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==History==
{{main|Thalidomide}}
Thalidomide was originally released in the ''Federal Republic of Germany'' (West Germany) under the label of ''Contergan'' on October 1, 1957 by ''Chemie Grünenthal'' (now [[Grünenthal]]). The drug was primarily prescribed as a [[sedative]] or hypnotic, but it was also used as an [[antiemetic]] for morning sickness in pregnant women. The drug was banned in 1961 after its [[teratology|teratogenic]] properties were observed. The problems with thalidomide were, aside from the teratogenic side effects, both high incidence of other [[adverse reaction]]s along with poor [[solubility]] in water and [[absorption (pharmacokinetics)|absorption]] from the [[intestines]].<ref name="oncozine.com">[http://oncozine.com/profiles/blogs/how-a-vilified-drug-became-a-life-saving-agent-against-cancer Reversal of Fortune: How a Vilified Drug Became a Life-saving Agent in the "War" Against Cancer - Onco'Zine - The International Oncology Network (November 30, 2013)] {{webarchive|url=https://archive.today/20140103191615/http://oncozine.com/profiles/blogs/how-a-vilified-drug-became-a-life-saving-agent-against-cancer |date=January 3, 2014 }}</ref><ref name=Mazzoccoli2012>{{cite journal|last=Mazzoccoli|first=L|author2=Cadoso, SH |author3=Amarante, GW |author4=de Souza, MV |author5=Domingues, R |author6=Machado, MA |author7=de Almeida, MV |author8=Teixeira, HC |title=Novel thalidomide analogues from diamines inhibit pro-inflammatory cytokine production and CD80 expression while enhancing IL-10.|journal=Biomedicine & Pharmacotherapy|date=July 2012|volume=66|issue=5|pages=323–9|pmid=22770990|doi=10.1016/j.biopha.2012.05.001}}</ref> Adverse reactions include [[peripheral neuropathy]] in large majority of patients, [[constipation]], [[thromboembolism]] along with [[dermatology|dermatological]] complications.<ref name = Prommer2009>{{cite journal|last=Prommer|first=E. E.|title=Review Article: Palliative Oncology: Thalidomide|journal=American Journal of Hospice and Palliative Medicine|date=20 October 2009|volume=27|issue=3|pages=198–204|doi=10.1177/1049909109348981|pmid=19843880|s2cid=24167431}}</ref>
Four years after thalidomide was withdrawn from the market for its ability to induce severe birth defects, its anti-inflammatory properties were discovered when patients suffering from [[Erythema nodosum|erythema nodosum leprosum (ENL)]] used thalidomide as a sedative and it reduced both the clinical signs and symptoms of the disease. Thalidomide was discovered to inhibit [[tumour necrosis factor-alpha]] (TNF-α) in 1991 (5a Sampaio, Sarno, Galilly Cohn and Kaplan, JEM 173 (3) 699-703, 1991) . TNF-α is a [[cytokine]] produced by [[macrophages]] of the immune system, and also a mediator of inflammatory response. Thus the drug is effective against some inflammatory diseases such as ENL (6a Sampaio, Kaplan, Miranda, Nery..... JID 168 (2) 408-414 2008). In 1994 Thalidomide was found to have anti-angiogenic activity<ref name="ncbi.nlm.nih.gov">{{cite journal|title= Thalidomide is an inhibitor of angiogenesis|pmid=7513432 | volume=91|issue=9 |pmc=43727|date=April 1994|vauthors=D'Amato RJ, Loughnan MS, Flynn E, Folkman J |journal=Proc. Natl. Acad. Sci. U.S.A.|pages=4082–5|doi= 10.1073/pnas.91.9.4082 |bibcode=1994PNAS...91.4082D }}</ref> and anti-tumor activity<ref name="nih">{{cite journal|title= Combination oral antiangiogenic therapy with thalidomide and sulindac inhibits tumour growth in rabbits|pmid=10408702 | doi=10.1038/sj.bjc.6690020|volume=79|issue=1 |pmc=2362163|date=January 1999|vauthors=Verheul HM, Panigrahy D, Yuan J, D'Amato RJ |journal=Br. J. Cancer|pages=114–8}}</ref> which propelled the initiation of clinical trials for cancer including multiple myeloma. The discovery of the anti-inflammatory, anti-angiogenic and anti-tumor activities of thalidomide increased the interest of further research and [[chemical synthesis|synthesis]] of safer analogs.<ref name=Bartlett2004>{{cite journal|last=Bartlett|first=J. Blake|author2=Dredge, Keith |author3=Dalgleish, Angus G. |title=Timeline: The evolution of thalidomide and its IMiD derivatives as anticancer agents|journal=Nature Reviews Cancer|date=1 April 2004|volume=4|issue=4|pages=314–322|doi=10.1038/nrc1323|pmid=15057291|s2cid=7293027}}</ref><ref name="ReferenceA">{{cite journal|title= Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma|pmid=11740816 | doi=10.1016/S0093-7754(01)90031-4|volume=28|issue=6 |date=December 2001|vauthors=D'Amato RJ, Lentzsch S, Anderson KC, Rogers MS |journal=Semin. Oncol.|pages=597–601}}</ref>
Lenalidomide is the first analog of thalidomide which is marketed. It is considerably more potent than its parent drug with only two differences at a molecular level, with an added [[amino group]] at position 4 of the phthaloyl ring and removal of a [[carbonyl]] group from the phthaloyl ring.<ref name=Zimmerman2009>{{cite journal|last=Zimmerman|first=Todd|title=Immunomodulatory agents in oncology|journal=Update on Cancer Therapeutics|date=1 May 2009|volume=3|issue=4|pages=170–181|doi=10.1016/j.uct.2009.03.003}}</ref>
Development of lenalidomide began in the late 1990s and clinical trials of lenalidomide began in 2000. In October 2001 lenalidomide was granted orphan status for the treatment of MM. In mid-2002 it entered phase II and by early 2003 phase III. In February 2003 FDA granted fast-track status to lenalidomide for the treatment of relapsed or refractory MM.<ref name=Bartlett2004 />
In 2006 it was approved for the treatment of MM along with dexamethasone and in 2007 by [[European Medicines Agency]] (EMA). In 2008, phase II trial observed efficacy in treating [[Non-Hodgkin lymphoma|Non-Hodgkin's lymphoma]].<ref name=Zeldis2011>{{cite journal|last=Zeldis|first=Jerome B.|author2=Knight, Robert |author3=Hussein, Mohamad |author4=Chopra, Rajesh |author5= Muller, George |title=A review of the history, properties, and use of the immunomodulatory compound lenalidomide|journal=Annals of the New York Academy of Sciences|date=1 March 2011|volume=1222|issue=1|pages=76–82|doi=10.1111/j.1749-6632.2011.05974.x |pmid=21434945|bibcode=2011NYASA1222...76Z|s2cid=5336195}}</ref>
Pomalidomide (3-aminothalidomide) was the second thalidomide analog to enter the clinic being more potent than both of its predecessors.<ref>http://vectorblog.org/2013/04/from-thalidomide-to-pomalyst-better-living-through-chemistry/</ref>
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* [[Multiple myeloma]]
Off-label indications for which they seem promising treatments include:<ref name = Haem2012>{{cite journal|last=Vallet|first=S|author2=Witzens-Harig, M |author3=Jaeger, D |author4= Podar, K |title=Update on immunomodulatory drugs (IMiDs) in hematologic and solid malignancies|journal=Expert Opinion on Pharmacotherapy|date=March 2012|volume=13|issue=4|pages=473–494|doi=10.1517/14656566.2012.656091|pmid=22324734|s2cid=7981368}}</ref>
* [[Hodgkin's lymphoma]]
* [[AL amyloidosis|Light chain-associated (AL) amyloidosis]]
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==Mechanism of action==
Their mechanism of action is not entirely clear, but it is known that they inhibit the production of [[tumour necrosis factor]], [[interleukin 6]] and [[immunoglobulin G]] and [[vascular endothelial growth factor|VEGF]] (which leads to its anti-angiogenic effects), co-stimulates [[T cell]]s and [[Natural killer cell|NK cells]] and increases [[interferon gamma]] and [[interleukin 2]] production.<ref>{{cite journal|last=Quach|first=H|author2=Ritchie, D |author3=Stewart, AK |author4=Neeson, P |author5=Harrison, S |author6=Smyth, MJ |author7= Prince, HM |title=Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma.|journal=Leukemia|date=January 2010|volume=24|issue=1|pages=22–32|doi=10.1038/leu.2009.236|pmid=19907437|pmc=3922408}}</ref><ref>{{cite journal|last=Andhavarapu|first=S|author2=Roy, V|title=Immunomodulatory drugs in multiple myeloma|journal=[[Expert Review of Hematology]]|date=February 2013|volume=6|issue=1|pages=69–82|doi=10.1586/ehm.12.62|pmid=23373782|s2cid=12782141|url=http://www.medscape.com/viewarticle/779560}}</ref><ref>{{cite journal|last=Sedlarikova|first=L|author2=Kubiczkova, L |author3=Sevcikova, S |author4= Hajek, R |title=Mechanism of immunomodulatory drugs in multiple myeloma|journal=Leukemia Research|date=October 2012|volume=36|issue=10|pages=1218–1224|doi=10.1016/j.leukres.2012.05.010|pmid=22727252}}</ref> Their teratogenic effects appear to be mediated by binding to [[cereblon]].<ref>{{cite journal|last=Chang|first=XB|author2=Stewart, AK|title=What is the functional role of the thalidomide binding protein cereblon?|journal=International Journal of Biochemistry and Molecular Biology|date=2011|volume=2|issue=3|pages=287–94|pmid=22003441|pmc=3193296}}</ref> Apremilast, on the other hand, inhibits [[phosphodiesterase 4|PDE4]].<ref name = Haem2012/>
Thalidomide and its analogs, lenalidomide and pomalidomide, are believed to act in a similar fashion even though their exact [[mechanism of action]] is not yet fully understood. It is believed that they work through different mechanisms in various diseases. The net effect is probably due to different mechanisms combined. Apremilast is, however, believed to work through a different mechanism and therefore will be discussed separately. Mechanism of action will be explained in light of today's knowledge, mainly in MM (Figure 2).
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====Altering cytokine production====
Thalidomide and its immune-modulating analogs alter the production of the inflammatory cytokines TNF-α, [[Interleukin 1 family|IL-1]], [[interleukin 6|IL-6]], [[interleukin 12|IL-12]] and anti-inflammatory cytokine [[interleukin 10|IL-10]].<ref name=Mariniani2012>{{cite journal|last=Martiniani|first=Roberta|author2=Di Loreto, Valentina |author3=Di Sano, Chiara |author4=Lombardo, Alessandra |author5=Liberati, Anna Marina |title=Biological Activity of Lenalidomide and Its Underlying Therapeutic Effects in Multiple Myeloma|journal=Advances in Hematology|date=1 January 2012|volume=2012|pages=842945|doi=10.1155/2012/842945|pmid=22919394|pmc=3417169}}</ref> The analogs are believed to inhibit the production of TNF-α, where the analogs are up to 50.000 times more potent ''in vitro'' than the parent drug thalidomide.<ref name=Huang2008>{{cite journal|last=Huang|first=Yen-Ta|author2=Hsu, Chih W. |author3=Chiu, Ted H. |title=Thalidomide and Its Analogs as Anticancer Agents|journal=Tzu Chi Medical Journal|date=1 September 2008|volume=20|issue=3|pages=188–195|doi=10.1016/S1016-3190(08)60034-8|doi-access=free}}</ref> The mechanism is believed to be through enhanced degradation of TNF-α [[mRNA]], resulting in diminished amounts of this pro-inflammatory cytokine secreted.<ref name=Melchert2007 /> This explains the effect of thalidomide when given to ENL patients, as they commonly have high levels of TNF-α in their blood and in dermatological lesions.<ref name=Bartlett2004 /> In contrast, ''in vitro'' assay demonstrated that TNF-α is actually enhanced in T-cell activation, where [[CD4|CD4+]] and [[CD8|CD8+]] T lymphocytes were stimulated by anti-CD3<ref name=Bartlett2004 /><ref name=Huang2008 /> which was later confirmed in an early phase trials involving [[solid tumors]] and inflammatory dermatologic diseases.<ref name=Melchert2007>{{cite journal|last=Melchert|first=Magda|author2=List, Alan|title=The thalidomide saga|journal=The International Journal of Biochemistry & Cell Biology|date=1 July 2007|volume=39|issue=7–8|pages=1489–1499|doi=10.1016/j.biocel.2007.01.022|pmid=17369076}}</ref>
[[Interleukin 12|IL-12]] is another cytokine both suppressed and enhanced by thalidomide and its analogs. When monocytes are stimulated by [[lipopolysaccharide]]s, IL-12 production is suppressed but during [[T cell activation|T-cell stimulation]] the production is enhanced.<ref name=Huang2008 />
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| '''T<sub>max</sub> [drug]'''
|1.5–2 hours in healthy subjects<ref name=Hoffmann2011>{{cite journal|last1=Hoffmann|first1=M|last2=Kumar|first2=G|last3=Schafer|first3=P|last4=Cedzik|first4=D|last5=Capone|first5=L|last6=Fong|first6=KL|last7=Gu|first7=Z|last8=Heller|first8=D|last9=Feng|first9=H|last10=Surapaneni|first10=S|last11=Laskin|first11=O|last12=Wu|first12=A|title=Disposition, Metabolism and Mass Balance of [<sup>14</sup>C]apremilast Following Oral Administration|journal=Xenobiotica|date=December 2011|volume=41|issue=12|pages=1063–75|doi=10.3109/00498254.2011.604745|pmid=21859393|pmc=3231940}}</ref><br />
Median 2 hours in patients with severe plaque-type psoriasis<ref name=Gottlieb2008>{{cite journal|last=Gottlieb|first=AB|author2=Strober, B |author3=Krueger, JG |author4=Rohane, P |author5=Zeldis, JB |author6=Hu, CC |author7= Kipnis, C |title=An open-label, single-arm pilot study in patients with severe plaque-type psoriasis treated with an oral anti-inflammatory agent, apremilast.|journal=Current Medical Research and Opinion|date=May 2008|volume=24|issue=5|pages=1529–38|pmid=18419879|doi=10.1185/030079908X301866|s2cid=72491350}}</ref>
|rowspan="4"|[[Image:Apremilast.svg|245px|Apremilast]]
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