View source for Thalidomide

{{Short description|Immunomodulatory drug which can cause birth defects}}
{{About|the drug|the thalidomide scandal and birth defect crisis|Thalidomide scandal}}
{{Use dmy dates|date=October 2022}}
{{cs1 config|name-list-style=vanc|display-authors=6}}
{{infobox drug
| Verifiedfields = changed
| Watchedfields = changed
| verifiedrevid = 420478187
| image = Thalidomide enantiomers.svg
| image_class = skin-invert-image
| 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 = [[Oral administration|By mouth]]
| 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 |date=11 March 2021 |title=Thalomid- thalidomide capsule |url=https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2eda833b-1357-4ed4-a093-194524fcb061 |url-status=live |archive-url=https://web.archive.org/web/20221021205855/https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=2eda833b-1357-4ed4-a093-194524fcb061 |archive-date=21 October 2022 |access-date=21 October 2022 |website=DailyMed}}</ref>
| legal_EU = Rx-only
| legal_EU_comment  = <ref>{{Cite web |date=17 September 2018 |title=Thalidomide BMS EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-celgene |url-status=live |archive-url=https://web.archive.org/web/20221021205855/https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-celgene |archive-date=21 October 2022 |access-date=21 October 2022 |website=European Medicines Agency}}</ref><ref>{{Cite web |date=18 July 2022 |title=Thalidomide Lipomed EPAR |url=https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-lipomed |url-status=live |archive-url=https://web.archive.org/web/20221021205902/https://www.ema.europa.eu/en/medicines/human/EPAR/thalidomide-lipomed |archive-date=21 October 2022 |access-date=21 October 2022 |website=European Medicines Agency}}</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 |year=2004 |title=Clinical pharmacokinetics of thalidomide |journal=Clinical Pharmacokinetics |volume=43 |issue=5 |pages=311–27 |doi=10.2165/00003088-200443050-00004 |pmid=15080764 |s2cid=37728304}}</ref>
| metabolism = [[Liver]] (minimally via [[CYP2C19]]-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 = 4Z8R6ORS6L
| KEGG_Ref = {{keggcite|correct|kegg}}
| KEGG = D00754
| ChEBI_Ref = {{ebicite|changed|EBI}}
| ChEBI = 9513
| ChEMBL_Ref = {{ebicite|correct|EBI}}
| 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 = 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 = UEJJHQNACJXSKW-UHFFFAOYSA-N
| density           =
| density_notes     =
| melting_point     =
| melting_high      =
| melting_notes     =
| boiling_point     =
| boiling_notes     =
| solubility        =
| sol_units         =
| specific_rotation =
}}

<!-- Definition and medical uses -->
'''Thalidomide''', sold under the brand names '''Contergan''' and '''Thalomid''' among others, is an [[oral administered]] medication used to treat a number of cancers (e.g., [[multiple myeloma]]), [[graft-versus-host disease]], and many [[skin disorder]]s (e.g., complications of [[leprosy]] such as [[skin lesion]]s).<ref name="AHFS">{{Cite web |date=7 April 2023 |title=Thalidomide Monograph for Professionals |url=https://www.drugs.com/monograph/thalidomide.html |website=Drugs.com}} Updated as required.</ref><ref name="pubchem">{{Cite web |title=Thalidomide {{!}} C13H10N2O4 |url=https://pubchem.ncbi.nlm.nih.gov/compound/Thalidomide |url-status=live |archive-url=https://web.archive.org/web/20230213133343/https://pubchem.ncbi.nlm.nih.gov/compound/Thalidomide |archive-date=13 February 2023 |access-date=13 February 2023 |website=PubChem |publisher=[[National Center for Biotechnology Information]], [[National Library of Medicine]] |id=CID 5426}}</ref> Thalidomide has been used to treat conditions associated with [[HIV]]: [[aphthous ulcers]], HIV-associated [[wasting syndrome]], diarrhea, and [[Kaposi's sarcoma]], but increases in HIV viral load have been reported.<ref name=AHFS/>

<!-- Side effects and mechanism -->
Common side effects include [[sleepiness]], [[rash]], and [[dizziness]].<ref name=AHFS/> Severe side effects include [[tumor lysis syndrome]], [[blood clots]], and [[peripheral neuropathy]].<ref name="BNF76">{{Cite book |title=British national formulary: BNF 76 |date=2018 |publisher=Pharmaceutical Press |isbn=978-0-85711-338-2 |edition=76 |pages=936}}</ref> Thalidomide is a known human [[Teratology|teratogen]] 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 [[Amelia (birth defect)|amelia]] (absence of legs and/or arms), absence of bones, and [[phocomelia]] (malformation of the limbs). A single dose of thalidomide, regardless of dosage, is enough to cause teratogenic effects.<ref name=AHFS/>

<!-- Early history -->
Thalidomide was first marketed in 1957 in West Germany, where it was available as an [[over-the-counter drug]].<ref name="OUP2003">{{Cite book |url=https://archive.org/details/oxfordcompaniont0000unse_z0k4/page/682 |title=The Oxford Companion to the Body |vauthors=Cuthbert A |publisher=Oxford University Press |year=2003 |isbn=978-0-19-852403-8 |page=[https://archive.org/details/oxfordcompaniont0000unse_z0k4/page/682 682] |doi=10.1093/acref/9780198524038.001.0001 |url-access=registration}}</ref><ref name=Mill1991/> When first released, thalidomide was promoted for [[anxiety]], [[insomnia|trouble sleeping]], "tension", and [[morning sickness]].<ref name="Mill1991">{{Cite journal |vauthors=Miller MT |year=1991 |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 |pmc=1298636 |pmid=1808819}}</ref><ref name="Lou2004">{{Cite book |url=https://books.google.com/books?id=LbHWgd-mDbsC&pg=PA644 |title=Encyclopedia of Women's Health |vauthors=Loue S, Sajatovic M |date=2004 |publisher=Springer Science & Business Media |isbn=978-0-306-48073-7 |page=644 |language=en |access-date=25 August 2020 |archive-url=https://web.archive.org/web/20211115114232/https://books.google.com/books?id=LbHWgd-mDbsC&pg=PA644 |archive-date=15 November 2021 |url-status=live}}</ref> While it was initially thought to be safe in pregnancy, [[Thalidomide scandal|thalidomide was found to cause birth defects]], 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 [[Frances Kelsey]], a reviewer at the FDA.<ref name=Lou2004/> The birth defects caused by thalidomide led to the development of greater [[drug regulation]] and monitoring in many countries.<ref name=OUP2003/><ref name=Lou2004/>

<!-- Current use -->
It was approved in the United States in 1998 for use as a treatment for cancer.<ref name=AHFS/> It is on the [[World Health Organization's List of Essential Medicines]].<ref name="WHO22nd">{{Cite book |title=Model list of essential medicines: 22nd list |vauthors=Organization WH |publisher=[[World Health Organization]] |year=2021 |location=Geneva |hdl=10665/345533 |id=WHO/MHP/HPS/EML/2021.02 |hdl-access=free}}</ref> It is available as a [[generic medication]].<ref name=BNF76/><ref>{{Cite web |date=30 May 2023 |title=First Generic Drug Approvals |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 |access-date=30 June 2023 |website=U.S. [[Food and Drug Administration]]}}</ref>

{{TOC limit}}

==Medical uses==
[[File:Pack of Thalidomide tablets.jpg|thumb|Pack of thalidomide capsules]]

Thalidomide is used as a first-line treatment for [[multiple myeloma]] in combination with [[dexamethasone]] or with [[melphalan]] and [[prednisone]] to treat acute episodes of [[erythema nodosum leprosum]], as well as for maintenance therapy.<ref name="UKlabel2017">{{Cite web |date=January 2017 |title=Thalidomide Celgene 50 mg Hard Capsules - Summary of Product Characteristics |url=https://www.medicines.org.uk/emc/medicine/21005 |url-status=live |archive-url=https://web.archive.org/web/20180830210156/https://www.medicines.org.uk/emc/medicine/21005 |archive-date=30 August 2018 |access-date=26 June 2017 |publisher=UK Electronic Medicines Compendium}}</ref><ref name="USlabel2017">{{Cite web |date=January 2017 |title=US Thalomid label |url=https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020785s061lbl.pdf |archive-url=https://web.archive.org/web/20170710160759/https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/020785s061lbl.pdf |archive-date=10 July 2017 |access-date=26 June 2017 |publisher=FDA}} 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>

The bacterium that causes [[tuberculosis]] (TB) is related to [[leprosy]]. Thalidomide may be helpful in some cases where [[Tuberculosis management|standard TB drugs]] and [[corticosteroid]]s are not sufficient to resolve severe inflammation in the brain.<ref>{{Cite journal |vauthors=Buonsenso D, Serranti D, Valentini P |date=October 2010 |title=Management of central nervous system tuberculosis in children: light and shade |url=http://www.europeanreview.org/wp/wp-content/uploads/827.pdf |journal=European Review for Medical and Pharmacological Sciences |volume=14 |issue=10 |pages=845–53 |pmid=21222370 |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 |date=March 2014 |title=Update on the diagnosis and management of tuberculous meningitis in children |journal=Seminars in Pediatric Neurology |volume=21 |issue=1 |pages=12–8 |doi=10.1016/j.spen.2014.01.006 |pmid=24655399}}</ref>

It is used as a second-line treatment to manage [[graft-versus-host disease]] and [[aphthous stomatitis]] in children and has been prescribed for other conditions in children, including [[actinic prurigo]] and [[epidermolysis bullosa]]; the evidence for these uses is weak.<ref>{{Cite journal |vauthors=Yang CS, Kim C, Antaya RJ |date=April 2015 |title=Review of thalidomide use in the pediatric population |journal=Journal of the American Academy of Dermatology |volume=72 |issue=4 |pages=703–11 |doi=10.1016/j.jaad.2015.01.002 |pmid=25617013}}</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 |date=December 2010 |title=Consensus conference on clinical practice in chronic graft-versus-host disease (GVHD): first-line and topical treatment of chronic GVHD |url=http://www.bbmt.org/article/S1083-8791(10)00275-2/fulltext |url-status=live |journal=Biology of Blood and Marrow Transplantation |volume=16 |issue=12 |pages=1611–28 |doi=10.1016/j.bbmt.2010.06.015 |pmid=20601036 |archive-url=https://web.archive.org/web/20210829083423/https://www.astctjournal.org/article/S1083-8791%2810%2900275-2/fulltext |archive-date=29 August 2021 |access-date=26 June 2017 |doi-access=free}}</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 |date=January 2011 |title=Consensus Conference on Clinical Practice in Chronic GVHD: Second-Line Treatment of Chronic Graft-versus-Host Disease |url=http://www.bbmt.org/article/S1083-8791(10)00223-5/fulltext |url-status=live |journal=Biology of Blood and Marrow Transplantation |volume=17 |issue=1 |pages=1–17 |doi=10.1016/j.bbmt.2010.05.011 |pmid=20685255 |archive-url=https://web.archive.org/web/20210829083352/https://www.astctjournal.org/article/S1083-8791%2810%2900223-5/fulltext |archive-date=29 August 2021 |access-date=26 June 2017 |doi-access=free}}</ref>

==Contraindications==
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 |date=April 2020 |title=Paternal safety of anti-rheumatic medications |journal=Best Practice & Research. Clinical Obstetrics & Gynaecology |volume=64 |pages=77–84 |doi=10.1016/j.bpobgyn.2019.09.004 |pmid=31727565 |s2cid=208034967}}</ref> In the United States, the prescribing doctor is required to ensure that [[contraception]] is being used and that regular pregnancy tests are taken.<ref name=USlabel2017/><ref name=UKlabel2017/>

==Adverse effects==
{{See also|List of thalidomide side effects}}
Thalidomide [[Teratogen|causes birth defects]].<ref name=UKlabel2017/><ref name=USlabel2017/><ref name="toxmech2009">{{Cite journal |vauthors=Smith SW |date=July 2009 |title=Chiral toxicology: it's the same thing...only different |journal=Toxicological Sciences |volume=110 |issue=1 |pages=4–30 |doi=10.1093/toxsci/kfp097 |pmid=19414517 |doi-access=free}}</ref><ref>Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, p3</ref> The U.S. [[FDA|Food and Drug Administration]] (FDA) and other regulatory agencies have approved marketing of the drug only with an auditable [[risk evaluation and mitigation strategy]] 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 [[semen]].<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 [[Thrombosis|blood clots]]. 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 [[neutropenia]], [[leukopenia]], and [[lymphopenia]], and risks that blood will not clot via [[thrombocytopenia]]. There is also a risk of [[anemia]] via lack of red blood cells.  The drug can also damage nerves, causing potentially irreversible [[peripheral neuropathy]].<ref name=UKlabel2017/><ref name=USlabel2017/>

Thalidomide has several adverse cardiovascular effects, including risk of [[heart attack]]s, [[pulmonary hypertension]], and changes in heart rhythm, such as [[syncope (medicine)|syncope]], [[bradycardia]], and [[atrioventricular block]].<ref name=UKlabel2017/><ref name=USlabel2017/>

Thalidomide can cause [[liver damage]] and severe skin reactions like [[Stevens–Johnson syndrome]]. It tends to make people sleepy, which creates risk when driving and operating other machinery. As it kills cancer cells, it can cause [[tumor lysis syndrome]]. Thalidomide can [[Amenorrhea|prevent menstruation]].<ref name=UKlabel2017/><ref name=USlabel2017/>

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

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/>

=== Interactions ===
There are no expected [[Pharmacokinetics|pharmacokinetic]] interactions between thalidomide and other medicines due to its neutral effects on [[P-glycoprotein]] and the [[cytochrome P450]] 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 [[peripheral neuropathy]] may be increased by concomitant treatment of thalidomide with other agents known to cause peripheral neuropathy.<ref name="TGA">{{Cite web |date=21 June 2013 |title=THALOMID® CAPSULES |url=https://www.ebs.tga.gov.au/ebs/picmi/picmirepository.nsf/pdf?OpenAgent&id=CP-2010-PI-03581-3 |url-status=live |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 |archive-date=4 September 2015 |access-date=17 January 2014 |website=TGA eBusiness Services |publisher=Celgene Pty Limited |format=PDF}}</ref> The risk of [[venous thromboembolism]]s with thalidomide seems to be increased when patients are treated with [[oral contraceptives]] or other cytotoxic agents (including [[doxorubicin]] and [[melphalan]]) 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/>

===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 [[Supportive treatment|supportive]].<ref name = TGA/>

==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 |date=August 2022 |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 |doi=10.1039/D2CS00116K |pmid=35796627 |s2cid=250337170 |doi-access=free}}</ref> although efforts to identify thalidomide's [[Teratology|teratogenic]] 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 |date=June 2000 |title=Mechanism of action in thalidomide teratogenesis |journal=Biochemical Pharmacology |volume=59 |issue=12 |pages=1489–1499 |doi=10.1016/S0006-2952(99)00388-3 |pmid=10799645}}</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 [[cereblon]] [[E3 ligase]] modulators.<ref name="Yamamoto" /><ref>{{Cite journal |vauthors=Ito T, Handa H |date=11 June 2020 |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 |bibcode=2020PJAB...96..189I |doi=10.2183/pjab.96.016 |pmc=7298168 |pmid=32522938}}</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 |date=November 2019 |title=p63 is a cereblon substrate involved in thalidomide teratogenicity |journal=Nature Chemical Biology |volume=15 |issue=11 |pages=1077–1084 |doi=10.1038/s41589-019-0366-7 |pmid=31591562 |s2cid=203853198}}</ref><ref>{{Cite journal |vauthors=Gao S, Wang S, Song Y |date=December 2020 |title=Novel immunomodulatory drugs and neo-substrates |journal=Biomarker Research |volume=8 |issue=1 |article-number=2 |doi=10.1186/s40364-020-0182-y |pmc=6953231 |pmid=31938543 |doi-access=free}}</ref>

Thalidomide also binds to and acts as an [[receptor antagonist|antagonist]] of the [[androgen receptor]] and hence is a [[nonsteroidal antiandrogen]] of some capacity.<ref name="LiuSu2010">{{Cite journal |vauthors=Liu B, Su L, Geng J, Liu J, Zhao G |date=October 2010 |title=Developments in nonsteroidal antiandrogens targeting the androgen receptor |journal=ChemMedChem |volume=5 |issue=10 |pages=1651–61 |doi=10.1002/cmdc.201000259 |pmid=20853390 |s2cid=23228778}}</ref> In accordance, it can produce [[gynecomastia]] and [[sexual dysfunction]] as side effects in men.<ref name="NuttallWarrier2015">{{Cite journal |vauthors=Nuttall FQ, Warrier RS, Gannon MC |date=May 2015 |title=Gynecomastia and drugs: a critical evaluation of the literature |journal=European Journal of Clinical Pharmacology |volume=71 |issue=5 |pages=569–78 |doi=10.1007/s00228-015-1835-x |pmc=4412434 |pmid=25827472}}</ref>

=== Chirality and biological activity ===
Thalidomide is provided as a [[racemic mixture]] of two [[enantiomer]]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. The use of ''R''-thalidomide does not remove the risk of birth defects, as it was demonstrated that the "safe" ''R''-thalidomide undergoes an ''in vivo'' [[chiral inversion]] to the teratogenic ''S''-thalidomide. Under biological conditions, the enantiomers interconvert (''bidirectional chiral inversion'' – (R)- to (S)- and vice versa).<ref>{{Cite book |title=Stereochemical aspects of drug action and disposition |vauthors=Branch SK, Eichelbaum M, Testa B, Somogyi A |date=2003 |publisher=Springer |isbn=978-3-540-41593-0 |location=Berlin |oclc=52515592}}</ref><ref>{{Cite web |date=20 August 2022 |title=Thalidomide |url=https://chiralpedia.com/blog/thalidomide/ |url-status=live |archive-url=https://web.archive.org/web/20220827093228/https://chiralpedia.com/blog/thalidomide/ |archive-date=27 August 2022 |access-date=27 August 2022 |website=Chiralpedia |language=en-US}}</ref>

== Chemistry ==
[[Image:Thalidomide-structures.png|thumb|right|300px|The two [[enantiomers]] of thalidomide:<br />Left: (''S'')-(−)-thalidomide<br />Right: (''R'')-(+)-thalidomide]]

Thalidomide is a chiral molecule, and when synthesized is formed as [[Racemic mixture|racemic]]; while ''S''-thalidomide is the bioactive form of the molecule, the individual enantiomers can [[Racemization|racemize]] to each other due to the acidic hydrogen at the [[chiral centre]], which is the carbon of the [[glutarimide]] ring bonded to the [[phthalimide]] [[substituent]]. The racemization process can occur ''[[in vivo]]''.<ref name = clinp/><ref name="stereospecific44">{{Cite journal |vauthors=Eriksson T, Björkman S, Roth B, Fyge A, Höglund P |year=1995 |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 |doi=10.1002/chir.530070109 |pmid=7702998}}</ref><ref name="pmid14505639">{{Cite journal |vauthors=Man HW, Corral LG, Stirling DI, Muller GW |date=October 2003 |title=Alpha-fluoro-substituted thalidomide analogues |journal=Bioorganic & Medicinal Chemistry Letters |volume=13 |issue=20 |pages=3415–7 |doi=10.1016/S0960-894X(03)00778-9 |pmid=14505639}}</ref><ref name="Bartlett2004">{{Cite journal |vauthors=Bartlett JB, Dredge K, Dalgleish AG |date=April 2004 |title=The evolution of thalidomide and its IMiD derivatives as anticancer agents |journal=Nature Reviews. Cancer |volume=4 |issue=4 |pages=314–22 |doi=10.1038/nrc1323 |pmid=15057291 |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 |date=December 2004 |title=Chiral inversion of drugs: coincidence or principle? |journal=Current Drug Metabolism |volume=5 |issue=6 |pages=517–533 |doi=10.2174/1389200043335360 |pmid=15578945}}</ref>

[[Celgene Corporation]] originally synthesized thalidomide using a three-step sequence starting with [[Glutamate|<small>L</small>-glutamic acid]] treatment, but this has since been reformed by the use of [[Glutamine|<small>L</small>-glutamine]].<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 [[carbonyldiimidazole]], 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.{{cn|date=January 2025}}

In 2023, it is reported that [[phthalic anhydride]] and [[Glutamine|<small>L</small>-glutamine]] under suitable conditions can react directly to form thalidomide. In the procedure, phthalic anhydride and <small>L</small>-glutamine are grounded and added into [[toluene]] solvent. The solution, along with [[triethylamine]] and [[acetic anhydride]], is refluxed at ~110°C for 9 hours; after that the solution goes through a simple [[vacuum filtration]] 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=[[ChemSpider]] |language=en}}</ref>

[[File:Thalidomide syntehsis.png|class=skin-invert-image|center|thumb|567x567px|Muller et al.'s two-step thalidomide synthesis]]

==History==
[[File:Kevadon (thalidomide), 1960.jpg|thumb|right|Container of Kevadon brand of thalidomide from 1960]]
In 1952, thalidomide was synthesised by [[Novartis#Ciba-Geigy|Chemical Industry Basel]], but was found "to have no effect on animals" and was discarded on that basis.<ref name="themee">{{Cite web |last=Royal Pharmaceutical Society |date=2011 |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/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 [[Grünenthal|Chemie Grünenthal]] 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 |title=Introducing HR Analytics with Machine Learning: Empowering Practitioners, Psychologists, and Organizations |vauthors=Rosett CM, Hagerty A |date=2021 |publisher=Springer International Publishing |isbn=978-3-030-67626-1 |veditors=Rosett CM, Hagerty A |location=Cham |pages=171–189 |language=en |chapter=What History Can Teach us About Using Machine Learning Well |doi=10.1007/978-3-030-67626-1_10 |s2cid=236710887}}</ref> [[Heinrich Mückter]]<ref name="ktnyt">{{Cite news |date=23 March 2020 |title=The Unseen Survivors of Thalidomide Want to Be Heard |url=https://www.nytimes.com/2020/03/23/health/thalidomide-survivors-usa.html |url-status=live |archive-url=https://web.archive.org/web/20200323154020/https://www.nytimes.com/2020/03/23/health/thalidomide-survivors-usa.html |archive-date=23 March 2020 |access-date=23 March 2020 |work=The New York Times |language=en-US |issn=0362-4331 |vauthors=Thomas K}}</ref> was appointed to head the discovery program based on his experience working with the German army's antiviral research. While preparing [[reagents]] for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of [[glutethimide]], a [[sedative]]. 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 |url=https://archive.org/details/drugdiscoveryhis00snea |title=Drug discovery: a history |vauthors=Sneader W |date=2005 |publisher=Wiley |isbn=978-0-471-89979-2 |edition=Rev. and updated |location=Chichester |page=[https://archive.org/details/drugdiscoveryhis00snea/page/n380 367] |url-access=limited}}</ref>

Researchers at Chemie Grünenthal found that thalidomide was a particularly effective [[antiemetic]] that had an inhibitory effect on [[morning sickness]].<ref name="pmid15172781">{{Cite journal |vauthors=Franks ME, Macpherson GR, Figg WD |date=May 2004 |title=Thalidomide |url=https://zenodo.org/record/1259793 |url-status=live |journal=Lancet |volume=363 |issue=9423 |pages=1802–11 |doi=10.1016/S0140-6736(04)16308-3 |pmid=15172781 |s2cid=208789946 |archive-url=https://web.archive.org/web/20190821212125/https://zenodo.org/record/1259793 |archive-date=21 August 2019 |access-date=30 June 2019}}</ref> On 1 October 1957, the company launched thalidomide and began marketing it under the trade name Contergan.<ref>{{Cite web |title=Grünenthal: Where we come from |url=https://www.grunenthal.com/about-us/history |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 |url=http://www.bhj.org.in/journal/2008_5003_july/download/page-472-476.pdf |url-status=live |journal=Bombay Hospital Journal |location=Bombay |publisher=Bombay Hospital |volume=50 |issue=3 |pages=472–6 |archive-url=https://web.archive.org/web/20160820114658/http://www.bhj.org.in/journal/2008_5003_july/download/page-472-476.pdf |archive-date=20 August 2016 |access-date=8 August 2016}}</ref> It was proclaimed a "wonder drug" for [[insomnia]], coughs, colds and headaches.<ref>Campbell, Denis. "'Wonder drug' left babies with deformed limbs." ''The Guardian''. 29 July 2009.</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 [[fetus]].<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 [[placental barrier]] and harm the developing fetus.<ref name="Chem1994">{{Cite book |title=The Chemical Industry |vauthors=Heaton CA |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 [[peripheral neuritis]] 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 |year=1967 |title=Events after thalidomide |journal=Journal of Dental Research |volume=46 |issue=6 |pages=1201–5 |doi=10.1177/00220345670460061201 |pmid=5235007 |s2cid=11175347}}</ref>

While initially considered safe, the drug was responsible for [[teratogenic]] 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 |date=December 2021 |title=Thalidomide: history, withdrawal, renaissance, and safety concerns |journal=Expert Opinion on Drug Safety |volume=20 |issue=12 |pages=1455–1457 |doi=10.1080/14740338.2021.1991307 |pmid=34623196 |s2cid=238476677 |hdl-access=free |hdl=2164/19455}}</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 |date=June 2015 |title=Thalidomide-induced teratogenesis: history and mechanisms |journal=Birth Defects Research. Part C, Embryo Today |volume=105 |issue=2 |pages=140–156 |doi=10.1002/bdrc.21096 |pmc=4737249 |pmid=26043938}}</ref> The regulatory authorities in [[East Germany]] never approved thalidomide.<ref name="oncozine.com">{{Cite web |date=December 2013 |title=Reversal of Fortune: How a Vilified Drug Became a Life-saving Agent in the "War" Against Cancer |url=https://oncozine.com/reversal-of-fortune-how-a-vilified-drug-became-a-life-saving-agent-in-the-war-against-cancer/ |url-status=live |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/ |archive-date=11 February 2018 |access-date=10 February 2018 |website=Onco'Zine |vauthors=Hofland P}}</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 |date=6 July 2011 |title=VFA: teratogenic effects |url=http://www.vfa.de/de/arzneimittel-forschung/artikel-arzneimittel-forschung/teratogenitaet.html |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}}</ref>

In the UK, the British pharmaceutical company [[The Distillers Company]] (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of [[Diageo plc]]), marketed thalidomide throughout the UK, Australia, and New Zealand, under the brand name Distaval, as a remedy for [[morning sickness]]. 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. Thalidomide was available in 46 countries under many different brand names.<ref>{{Cite book | vauthors = Ghosh TK, Jasti BR |url=https://books.google.com/books?id=RFwkEAAAQBAJ&dq=marketing+thalidomide+46+countries&pg=PA260 |title=Theory and Practice of Contemporary Pharmaceutics |date=2021-02-25 |publisher=CRC Press |isbn=978-1-134-44195-2 |language=en}}</ref>

In the US, representatives from Chemie Grünenthal approached [[Smith, Kline & French]] (SKF), now [[GlaxoSmithKline]], 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/ |url-status=live |archive-url=https://web.archive.org/web/20230204035126/https://www.scientificamerican.com/article/lawsuit-blames-thalidomide-for-more/ |archive-date=4 February 2023 |access-date=2023-02-04 |website=Scientific American |language=en}}</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.<ref>{{Cite book |url=https://books.google.com/books?id=XAxYur9IzCsC&dq=thalidomide+sleep+mice&pg=PA111 |title=Animal Research Takes Lives: Humans and Animals Both Suffer |date=1993 |publisher=NZ Anti-Vivisection Society Inc. |isbn=978-0-473-01846-7 |language=en}}</ref> 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 ([[Marion Merrell Dow#Richardson-Merrell|later Richardson-Merrell]], now part of [[Sanofi]]), to market and distribute thalidomide throughout the US.<ref name="oncozine.com" />

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 [[Marion Merrell Dow#Richardson-Merrell|Richardson-Merrell]] had applied for its approval in September 1960.<ref>{{Cite book | vauthors = Hawthorne F |url=https://books.google.com/books?id=dfVGMxn9GwcC&dq=thalidomide+Richardson-Merrell+1960+september&pg=PT37 |title=Inside the FDA: The Business and Politics Behind the Drugs We Take and the Food We Eat |date=2010-12-13 |publisher=John Wiley & Sons |isbn=978-1-118-04006-5 |language=en}}</ref> The official in charge of the FDA review, [[Frances Oldham Kelsey]], 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 [[President's Award for Distinguished Federal Civilian Service]] by President Kennedy in 1962 for not allowing thalidomide to be approved for sale in the US. She was also inducted into the [[National Women's Hall of Fame]] in 2000.<ref>{{Cite web |date=12 May 2009 |title=Report |url=https://www.fda.gov/fdac/features/2001/201_kelsey.html |archive-url=https://web.archive.org/web/20090512235601/https://www.fda.gov/fdac/features/2001/201_kelsey.html |archive-date=12 May 2009 |publisher=U.S. Food and Drug Administration}}</ref>

Canada's Food and Drug Directorate approved the sale of thalidomide by prescription in November 1960.<ref name="Peritz2014">{{Cite news |date=November 21, 2014 |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/ |url-status=live |archive-url=https://web.archive.org/web/20230205215237/https://www.theglobeandmail.com/news/national/the-aftermath-of-thalidomide/article21689771/ |archive-date=5 February 2023 |access-date=5 February 2023 |work=[[The Globe and Mail]] |vauthors=Peritz I}}</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 |date=November 1963 |title=Canadian Thalidomide Experience |journal=Canadian Medical Association Journal |volume=89 |issue=19 |pages=987–92 |pmc=1921912 |pmid=14076167}}</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/>

===Leprosy treatment===
In 1964, Israeli physician [[Jacob Sheskin]] administered thalidomide to a patient critically ill with [[leprosy]]. The patient exhibited [[Erythema nodosum|erythema nodosum leprosum]] (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 |date=August 2002 |title=The schizophrenic career of a "monster drug" |journal=Pediatrics |volume=110 |issue=2 Pt 1 |pages=404–6 |doi=10.1542/peds.110.2.404 |pmid=12165600}}</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 |date=December 1996 |title=Thalidomide, a current teratogen in South America |journal=Teratology |volume=54 |issue=6 |pages=273–7 |doi=10.1002/(SICI)1096-9926(199702)55:2<156::AID-TERA6>3.0.CO;2-1 |pmid=9098920 |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 |date=July 2006 |title=Thalidomide embryopathy cases in Brazil after 1965 |journal=Reproductive Toxicology |volume=22 |issue=1 |pages=1–2 |bibcode=2006RepTx..22....1P |doi=10.1016/j.reprotox.2005.11.007 |pmid=16427249}}</ref><ref>{{Cite web |date=January 2006 |title=Talidomida volta a assustar |trans-title=Thalidomide again scare |url=http://www.saude.df.gov.br/003/00301009.asp?ttCD_CHAVE=31041 |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 |language=pt |vauthors=Braziliense C}}</ref> with at least 100 cases identified in Brazil between 2005 and 2010.<ref>{{Cite news |date=23 July 2013 |title=Brazil's new generation of Thalidomide babies |url=https://www.bbc.com/news/magazine-23418102 |url-status=live |archive-url=https://web.archive.org/web/20201110015129/https://www.bbc.com/news/magazine-23418102 |archive-date=10 November 2020 |access-date=21 June 2018 |work=BBC News |vauthors=Crawford A}}</ref> Nearly 6 million thalidomide pills were distributed throughout Brazil in this time period, and these cases have occurred despite the controls.<ref>{{Cite book | vauthors = Yasmin S |url=https://books.google.com/books?id=QrwLEAAAQBAJ&dq=million+thalidomide+Brazil&pg=PA132 |title=Viral BS: Medical Myths and Why We Fall for Them |date=2021-01-12 |publisher=JHU Press |isbn=978-1-4214-4041-5 |language=en}}</ref>

In 1998, the FDA approved the drug's use in the treatment of ENL.<ref name="nyt-fda">{{Cite news |date=17 July 1998 |title=Thalidomide Approved to Treat Leprosy, With Other Uses Seen |url=https://www.nytimes.com/1998/07/17/us/thalidomide-approved-to-treat-leprosy-with-other-uses-seen.html |url-status=live |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 |archive-date=3 December 2020 |access-date=8 January 2012 |work=New York Times |vauthors=Stolberg SG}}</ref> Because of thalidomide's potential for causing birth defects, the drug may be distributed only under tightly controlled conditions. The FDA required that [[Celgene Corporation]], 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" />

In 2010, the [[World Health Organization]] stated that it did not recommend thalidomide for leprosy due to the difficulty of adequately controlling its use, and due to the availability of [[clofazimine]].<ref>{{Cite web |last=Anon |title=Use of thalidomide in leprosy |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 |archive-date=10 November 2006 |access-date=22 April 2010 |website=WHO:leprosy elimination |publisher=WHO}}</ref>

===Cancer treatment===
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 |date=March 2008 |title=Multiple myeloma |journal=Blood |volume=111 |issue=6 |pages=2962–72 |doi=10.1182/blood-2007-10-078022 |pmc=2265446 |pmid=18332230}}</ref>

Little further work was done with thalidomide in cancer until the 1990s.<ref name=Kyle/>

[[Judah Folkman]] pioneered studies into the role of [[angiogenesis]] (the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that [[solid tumors]] could not expand without it.<ref name="NASbio">{{Cite web |year=2014 |title=Judah Folkman: 1933–2008. A Biographical Memoir |url=http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/folkman-judah.pdf |url-status=live |archive-url=https://web.archive.org/web/20200802184808/http://www.nasonline.org/publications/biographical-memoirs/memoir-pdfs/folkman-judah.pdf |archive-date=2 August 2020 |access-date=11 August 2015 |publisher=National Academy of Sciences |vauthors=Donahoe PK}}</ref><ref name="Beilenberg">{{Cite journal |vauthors=Bielenberg DR, D'Amore PA |year=2008 |title=Judah Folkman's contribution to the inhibition of angiogenesis |journal=Lymphatic Research and Biology |volume=6 |issue=3–4 |pages=203–7 |doi=10.1089/lrb.2008.1016 |pmid=19093793}}</ref> In 1993 he surprised the scientific world by hypothesizing the same was true of [[blood cancers]],<ref name="Folkman">{{Cite journal |vauthors=Folkman J |date=December 2001 |title=Angiogenesis-dependent diseases |journal=Seminars in Oncology |volume=28 |issue=6 |pages=536–42 |doi=10.1016/s0093-7754(01)90021-1 |pmid=11740806}}</ref> and the next year he published work showing that a [[biomarker]] 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 |year=2008 |title=Judah Folkman, a pioneer in the study of angiogenesis |journal=Angiogenesis |volume=11 |issue=1 |pages=3–10 |doi=10.1007/s10456-008-9092-6 |pmc=2268723 |pmid=18247146}}</ref>  Meanwhile, a member of his lab, Robert D'Amato, who was looking for [[angiogenesis inhibitors]], discovered in 1994 that thalidomide inhibited angiogenesis<ref>{{Cite journal |vauthors=D'Amato RJ, Loughnan MS, Flynn E, Folkman J |date=April 1994 |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 |bibcode=1994PNAS...91.4082D |doi=10.1073/pnas.91.9.4082 |pmc=43727 |pmid=7513432 |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 |date=January 1999 |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 |doi=10.1038/sj.bjc.6690020 |pmc=2362163 |pmid=10408702}}</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 |date=November 1999 |title=Antitumor activity of thalidomide in refractory multiple myeloma |journal=The New England Journal of Medicine |volume=341 |issue=21 |pages=1565–71 |doi=10.1056/NEJM199911183412102 |pmid=10564685 |doi-access=free}}</ref>

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 [[multiple myeloma]] patients.<ref name=Beilenberg/><ref>{{Cite web |title=FDA Approval for Thalidomide |url=http://www.cancer.gov/cancertopics/druginfo/fda-thalidomide |archive-url=https://web.archive.org/web/20120128120343/http://www.cancer.gov/cancertopics/druginfo/fda-thalidomide |archive-date=28 January 2012 |access-date=8 January 2012 |publisher=National Cancer Institute}}</ref>

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 |date=November 2019 |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 |doi=10.1002/14651858.CD013487 |pmc=6876545 |pmid=31765002 |collaboration=Cochrane Haematology Group}}</ref>

==Society and culture==
===Birth defect crisis===
{{main|Thalidomide scandal}}
[[Image:NCP14053.jpg|thumb|Baby born to a mother who had taken thalidomide while pregnant]]
In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities, such as [[phocomelia]], as a consequence of thalidomide use.<ref name="Bren">{{Cite news | vauthors = Bren L |date=28 February 2001 |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 |url-status=live |archive-url=https://web.archive.org/web/20110629135137/http://permanent.access.gpo.gov/lps1609/www.fda.gov/fdac/features/2001/201_kelsey.html |archive-date=29 June 2011 |access-date=23 December 2009 |work=FDA Consumer |publisher=U.S. [[Food and Drug Administration]]}}</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 22 the ears and face, day 24 the arms, and leg damage would occur if taken up to day 28.<ref>{{Cite book | vauthors = Black S |url=https://books.google.com/books?id=DfcDEAAAQBAJ&dq=thalidomide+day+20+central+brain+damage&pg=PT208 |title=Written in Bone: Hidden Stories in What We Leave Behind |date=2021-06-01 |publisher=Simon and Schuster |isbn=978-1-951627-94-2 |language=en}}</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="nyt-answers">{{Cite news | vauthors = Zimmer C |author-link=Carl Zimmer |date=15 March 2010 |title=Answers Begin to Emerge on How Thalidomide Caused Defects |url=https://www.nytimes.com/2010/03/16/science/16limb.html |url-status=live |archive-url=https://web.archive.org/web/20100323152804/http://www.nytimes.com/2010/03/16/science/16limb.html |archive-date=23 March 2010 |access-date=21 March 2010 |work=[[New York Times]] |quote=As they report in the current issue of Science, a protein known as cereblon latched on tightly to the thalidomide}}</ref> Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962.<ref name=pmid14076167/><ref>{{Cite web |title=Turning Points of History–Prescription for Disaster |url=http://www.history.ca/ontv/titledetails.aspx?titleid=21267 |archive-url=https://web.archive.org/web/20110929135332/http://www.history.ca/ontv/titledetails.aspx?titleid=21267 |archive-date=29 September 2011 |access-date=24 February 2010 |publisher=History Television}}</ref>

====Notable cases====
[[File:Niko von Glasow.jpg|thumb|right|Niko von Glasow, German filmmaker]]
* [[Lorraine Mercer]]  [[Order of the British Empire|MBE]]  of the United Kingdom, born with [[phocomelia]] of both arms and legs, is the only thalidomide survivor to carry the Olympic Torch.<ref name="Tamplin">{{Cite news |date=12 June 2015 |title=Mid Sussex residents honoured by Queen |url=http://www.midsussextimes.co.uk/news/local/mid-sussex-residents-honoured-by-queen-1-6795898 |url-status=live |archive-url=https://web.archive.org/web/20160102040642/http://www.midsussextimes.co.uk/news/local/mid-sussex-residents-honoured-by-queen-1-6795898 |archive-date=2 January 2016 |access-date=27 December 2015 |work=Mid Sussex Times |vauthors=Tamplin H}}</ref>
* [[Thomas Quasthoff]], 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 |date=19 April 2002 |title=Orpheus lives: A small good thing in Quastoff |url=http://www.portlandphoenix.com/archive/music/02/04/19/classical_Orpheus.html |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 |access-date=6 June 2013 |website=The Portland Phoenix}}</ref>
* [[Niko von Glasow]] produced a documentary called ''[[NoBody's Perfect]]'', based on the lives of 12 people affected by the drug, which was released in 2008.<ref>{{Cite web |title=NoBody's Perfect (2008): Release Info |url=https://www.imdb.com/title/tt1266093/releaseinfo |url-status=live |archive-url=https://web.archive.org/web/20130623182019/http://www.imdb.com/title/tt1266093/releaseinfo |archive-date=23 June 2013 |access-date=6 June 2013 |publisher=IMDB}}</ref><ref>{{Cite web |title=Film Review: NoBody's Perfect |url=http://www.spiritualityandpractice.com/films/films.php?id=19559 |url-status=live |archive-url=https://web.archive.org/web/20130509033726/http://www.spiritualityandpractice.com/films/films.php?id=19559 |archive-date=9 May 2013 |access-date=6 June 2013 |publisher=Spirituality & Practice |vauthors=Brussat F, Brussat MA}}</ref>
* [[Mercédes Benegbi]], 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 |last=<!--Staff writer(s); no by-line.--> |date=9 June 2016 |title=Outstanding eight to receive honorary doctorates at Convocation |url=http://www.uwindsor.ca/dailynews/2016-06-07/outstanding-eight-receive-honorary-doctorates-convocation |url-status=live |archive-url=https://web.archive.org/web/20170307123542/http://www.uwindsor.ca/dailynews/2016-06-07/outstanding-eight-receive-honorary-doctorates-convocation |archive-date=7 March 2017 |access-date=6 March 2017 |website=Daily News |publisher=University of Windsor |location=Windsor, Ontario, Canada}}</ref>
* [[Mat Fraser (actor)|Mat Fraser]], 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 |date=June 2005 |title=Exploitations of embodiment: Born Freak and the academic bally plank. |url=https://www.dsq-sds.org/article/view/575/752 |url-status=live |journal=Disability Studies Quarterly |volume=25 |issue=3 |doi=10.18061/dsq.v25i3.575 |archive-url=https://web.archive.org/web/20201023214836/https://dsq-sds.org/article/view/575/752 |archive-date=23 October 2020 |access-date=30 May 2019 |doi-access=free}}</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 ''[[Gardener's World]]'' 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>
* [[Christian Lohr]], born in 1962 with phocomelia of both arms and both legs, is a Swiss politician in the legislature in the [[Canton Thurgau]] including 2 years as its president and has been a member of the [[National Council (Switzerland)|national legislature]] since 2011.<ref>{{Cite web | vauthors = Gigon A |date=2011-12-27 |title="Fighter" politician unfazed by his disability |url=https://www.swissinfo.ch/eng/swiss-politics/fighter-politician-unfazed-by-his-disability/31842262 |access-date=2025-03-01 |website=SWI swissinfo.ch |language=en}}</ref>

===Change in drug regulations===
The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the 1962 [[Kefauver Harris Amendment]]<ref>{{Cite web |title=50 Years: The Kefauver-Harris Amendments |url=https://www.fda.gov/Drugs/NewsEvents/ucm320924.htm |archive-url=https://web.archive.org/web/20130307165433/http://www.fda.gov/Drugs/NewsEvents/ucm320924.htm |archive-date=7 March 2013 |access-date=6 June 2013 |publisher=[[Food and Drug Administration (United States)]]}}</ref>  (US), 1965 [[Directive 65/65/EEC1]] (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 |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 |access-date=6 June 2013 |publisher=[[National Health Service (England)]]}}</ref> and the [[Medicines Act 1968]] (UK).<ref>{{Cite journal |vauthors=Conroy S, McIntyre J, Choonara I |date=March 1999 |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 |doi=10.1136/fn.80.2.F142 |pmc=1720896 |pmid=10325794}}</ref><ref>{{Cite web |date=2011 |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 |archive-date=14 October 2011 |publisher=Royal Pharmaceutical Society}}</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 [[Drug Efficacy Study Implementation]] to reclassify drugs already on the market.<ref>{{Cite book | vauthors = Sivamani RK, Jagdeo JR, Elsner P, Maibach HI |url=https://books.google.com/books?id=zcF5CgAAQBAJ&dq=%22Drug+Efficacy+Study+Implementation%22+reclassify&pg=PA434 |title=Cosmeceuticals and Active Cosmetics  |date=2015-09-18 |publisher=CRC Press |isbn=978-1-4822-1417-8 |language=en}}</ref>

=== 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 |date=January 1998 |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 |doi=10.1111/j.1552-6909.1998.tb02594.x |pmid=9475131 |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 [[barbiturate]]s. Due to a successful marketing campaign, thalidomide was widely used by pregnant women during the first trimester of pregnancy. However, thalidomide is a [[teratogenic]] 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 |date=16 January 2019 |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 |article-number=e0210222 |bibcode=2019PLoSO..1410222N |doi=10.1371/journal.pone.0210222 |pmc=6334953 |pmid=30650111 |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 |date=2002 |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 |doi=10.1159/000066691 |pmid=14960874 |s2cid=29641011}}</ref> The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE.<ref>{{Cite news |date=2011-11-03 |title=What's happened to Thalidomide babies? |url=https://www.bbc.com/news/magazine-15536544 |access-date=2025-02-11 |work=BBC News |language=en-GB}}</ref><ref>{{Cite web |title=Thalidomide survivors still struggle 60 years on – DW – 11/27/2021 |url=https://www.dw.com/en/thalidomide-babies-birth-defects-caused-by-a-harmless-pill-60-years-ago/a-59952155 |access-date=2025-02-11 |website=dw.com |language=en}}</ref>

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.<ref>{{Cite book | vauthors = Mathias CB, McAleer JP, Szollosi DE |url=https://books.google.com/books?id=4sK3DwAAQBAJ&dq=thalidomide+efforts++safer+analogs&pg=PA336 |title=Pharmacology of Immunotherapeutic Drugs |date=2019-10-18 |publisher=Springer Nature |isbn=978-3-030-19922-7 |language=en}}</ref>

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

Interest turned to [[pomalidomide]], a [[derivative (chemistry)|derivative]] of thalidomide marketed by [[Celgene Corporation|Celgene]]. It is a very active anti-angiogenic agent<ref name=pmid11740816/>  and also acts as an [[immunomodulator]]. Pomalidomide was approved in February 2013 by the FDA as a treatment for relapsed and refractory [[multiple myeloma]].<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/ |url-status=live |archive-url=https://web.archive.org/web/20140107033928/http://www.myelomabeacon.com/news/2013/02/08/pomalyst-pomalidomide-fda-approval-multiple-myeloma/ |archive-date=7 January 2014 |access-date=10 August 2013 |publisher=The Myeloma Beacon}}</ref> It received a similar approval from the [[European Commission]] 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/ |url-status=live |archive-url=https://web.archive.org/web/20140118140152/http://www.myelomabeacon.com/news/2013/08/09/pomalidomide-imnovid-pomalyst-europe-ema-approval-multiple-myeloma/ |archive-date=18 January 2014 |access-date=10 August 2013 |publisher=The Myeloma Beacon}}</ref>

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

Thalidomide was studied in a Phase II trial for [[Kaposi's sarcoma]], a rare soft-tissue cancer most commonly seen in the immunocompromised, that is caused by the [[Kaposi's sarcoma-associated herpesvirus]] (KSHV).<ref>{{Cite web |date=11 March 2013 |title=Kaposi Sarcoma Treatment & Management |url=http://emedicine.medscape.com/article/279734-treatment#showall |url-status=live |archive-url=https://web.archive.org/web/20140202145013/http://emedicine.medscape.com/article/279734-treatment#showall |archive-date=2 February 2014 |access-date=19 January 2014 |website=Medscape Reference |publisher=WebMD |vauthors=Rose LJ, Fishman AD, Sparano JA |veditors=Talavera F, McKenna R, Harris JE}}</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 |date=April 2005 |title=Thalidomide in the treatment of cancer cachexia: a randomised placebo controlled trial |journal=Gut |volume=54 |issue=4 |pages=540–5 |doi=10.1136/gut.2004.047563 |pmc=1774430 |pmid=15753541}}</ref> associated diarrhea<ref>{{Cite journal |vauthors=Sharpstone D, Rowbottom A, Francis N, Tovey G, Ellis D, Barrett M, Gazzard B |date=June 1997 |title=Thalidomide: a novel therapy for microsporidiosis |journal=Gastroenterology |volume=112 |issue=6 |pages=1823–9 |doi=10.1053/gast.1997.v112.pm9178672 |pmid=9178672 |doi-access=free}}</ref>
* [[Renal cell carcinoma]] (RCC)<ref name="pmid15172781" /><ref>{{Cite journal |vauthors=Tunio MA, Hashmi A, Qayyum A, Naimatullah N, Masood R |date=September 2012 |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 |pmid=23139966}}</ref>
* [[Glioblastoma multiforme]]<ref name="pmid15172781" />
* [[Prostate cancer]]<ref name="pmid15172781" />
* [[Melanoma]]<ref name="pmid15172781" />
* [[Colorectal cancer]]<ref name="pmid15172781" />
* [[Crohn's disease]]<ref name="pmid15172781" />
* [[Rheumatoid arthritis]]<ref name="pmid15172781" />
* [[Behcet's syndrome]]<ref>{{Cite journal |vauthors=Hamuryudan V, Mat C, Saip S, Ozyazgan Y, Siva A, Yurdakul S, Zwingenberger K, Yazici H |date=March 1998 |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 |doi=10.7326/0003-4819-128-6-199803150-00004 |pmid=9499327 |s2cid=12089634}}</ref>
* [[Breast cancer]]<ref name="pmid15172781" />
* [[Head and neck cancer]]<ref name="pmid15172781" />
* [[Ovarian cancer]]<ref name="pmid15172781" />
* Chronic heart failure<ref name="pmid15172781" />
* Graft-versus-host disease<ref name="pmid15172781" />
* [[Tuberculous meningitis]]<ref>{{Cite journal |vauthors=Wallis RS, Hafner R |date=April 2015 |title=Advancing host-directed therapy for tuberculosis |journal=Nature Reviews. Immunology |volume=15 |issue=4 |pages=255–63 |doi=10.1038/nri3813 |pmid=25765201 |s2cid=1452130}}</ref>
{{div col end}}

== References ==
{{reflist}}

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

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

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