmid = 9098920 | doi = 10.1002/(SICI)1096-9926(199702)55:2<156::AID-TERA6>3.0.CO;2-1 | doi-access = free }}</ref> Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, requiring women to use two forms of birth control and submit to regular pregnancy tests. Despite this, cases of thalidomide embryopathy continue,<ref>{{cite journal | vauthors = Paumgartten FJ, Chahoud I | title = Thalidomide embryopathy cases in Brazil after 1965 | journal = Reproductive Toxicology | volume = 22 | issue = 1 | pages = 1–2 | date = July 2006 | pmid = 16427249 | doi = 10.1016/j.reprotox.2005.11.007 | bibcode = 2006RepTx..22....1P }}</ref><ref>{{cite web | vauthors = Braziliense C | date = January 2006 | title = Talidomida volta a assustar | trans-title = Thalidomide again scare | language = pt | url = http://www.saude.df.gov.br/003/00301009.asp?ttCD_CHAVE=31041 | url-status = dead | archive-url = https://web.archive.org/web/20120313095445/http://www.saude.df.gov.br/003/00301009.asp?ttCD_CHAVE=31041 | archive-date = 13 March 2012 }}</ref> with at least 100 cases identified in Brazil between 2005 and 2010.<ref>{{cite news | title = Brazil's new generation of Thalidomide babies | date = 23 July 2013 | url = https://www.bbc.com/news/magazine-23418102 | vauthors = Crawford A | newspaper = BBC News | access-date = 21 June 2018 | archive-date = 10 November 2020 | archive-url = https://web.archive.org/web/20201110015129/https://www.bbc.com/news/magazine-23418102 | url-status = live }}</ref> 5.8 million thalidomide pills were distributed throughout Brazil in this time period, largely to poor Brazilians in areas with little access to healthcare, and these cases have occurred despite the controls.
==Notable people affected==


In 1998, the FDA approved the drug's use in the treatment of ENL.<ref name="nyt-fda">{{cite news | url = https://www.nytimes.com/1998/07/17/us/thalidomide-approved-to-treat-leprosy-with-other-uses-seen.html | title = Thalidomide Approved to Treat Leprosy, With Other Uses Seen | newspaper = New York Times | vauthors = Stolberg SG | access-date = 8 January 2012 | date = 17 July 1998 | archive-date = 3 December 2020 | archive-url = https://web.archive.org/web/20201203003055/https://www.nytimes.com/1998/07/17/us/thalidomide-approved-to-treat-leprosy-with-other-uses-seen.html | url-status = live }}</ref> Because of thalidomide's potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that ], which planned to market thalidomide under the brand name ''Thalomid'', establish a system for thalidomide education and prescribing safety (STEPS) oversight program. The conditions required under the program include limiting prescription and dispensing rights to authorized prescribers and pharmacies only, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug.<ref name="nyt-fda"/>
*], son of ], author of ]<ref>{{cite news
| title = A CONVERSATION WITH ROCK BRYNNER - A 'Dark Remedy' Is Now Generating Light
| author = Dreifus
| first = Claudia
| url = http://www.nytimes.com/2001/07/31/health/a-conversation-with-rock-brynner-a-dark-remedy-is-now-generating-light.html?pagewanted=1
| publisher = The New York Times
| date = 2001-07-31
| accessdate = 2010-10-11
}}
</ref>
*], daughter of David Mason, campaigner for increased compensation for thalidomide children, born with no arms or legs.<ref>{{cite news
| title = A truly special love story: Two married thalidomide survivors living happily 50 years after drug's launch
| author = Courtenay-Smith
| first = Natasha
| url = http://www.dailymail.co.uk/news/article-561360/A-truly-special-love-story-Two-married-thalidomide-survivors-living-happily-50-years-drugs-launch.html
| publisher = The Daily Mail
| location = London
| date = 2008-04-23
| accessdate = 2009-06-18
}}
</ref>
*] is an internationally acclaimed bass-baritone who describes himself: "1.34 meters tall, short arms, seven fingers&nbsp;— four right, three left&nbsp;— large, relatively well formed head, brown eyes, distinctive lips; profession: singer."<ref> Retrieved on 2008-10-22</ref>
*], musician, actor and performance artist born with ] of both arms.
*], born with phocomelia of both arms and legs and has become known internationally through the television drama ''On Giant's Shoulders'' and the best-selling book of the same name.
*] produced a documentary based on the lives of 12 people affected by the drug, which was released in 2008 entitled ''Nobody's perfect''.<ref></ref><ref></ref>
*], award winning singer and guitarist who has become known internationally due to the recognition received from ] and ] ].
*]


In 2010, the ] stated that it did not recommend thalidomide for leprosy due to the difficulty of adequately controlling its use, and due to the availability of ].<ref>{{cite web |url=https://www.who.int/lep/research/thalidomide/en/index.html |archive-url=https://web.archive.org/web/20061110083549/http://www.who.int/lep/research/thalidomide/en/index.html |url-status=dead |archive-date=10 November 2006 |title=Use of thalidomide in leprosy|last=Anon|work=WHO:leprosy elimination |publisher=WHO |access-date=22 April 2010}}</ref>
==References==


===Cancer treatment===
{{Reflist|2}}
Shortly after the teratogenic properties of thalidomide were recognized in the mid-1960s, its anti-cancer potential was explored and two clinical trials were conducted in people with advanced cancer, including some people with multiple myeloma; the trials were inconclusive.<ref name=Kyle>{{cite journal | vauthors = Kyle RA, Rajkumar SV | title = Multiple myeloma | journal = Blood | volume = 111 | issue = 6 | pages = 2962–72 | date = March 2008 | pmid = 18332230 | pmc = 2265446 | doi = 10.1182/blood-2007-10-078022 }}</ref>


Little further work was done with thalidomide in cancer until the 1990s.<ref name=Kyle/>
==Further reading==
* {{cite book |last=Stephens |first=Trent |authorlink= |coauthors=Brynner, Rock |title=Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine |date=2001-12-24 |publisher=Perseus |location= |isbn=0-7382-0590-7 }}


] pioneered studies into the role of ] (the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that ] could not expand without it.<ref name=NASbio>{{cite web | vauthors = Donahoe PK | url = http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/folkman-judah.pdf | title = Judah Folkman: 1933–2008. A Biographical Memoir | publisher = National Academy of Sciences | year = 2014 | access-date = 11 August 2015 | archive-date = 2 August 2020 | archive-url = https://web.archive.org/web/20200802184808/http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/folkman-judah.pdf | url-status = live }}</ref><ref name=Beilenberg>{{cite journal | vauthors = Bielenberg DR, D'Amore PA | title = Judah Folkman's contribution to the inhibition of angiogenesis | journal = Lymphatic Research and Biology | volume = 6 | issue = 3–4 | pages = 203–7 | year = 2008 | pmid = 19093793 | doi = 10.1089/lrb.2008.1016 }}</ref> In 1993 he surprised the scientific world by hypothesizing the same was true of ],<ref name=Folkman>{{cite journal | vauthors = Folkman J | title = Angiogenesis-dependent diseases | journal = Seminars in Oncology | volume = 28 | issue = 6 | pages = 536–42 | date = December 2001 | pmid = 11740806 | doi = 10.1016/s0093-7754(01)90021-1 }}</ref> and the next year he published work showing that a ] of angiogenesis was higher in all people with cancer, but especially high in people with blood cancers, and other evidence emerged as well.<ref>{{cite journal | vauthors = Ribatti D | title = Judah Folkman, a pioneer in the study of angiogenesis | journal = Angiogenesis | volume = 11 | issue = 1 | pages = 3–10 | year = 2008 | pmid = 18247146 | pmc = 2268723 | doi = 10.1007/s10456-008-9092-6 }}</ref> Meanwhile, a member of his lab, Robert D'Amato, who was looking for ], discovered in 1994 that thalidomide inhibited angiogenesis<ref>{{cite journal | vauthors = D'Amato RJ, Loughnan MS, Flynn E, Folkman J | title = Thalidomide is an inhibitor of angiogenesis | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 91 | issue = 9 | pages = 4082–5 | date = April 1994 | pmid = 7513432 | pmc = 43727 | doi = 10.1073/pnas.91.9.4082 | bibcode = 1994PNAS...91.4082D | doi-access = free }}</ref> and was effective in suppressing tumor growth in rabbits.<ref>{{cite journal | vauthors = Verheul HM, Panigrahy D, Yuan J, D'Amato RJ | title = Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits | journal = British Journal of Cancer | volume = 79 | issue = 1 | pages = 114–8 | date = January 1999 | pmid = 10408702 | pmc = 2362163 | doi = 10.1038/sj.bjc.6690020 }}</ref> Around that time, the wife of a man who was dying of multiple myeloma and whom standard treatments had failed, called Folkman asking him about his anti-angiogenesis ideas.<ref name=Beilenberg/> Folkman persuaded the patient's doctor to try thalidomide, and that doctor conducted a clinical trial of thalidomide for people with multiple myeloma in which about a third of the subjects responded to the treatment.<ref name=Beilenberg/> The results of that trial were published in the New England Journal of Medicine in 1999.<ref name=Beilenberg/><ref name="nejm-myeloma">{{cite journal | vauthors = Singhal S, Mehta J, Desikan R, Ayers D, Roberson P, Eddlemon P, Munshi N, Anaissie E, Wilson C, Dhodapkar M, Zeddis J, Barlogie B | title = Antitumor activity of thalidomide in refractory multiple myeloma | journal = The New England Journal of Medicine | volume = 341 | issue = 21 | pages = 1565–71 | date = November 1999 | pmid = 10564685 | doi = 10.1056/NEJM199911183412102 | doi-access = free }}</ref>
* {{cite book | last=Knightley |first=Phillip |coauthors=Evans, Harold. Potter, Elaine. Wallace, Marjorie. |title=Suffer The Children: The Story of Thalidomide |year=1979| publisher=The Viking Press|location=New York|isbn=0-670-68114-8}}


After further work was done by Celgene and others, in 2006 the US&nbsp;Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed ] patients.<ref name=Beilenberg/><ref>{{cite web|url=http://www.cancer.gov/cancertopics/druginfo/fda-thalidomide|publisher=National Cancer Institute|access-date=8 January 2012|title=FDA Approval for Thalidomide|archive-date=28 January 2012|archive-url=https://web.archive.org/web/20120128120343/http://www.cancer.gov/cancertopics/druginfo/fda-thalidomide|url-status=dead}}</ref>
==External links==
* from Chemical and Engineering News. (Archived by WebCite® at http://www.webcitation.org/5nWHyOCfI)
* (Needs registration)
*
*
*
*
*
*
*
*
*
*
*
*, forum of pharmaceutical and medical marketing professionals commenting on how they would address the thalidomine controversies.


It was also evaluated whether thalidomide can be combined with melphalan and prednisone for patients with multiple myeloma. This combination of drugs probably increases the overall survival.<ref>{{cite journal | vauthors = Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, Ocheni S, Theurich S, Kuhr K, Scheckel B, Adams A, Skoetz N | title = Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis | journal = The Cochrane Database of Systematic Reviews | volume = 2019 | issue = 11 | date = November 2019 | pmid = 31765002 | doi = 10.1002/14651858.CD013487 | pmc = 6876545 | collaboration = Cochrane Haematology Group }}</ref>

==Society and culture==
===Birth defect crisis===
{{main|Thalidomide scandal}}
]
In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities, such as ], as a consequence of thalidomide use.<ref name="Bren">{{cite news | author =Bren L | title =Frances Oldham Kelsey: FDA Medical Reviewer Leaves Her Mark on History | url =http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2001/201_kelsey.html | work =FDA Consumer | publisher =U.S. ] | date =28 February 2001 | access-date =23 December 2009 | archive-date =29 June 2011 | archive-url =https://web.archive.org/web/20110629135137/http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2001/201_kelsey.html | url-status =live }}</ref> The severity and location of the deformities depended on how many days into the pregnancy the mother was before beginning treatment, with the time-sensitive window occurring approximately between day 20 and day 36 post-fertilisation.<ref name="Thalidomide-induced teratogenesis"/> Thalidomide taken on the 20th day of pregnancy caused central brain damage, day 21 would damage the eyes, day 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28.

It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000.<ref name="nyt-answers">{{cite news | author = Zimmer C | title = Answers Begin to Emerge on How Thalidomide Caused Defects | url = https://www.nytimes.com/2010/03/16/science/16limb.html | quote = As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide | newspaper = ] | date = 15 March 2010 | access-date = 21 March 2010 | author-link = Carl Zimmer | archive-date = 23 March 2010 | archive-url = https://web.archive.org/web/20100323152804/http://www.nytimes.com/2010/03/16/science/16limb.html | url-status = live }}</ref> Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962.<ref name=pmid14076167/><ref>{{cite web|url=http://www.history.ca/ontv/titledetails.aspx?titleid=21267 |title=Turning Points of History–Prescription for Disaster |publisher=History Television |access-date=24 February 2010 |url-status=dead |archive-url=https://web.archive.org/web/20110929135332/http://www.history.ca/ontv/titledetails.aspx?titleid=21267 |archive-date=29 September 2011 }}</ref>

===Notable cases===
]
*] ] of the United Kingdom, born with ] of both arms and legs, is the only thalidomide survivor to carry the Olympic Torch.<ref name=Tamplin>{{cite news | vauthors = Tamplin H | title = Mid Sussex residents honoured by Queen | newspaper = Mid Sussex Times | date = 12 June 2015 | url = http://www.midsussextimes.co.uk/news/local/mid-sussex-residents-honoured-by-queen-1-6795898 | access-date = 27 December 2015 | archive-date = 2 January 2016 | archive-url = https://web.archive.org/web/20160102040642/http://www.midsussextimes.co.uk/news/local/mid-sussex-residents-honoured-by-queen-1-6795898 | url-status = live }}</ref>
*], an internationally acclaimed bass-baritone, describes himself: "1.34 meters tall, short arms, seven fingers&nbsp;— four right, three left&nbsp;— large, relatively well-formed head, brown eyes, distinctive lips; profession: singer".<ref>{{cite web|url=http://www.portlandphoenix.com/archive/music/02/04/19/classical_Orpheus.html |title=Orpheus lives: A small good thing in Quastoff |work=The Portland Phoenix |date=19 April 2002 |access-date=6 June 2013 |url-status=dead |archive-url=https://web.archive.org/web/20120306201745/https://www.portlandphoenix.com/archive/music/02/04/19/classical_Orpheus.html |archive-date=6 March 2012 }}</ref>
*] produced a documentary called '']'', based on the lives of 12 people affected by the drug, which was released in 2008.<ref>{{cite web |url=https://www.imdb.com/title/tt1266093/releaseinfo |title=NoBody's Perfect (2008): Release Info |publisher=IMDB |access-date=6 June 2013 |archive-date=23 June 2013 |archive-url=https://web.archive.org/web/20130623182019/http://www.imdb.com/title/tt1266093/releaseinfo |url-status=live }}</ref><ref>{{cite web |url=http://www.spiritualityandpractice.com/films/films.php?id=19559 |title=Film Review: NoBody's Perfect | vauthors = Brussat F, Brussat MA |publisher=Spirituality & Practice |access-date=6 June 2013 |archive-date=9 May 2013 |archive-url= https://web.archive.org/web/20130509033726/http://www.spiritualityandpractice.com/films/films.php?id=19559 |url-status=live }}</ref>
*], born with phocomelia of both arms, drove the successful campaign for compensation from her government for Canadians who were affected by thalidomide.<ref>{{cite web|author=<!--Staff writer(s); no by-line.-->|title=Outstanding eight to receive honorary doctorates at Convocation|url=http://www.uwindsor.ca/dailynews/2016-06-07/outstanding-eight-receive-honorary-doctorates-convocation|website=Daily News|publisher=University of Windsor|access-date=6 March 2017|location=Windsor, Ontario, Canada|date=9 June 2016|archive-date=7 March 2017|archive-url=https://web.archive.org/web/20170307123542/http://www.uwindsor.ca/dailynews/2016-06-07/outstanding-eight-receive-honorary-doctorates-convocation|url-status=live}}</ref>
*], born with phocomelia of both arms, is an English rock musician, actor, writer and performance artist. He produced a 2002 television documentary "Born Freak", which looked at this historical tradition and its relevance to modern disabled performers. This work has become the subject of academic analysis in the field of disability studies.<ref>{{Cite journal | vauthors = Mitchell D, Snyder S | title = Exploitations of embodiment: Born Freak and the academic bally plank. | journal = Disability Studies Quarterly | date = June 2005 | volume = 25 | issue = 3 | url = http://www.dsq-sds.org/article/view/575/752 | doi = 10.18061/dsq.v25i3.575 | doi-access = free | access-date = 30 May 2019 | archive-date = 23 October 2020 | archive-url = https://web.archive.org/web/20201023214836/https://dsq-sds.org/article/view/575/752 | url-status = live }}</ref>
*Sue Kent, born in 1963 with phocomelia of both arms, eight inches long, no thumbs, and seven fingers – three on one hand, four on the other - has appeared as a presenter on the BBC TV show '']'' since 2020, demonstrating her ability to garden using her feet and toes where others would use their hands.<ref>The Thalidomide Trust, Sue Kent's Garden Featured on the BBC, 16 September 2020. https://www.thalidomidetrust.org/sue-kents-garden-featured-on-the-bbc/ {{Webarchive|url=https://web.archive.org/web/20221023225648/https://www.thalidomidetrust.org/sue-kents-garden-featured-on-the-bbc/ |date=23 October 2022 }}</ref>
*], born in 1962 with phocomelia of both arms and both legs, is a Swiss politician who served for 14 years in the legislature in the ] including 2 years as its president and has been a member of the ] since 2011.

===Change in drug regulations===
The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the 1962 ]<ref>{{cite web|title=50 Years: The Kefauver-Harris Amendments|url=https://www.fda.gov/Drugs/NewsEvents/ucm320924.htm|publisher=]|access-date=6 June 2013|archive-date=7 March 2013|archive-url=https://web.archive.org/web/20130307165433/http://www.fda.gov/Drugs/NewsEvents/ucm320924.htm|url-status=live}}</ref> (US), 1965 ] (EU),<ref>{{cite web|title=Thalidomide |url=http://www.crncc.nihr.ac.uk/workforce_development/learning_and_development/gcp/gcp_resource/research_standards/history/thalidomide |publisher=] |access-date=6 June 2013 |url-status=dead |archive-url=https://web.archive.org/web/20131203020225/http://www.crncc.nihr.ac.uk/workforce_development/learning_and_development/gcp/gcp_resource/research_standards/history/thalidomide |archive-date=3 December 2013 }}</ref> and the ] (UK).<ref>{{cite journal | vauthors = Conroy S, McIntyre J, Choonara I | title = Unlicensed and off label drug use in neonates | journal = Archives of Disease in Childhood. Fetal and Neonatal Edition | volume = 80 | issue = 2 | pages = F142-4; discussion F144-5 | date = March 1999 | pmid = 10325794 | pmc = 1720896 | doi = 10.1136/fn.80.2.F142 }}</ref><ref>{{cite web | publisher = Royal Pharmaceutical Society | title = The evolution of pharmacy, Theme E, Level 3 Thalidomide and its aftermath | url = https://www.rpharms.com/museum-pdfs/e3a-thalidomide-and-its-aftermath-2011.pdf | archive-url = https://web.archive.org/web/20111014114005/https://www.rpharms.com/museum-pdfs/e3a-thalidomide-and-its-aftermath-2011.pdf | url-status = dead | archive-date = 14 October 2011 | date = 2011 }}</ref> In the United States, the new regulations strengthened the FDA, among other ways, by requiring applicants to prove efficacy and to disclose all side effects encountered in testing.<ref name=Bren /> The FDA subsequently initiated the ] to reclassify drugs already on the market.

=== Impact on research involving women ===
In 1977 the US Federal Drug Administration published a clinical trial guideline that excluded women of "childbearing potential" from the early phases of most clinical trials, which in practice led to their exclusion from later trial phases as well.<ref name="Merkatz 1998">{{cite journal | vauthors = Merkatz RB | title = Inclusion of women in clinical trials: a historical overview of scientific, ethical, and legal issues | journal = Journal of Obstetric, Gynecologic, and Neonatal Nursing | volume = 27 | issue = 1 | pages = 78–84 | date = January 1998 | pmid = 9475131 | doi = 10.1111/j.1552-6909.1998.tb02594.x | doi-access = free }}</ref> This 1977 FDA guideline was implemented in response to a protectionist climate caused by the thalidomide tragedy.<ref name="Merkatz 1998" /> In the 1980s, a US task force on women's health concluded that a lack of women's health research (in part due to the FDA guideline) had compromised the amount and quality of information available about diseases and treatments affecting women.<ref name="Merkatz 1998" /> This led to the National Institute of Health policy that women should, when beneficial, be included in clinical trials.<ref name="Merkatz 1998" />

=== Quality of life ===
In the 1960s, thalidomide was successfully marketed as a safer alternative to ]s. Due to a successful marketing campaign, thalidomide was widely used by pregnant women during the first trimester of pregnancy. However, thalidomide is a ] substance, and a proportion of children born during the 1960s had thalidomide embryopathy (TE).<ref name="Wadman e0210222">{{cite journal | vauthors = Newbronner E, Glendinning C, Atkin K, Wadman R | title = The health and quality of life of Thalidomide survivors as they age - Evidence from a UK survey | journal = PLOS ONE | volume = 14 | issue = 1 | pages = e0210222 | date = 16 January 2019 | pmid = 30650111 | pmc = 6334953 | doi = 10.1371/journal.pone.0210222 | bibcode = 2019PLoSO..1410222N | doi-access = free }}</ref> Of these babies born with TE, "about 40% of them died before their first birthday".<ref name="40 years later: the health related">{{cite journal | vauthors = Nippert I, Edler B, Schmidt-Herterich C | title = 40 years later: the health related quality of life of women affected by thalidomide | journal = Community Genetics | volume = 5 | issue = 4 | pages = 209–16 | date = 2002 | pmid = 14960874 | doi = 10.1159/000066691 | s2cid = 29641011 }}</ref> The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE.

Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health.<ref name="Wadman e0210222"/> Access to healthcare services can also be a challenge for these people, and women, in particular, have experienced difficulty in locating healthcare professionals who can understand and embrace their needs.<ref name="40 years later: the health related"/>

===Brand names===
Brand names include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval, and many others.<ref name="pubchem" />

==Research==
Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide.

===Thalidomide analogs===
{{Main|Development of analogs of thalidomide}}
The exploration of the ] and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide ]s.<ref name="pmid10447943">{{cite journal | vauthors = Shah JH, Swartz GM, Papathanassiu AE, Treston AM, Fogler WE, Madsen JW, Green SJ | title = Synthesis and enantiomeric separation of 2-phthalimidino-glutaric acid analogues: potent inhibitors of tumor metastasis | journal = Journal of Medicinal Chemistry | volume = 42 | issue = 16 | pages = 3014–7 | date = August 1999 | pmid = 10447943 | doi = 10.1021/jm990083y }}</ref><ref name=pmid11740816>{{cite journal | vauthors = D'Amato RJ, Lentzsch S, Anderson KC, Rogers MS | title = Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma | journal = Seminars in Oncology | volume = 28 | issue = 6 | pages = 597–601 | date = December 2001 | pmid = 11740816 | doi = 10.1016/S0093-7754(01)90031-4 }}</ref> Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as ], that are substantially more powerful and have fewer side effects&nbsp;— except for greater ].<ref>{{cite journal | vauthors = Rao KV | title = Lenalidomide in the treatment of multiple myeloma | journal = American Journal of Health-System Pharmacy | volume = 64 | issue = 17 | pages = 1799–807 | date = September 2007 | pmid = 17724360 | doi = 10.2146/ajhp070029 }}</ref> In 2005, Celgene received FDA approval for ] (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, ], is now FDA-approved.<ref>{{cite web|url=http://clinicaltrials.gov/ct/search?term=pomalidomide&submit=Search|title=Search of: pomalidomide|publisher=Clinicaltrials.gov|access-date=1 September 2012|archive-date=3 July 2015|archive-url=https://web.archive.org/web/20150703130302/https://clinicaltrials.gov/ct/search?term=pomalidomide&submit=Search|url-status=live}}</ref> Additionally, ] was approved by the FDA in March 2014. These ] can be used to treat different diseases, or used in a regimen to fight two conditions.<ref>{{cite journal | vauthors = Raghupathy R, Billett HH | title = Promising therapies in sickle cell disease | journal = Cardiovascular & Hematological Disorders Drug Targets | volume = 9 | issue = 1 | pages = 1–8 | date = March 2009 | pmid = 19275572 | doi = 10.2174/187152909787581354 }}</ref>

Interest turned to ], a ] of thalidomide marketed by ]. It is a very active anti-angiogenic agent<ref name=pmid11740816/> and also acts as an ]. Pomalidomide was approved in February 2013 by the FDA as a treatment for relapsed and refractory ].<ref name=P1>{{cite web|title=Pomalyst (Pomalidomide) Approved By FDA For Relapsed And Refractory Multiple Myeloma|url=http://www.myelomabeacon.com/news/2013/02/08/pomalyst-pomalidomide-fda-approval-multiple-myeloma/|publisher=The Myeloma Beacon|access-date=10 August 2013|archive-date=7 January 2014|archive-url=https://web.archive.org/web/20140107033928/http://www.myelomabeacon.com/news/2013/02/08/pomalyst-pomalidomide-fda-approval-multiple-myeloma/|url-status=live}}</ref> It received a similar approval from the ] in August 2013, and is expected to be marketed in Europe under the brand name '''Imnovid'''.<ref name=P2>{{cite web|title=Pomalidomide Approved In Europe For Relapsed And Refractory Multiple Myeloma|url=http://www.myelomabeacon.com/news/2013/08/09/pomalidomide-imnovid-pomalyst-europe-ema-approval-multiple-myeloma/|publisher=The Myeloma Beacon|access-date=10 August 2013|archive-date=18 January 2014|archive-url=https://web.archive.org/web/20140118140152/http://www.myelomabeacon.com/news/2013/08/09/pomalidomide-imnovid-pomalyst-europe-ema-approval-multiple-myeloma/|url-status=live}}</ref>

===Clinical research===
There is no conclusive evidence that thalidomide or ] is useful to bring about or maintain remission in Crohn's disease.<ref>{{cite journal | vauthors = Srinivasan R, Akobeng AK | title = Thalidomide and thalidomide analogues for induction of remission in Crohn's disease | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD007350 | date = April 2009 | pmid = 19370684 | doi = 10.1002/14651858.CD007350.pub2 }}</ref><ref>{{cite journal | vauthors = Akobeng AK, Stokkers PC | title = Thalidomide and thalidomide analogues for maintenance of remission in Crohn's disease | journal = The Cochrane Database of Systematic Reviews | issue = 2 | pages = CD007351 | date = April 2009 | volume = 2009 | pmid = 19370685 | pmc = 7207562 | doi = 10.1002/14651858.CD007351.pub2 }}</ref>

Thalidomide was studied in a Phase II trial for ], a rare soft-tissue cancer most commonly seen in the immunocompromised, that is caused by the ] (KSHV).<ref>{{cite web | title = Kaposi Sarcoma Treatment & Management | work = Medscape Reference | publisher = WebMD | date = 11 March 2013 | access-date = 19 January 2014 | url = http://emedicine.medscape.com/article/279734-treatment#showall | vauthors = Rose LJ, Fishman AD, Sparano JA | veditors = Talavera F, McKenna R, Harris JE | archive-date = 2 February 2014 | archive-url = https://web.archive.org/web/20140202145013/http://emedicine.medscape.com/article/279734-treatment#showall | url-status = live }}</ref><ref name="pmid15172781"/>

{{Div col}}
* AIDS wasting syndrome,<ref>{{cite journal | vauthors = Gordon JN, Trebble TM, Ellis RD, Duncan HD, Johns T, Goggin PM | title = Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial | journal = Gut | volume = 54 | issue = 4 | pages = 540–5 | date = April 2005 | pmid = 15753541 | pmc = 1774430 | doi = 10.1136/gut.2004.047563 }}</ref> associated diarrhea<ref>{{cite journal | vauthors = Sharpstone D, Rowbottom A, Francis N, Tovey G, Ellis D, Barrett M, Gazzard B | title = Thalidomide: a novel therapy for microsporidiosis | journal = Gastroenterology | volume = 112 | issue = 6 | pages = 1823–9 | date = June 1997 | pmid = 9178672 | doi = 10.1053/gast.1997.v112.pm9178672 | doi-access = free }}</ref>
* ] (RCC)<ref name="pmid15172781"/><ref>{{cite journal | vauthors = Tunio MA, Hashmi A, Qayyum A, Naimatullah N, Masood R | title = Low-dose thalidomide in patients with metastatic renal cell carcinoma | journal = The Journal of the Pakistan Medical Association | volume = 62 | issue = 9 | pages = 876–9 | date = September 2012 | pmid = 23139966 }}</ref>
* ]<ref name="pmid15172781"/>
* ]<ref name="pmid15172781"/>
* ]<ref name="pmid15172781"/>
* ]<ref name="pmid15172781"/>
* ]<ref name="pmid15172781"/>
* ]<ref name="pmid15172781"/>
* ]<ref>{{cite journal | vauthors = Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H | title = Thalidomide in the treatment of the mucocutaneous lesions of the Behçet syndrome. A randomized, double-blind, placebo-controlled trial | journal = Annals of Internal Medicine | volume = 128 | issue = 6 | pages = 443–50 | date = March 1998 | pmid = 9499327 | doi = 10.7326/0003-4819-128-6-199803150-00004 | s2cid = 12089634 }}</ref>
* ]<ref name="pmid15172781"/>
* ]<ref name="pmid15172781"/>
* ]<ref name="pmid15172781"/>
* Chronic heart failure<ref name="pmid15172781"/>
* Graft-versus-host disease<ref name="pmid15172781"/>
* ]<ref>{{cite journal | vauthors = Wallis RS, Hafner R | title = Advancing host-directed therapy for tuberculosis | journal = Nature Reviews. Immunology | volume = 15 | issue = 4 | pages = 255–63 | date = April 2015 | pmid = 25765201 | doi = 10.1038/nri3813 | s2cid = 1452130 }}</ref>
{{div col end}}

== References ==
{{reflist}}

== Further reading ==
{{refbegin}}
* {{cite book | vauthors = Stephens T, Brynner R |title=Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine |date=24 December 2001 |publisher=] |isbn=978-0-7382-0590-8 |url-access=registration |url=https://archive.org/details/darkremedyimpact00step }}
* {{cite book | vauthors = Knightley P, Evans H |author-link1 = Phillip Knightley | author-link2 = Harold Evans|title=Suffer The Children: The Story of Thalidomide |year=1979| publisher=]|location=New York|isbn=978-0-670-68114-3}}
{{refend}}

== External links ==
* {{cite web | vauthors = Daemmrich A | url = https://theconversation.com/remind-me-again-what-is-thalidomide-and-how-did-it-cause-so-much-harm-46847 | title = Remind me again, what is thalidomide and how did it cause so much harm | work = The Conversation | date = 7 December 2015 }}

{{Angiogenesis inhibitors}}
{{Immunosuppressants}} {{Immunosuppressants}}
{{Androgen receptor modulators}}
{{Portal bar | Medicine}}
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