Thalidomide
51078
225540955
2008-07-14T05:58:14Z
69.111.176.43
akward phrasing edit
{{otheruses4|the drug|the musical about a Thalidomide victim|Thalidomide!! A Musical}}
{{drugbox |
| IUPAC_name = 2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione
| image = Thalidomide-2D-skeletal-wavy.svg
| CAS_number = 50-35-1
| ATC_prefix = L04
| ATC_suffix = AX02
| ATC_supplemental =
| PubChem = 5426
| DrugBank = APRD01251
| 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 =
| 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''' is a [[sedative]]-[[hypnotic]], and [[multiple myeloma]] [[medication]]. The drug is a potent [[Teratology|teratogen]] in rats, rabbits, and [[primate]]s including humans: this means that severe birth defects may result if the drug is taken during pregnancy.<ref>[http://drugsafetysite.com/thalidomide Thalidomide: Drug safety during pregnancy and breastfeeding / DRUGSAFETYSITE.COM<!-- Bot generated title -->]</ref>
Thalidomide was developed by [[Germany|German]] pharmaceutical company [[Grünenthal]] in [[Stolberg (Rhineland)]] near [[Aachen]]. It was sold from 1957 to 1961 in almost 50 countries under at least 40 names, including Distaval, Talimol, Nibrol, Sedimide, Quietoplex, Contergan, Neurosedyn, and Softenon. Thalidomide was chiefly sold and prescribed during the late 1950s and early 1960s to [[pregnant]] women, as an [[antiemetic]] to combat [[morning sickness]] and as an aid to help them sleep. Before its release, inadequate tests were performed to assess the drug's safety, with catastrophic results for the children of women who had taken thalidomide during their pregnancies.
From 1956 to 1962, approximately 10,000 children were born with severe malformities, including [[phocomelia]], because their mothers had taken thalidomide during pregnancy.<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://www.fda.gov/fdac/features/2001/201_kelsey.html | work =FDA Consumer | publisher =US [[Food and Drug Administration]] | date =[[2001-02-28]] | accessdate =2006-09-21 }}</ref> In 1962, in reaction to the tragedy, the [[United States Congress]] 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 | format = | work =FDA Consumer | publisher =US [[Food and Drug Administration]] | date =[[1997-09-01]] | accessdate =2006-09-21 }}</ref> Other countries enacted similar legislation, and thalidomide was not prescribed or sold for decades.
Researchers, however, continued to work with the drug. Soon after its banishment, an Israeli doctor discovered anti-inflammatory effects of thalidomide and began to look for uses of the medication despite its [[teratogenic]] effects. He found that patients with [[erythema nodosum]] leprosum, a painful skin condition associated with [[leprosy]], experienced relief of their pain by taking thalidomide. 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. Kaplan partnered with Celgene Corporation to further develop the potential for thalidomide. Subsequent research has shown that it is effective in [[multiple myeloma]], and it was approved by the FDA for use in this [[malignancy]]. The FDA has also since approved the drug's use in the treatment of [[erythema nodosum]] leprosum. There are studies underway to determine the drug's effects on [[arachnoiditis]] and several types of [[cancer]]s. However, [[physicians]] and patients alike must go through a special process to prescribe and receive thalidomide (S.T.E.P.S and RevAssist) to ensure no more children are born with birth defects traceable to the medication. Celgene Corporation has also developed analogues to thalidomide, such as [[lenalidomide]], that are substantially more powerful and have fewer side effects - except for greater [[myelosuppression]].<ref>http://www.medscape.com/viewarticle/562417_3</ref>
==History==
{{Expand-section|date=June 2008}}
A German pharmaceutical company, [[Grünenthal|Chemie Grünenthal]] at [[Stolberg (Rhld.)|Stolberg]], synthesized thalidomide in [[West Germany]] in 1953. It had accidentally been discovered during a search for cheap [[antibiotic]]s, but was soon marketed with little evidence as a [[sedative]]. In 1961 the drug was found to be harmful to the unborn children of pregnant women.<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>
==Thalidomide today==
===FDA approval===
On July 16, 1998, the FDA approved the use of thalidomide for the treatment of lesions associated with erythema nodosum leprosum. Because of thalidomide’s potential for causing birth defects, the distribution of thalidomide was permitted only under tightly controlled conditions. The FDA required that Celgene Corporation, which planned to market thalidomide under the brand name Thalomid, to establish a System for Thalidomide Education and Prescribing Safety (S.T.E.P.S) oversight program. The S.T.E.P.S program includes limiting prescription and dispensing rights only to authorized prescribers and pharmacies, extensive patient education about the risks associated with thalidomide, periodic pregnancy tests, and a patient registry.<ref>[http://www.fda.gov/cder/news/thalinfo/ FDA, Center for Drug Evaluation and Research, July 16, 1998]</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 [[multiple myeloma]] (MM) patients."<ref>[http://www.fda.gov/cder/Offices/OODP/whatsnew/thalidomide.htm FDA Approves Thalomid (thalidomide) to Treat Multiple Myeloma<!-- Bot generated title -->]</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 = | date = 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>[http://www.publicintegrity.org/rx/report.aspx?aid=722 Pushing Prescriptions - The Center for Public Integrity<!-- Bot generated title -->]</ref>
Thalidomide was and, as of 2006, still is an important advance in the treatment of multiple myeloma, ever since news of its efficacy appeared in the Desikan et al. report.<ref name =Desikan /> The drug has some bothersome side effects such as neuropathy, constipation and fatigue, but is likely more effective than standard chemotherapy for multiple myeloma. Thalidomide, along with another new drug, [[bortezomib]], is changing multiple myeloma treatment, such that [[Hematopoietic stem cell transplantation|stem cell transplant]]s may no longer be the standard treatment for this incurable malignancy.
===Possible indications===
Research on thalidomide slowed in the 1960s, but never stopped. At least one university in the United States pursues thalidomide research, even though performed by only one tenured professor. The medication is an example of how potentially dangerous compounds can be used therapeutically with appropriate precautions and procedures.
In 1964 Israeli physician Jacob Sheskin was trying to help a critically ill French patient with erythema nodosum leprosum (ENL), a painful complication of [[leprosy]]. He searched his small hospital for anything to help his patient stop aching long enough to sleep. He found a bottle of thalidomide tablets, and remembered that it had been effective in helping mentally ill patients sleep, and also that it was banned. Sheskin administered two tablets of thalidomide, and 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 followed by a clinical trial. Dr. Sheskin's drug of last resort revolutionized the care of leprosy, and led to the closing of most leprosy hospitals.<ref name =Silverman />
Serious infections including [[sepsis]] and [[tuberculosis]] cause the level of [[Tumor necrosis factor-alpha]] (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 />
Thalidomide also has potent anti-inflammatory effects that may help ENL patients. In July 1998, the FDA approved the application of [[Celgene]] 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 [[multiple myeloma]] in Australia and New Zealand 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=[[American Chemical Society]] }}</ref> Thalomid, in conjunction with [[dexamethasone]], is now standard therapy for multiple myeloma.
Thalidomide also inhibits the growth of new blood vessels ([[angiogenesis]]), which may be useful in treating [[macular degeneration]] and other diseases. This effect helps [[AIDS]] patients with [[Kaposi's sarcoma]], although there are better and cheaper drugs to treat the condition. Thalidomide may be able to fight painful, debilitating [[aphthous]] lesions in the mouth and esophagus 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 />
Thalidomide is also being investigated for treating symptoms of [[prostate cancer]], [[glioblastoma]], [[lymphoma]], [[arachnoiditis]], [[Behçet's disease]], and Crohn's disease. In a small trial, Australian researchers found thalidomide sparked a doubling of the number of [[T cell]]s in patients, allowing the patients' own [[immune system]] to attack cancer cells.
On [[October 5]], [[2007]], Thierry Facon, specialist in blood diseases at Lille University, [[France]] who led a research, stated that: "''The main message is the addition of thalidomide is able to improve survival. Elderly patients with an aggressive form of blood cancer lived about 20 months longer when given the drug thalidomide as part of their treatment''." The drug also slowed the spread of [[myeloma]] and had also been approved to treat [[leprosy]].<ref>[http://www.reuters.com/article/healthNews/idUSL0422470720071005 Reuters, Thalidomide helps elderly cancer patients: study]</ref>
===Teratogenic mechanism===
[[Image:Thalidomide-structures.png|thumb|right|300px|The two enantiomers of thalidomide:<br>Left: '''(''S'')-thalidomide'''<br>Right: '''(''R'')-thalidomide''']]
Thalidomide is [[racemic]] – it contains both left- and right-handed [[isomer]]s in equal amounts. The (''R'') [[optical isomerism|enantiomer]] is effective against morning sickness. The (''S'') is [[teratology|teratogenic]] and causes birth defects. The enantiomers can interconvert ''[[in vivo]]'' – that is, if a human is given pure (''R'')-thalidomide or (''S'')-thalidomide, both isomers can be found in the [[blood plasma|serum]] – therefore, administering only one enantiomer will not prevent the teratogenic effect in humans. The mechanism of its biological action is being debated, with current literature that suggests that it [[Intercalation (chemistry)|intercalates]] into [[DNA]] in [[guanine|G]]-[[cytosine|C]] rich regions.
===Other side effects===
Apart from its infamous tendency to induce birth defects and peripheral neuropathy, the main side effects of thalidomide include fatigue and [[constipation]]. It also is associated with an increased risk of [[deep vein thrombosis]] especially when combined with [[dexamethasone]], as it is for treatment of multiple myeloma. High doses can lead to [[pulmonary oedema]], [[atelectasis]], [[aspiration pneumonia]] and refractory [[hypotension]]. In multiple myeloma patients, concomitant use with zoledronic acid may lead to increased incidence of renal dysfunction.
==Thalidomide analogs==
The exploration of the [[antiangiogenic]] and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide [[Analog (chemistry)|analog]]s. In 2005, Celgene received FDA approval for [[lenalidomide]] (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 conducted to find safer compounds with useful qualities. Another analog, Actimid (CC-4047), is in the clinical trial phase.<ref>[http://clinicaltrials.gov/ct/search?term=Actimid&submit=Search Search of: Actimid - List Results - ClinicalTrials.gov<!-- Bot generated title -->]</ref> These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.
==Notable children affected==
*[[Mat Fraser]], a comedian, actor, co-presenter of the BBC's [http://www.bbc.co.uk/ouch/ Ouch Podcast].
*[[Alvin Law]], a motivational speaker and former radio broadcaster.
*[[Tony Meléndez]] is a guitarist who was born without arms. He plays only with his feet.
*[[Terry Wiles]] internationally known through ''On Giants' Shoulders'', a book and film about his life.
*[[Jon Hendren]], also known as "DocEvil," a notable humor columnist that has contributed to [[Something Awful]] as well as the [[Wall Street Journal]].
*[[Brett Nielsen]], a musician, was the first Australian thalidomide child.
*Louise Mason, daughter of David Mason, campaigner for increased compensation for Thalidomide children, born with no arms or legs.
*[[Thomas Quasthoff]] is an internationally acclaimed bass-baritone who describes himself: "1.34 meters tall, short arms, seven fingers - four right, three left - large, relatively well formed head, brown eyes, distinctive lips; profession: singer."
*[[Melody Potter]] Native Alabamian disability activist, severe deformities, no arms or legs.
*[http://it.wikipedia.org/wiki/Giancarlo_Cosio Giancarlo Cosio], Italian Waterski World disabled Champion.
==Thalidomide in literature, music and arts==
* In the book ''Something From the Nightside'' by Simon R. Green, he mentions a shirt that reads ''"My mother took thalidomide and all I got was this lousy clubfoot."''
* ''On Giant's Shoulders: The Story of Terry Wiles'' (ISBN 0-7230-0146-4) by [[Marjorie Wallace (SANE)|Marjorie Wallace]], a book & movie about the life of [[Terry Wiles]].
* [[Peter Milligan]] and [[Brendan McCarthy]]'s short [[graphic novel]] ''[[Skin (comic)|Skin]]'' (1992) features a teenage [[skinhead]] who is a child of thalidomide.
* [[Martin Luther King Jr.]], in "[[Letter From A Birmingham City Jail]]," compares the white moderate position of waiting for civil rights gains to occur over time as a "tranquilizing thalidomide" with deleterious long-term effects and dubious efficacy.
* The [[Punk rock]] band [[NOFX]] wrote a song entitled "Thalidomide Child".
* The song "[[We Didn't Start the Fire]]" by [[Billy Joel]] mentions "...children of thalidomide".
* The novel ''[[Mount Dragon]]'' by [[Douglas Preston]] and [[Lincoln Child]] contains a computer hacker character named Mime who is a thalidomide survivor.
* The poem "Thalidomide" by [[Sylvia Plath]]
* [[Douglas Coupland]]'s novel ''All Families are Psychotic'' refers to thalidomide.
* The short story "Fortune's Always Hiding" by [[Irvine Welsh]] in the novel ''[[Ecstasy: Three Tales of Chemical Romance]]'' (1996) is a story of revenge-seeking thalidomide victims.
* "Left Behind" by [[Slipknot (band)|Slipknot]] makes reference to Thalidomide, "I can't stand to see your thalidomide robot face".
* "The drugs song" by [[Amateur Transplants]] advises "if you're up the duff you'd best avoid Thalidomide".
* Although ''[[Geek Love]]'' by [[Katherine Dunn]] never actually mentions thalidomide the eldest child, Arturo, suffers from phocomelia.
* Several books by [[Philip K. Dick]] feature thalidomide phocomeli.
* One of the main characters in Steven Harriman's novel, ''Sleeper'', was a thalidomide child and uses a mechanical arm that senses the movements of his "tiny arm"
* In the movie ''[[Brain Candy]]'', a pharmaceutical company is asking several discovery scientists if their drug is ready. One of them is seen being dragged out of the boardroom screaming, "It was only a couple of flipper babies!", meaning the drug was like thalidomide.
*In the video game, ''[[Scratches (game)|Scratches]]'', the climax involves finding the Blackwood son imprisoned in the basement, having been born deformed by Thalidomide poisoning.
* In "[[Lost in Parking Space, Part Two]]", an episode of the animated show ''[[Drawn Together]]'', the UPS driver is thrown out of the Satan Mobile by Princess Clara into Thalidomide Lake, and is surrounded by deformed flippers.
* In the Australian clay-mation, [[Harvie Krumpet]], the protagonist Harvie Krumpet's adopted daughter is a 'thalidomide baby'. She grows up to become a lawyer who fights for disabled people's rights.
* [[Mat Fraser]] wrote and performed in ''[[Thalidomide!! A Musical]]'' which opened in London in 2005, and featured the song "It's Hard to Hitch Down Life’s Highway With No Thumbs".
* Comedian/Musician [[Tim Minchin]] in his song "Some People Have It Worse Than I" identifies a thalidomide kid with something in his eye as having it worse.
* The movie ''[[Scanners]]'' draws from the Thalidomide tragedy. The plot involves the children of women who have been prescribed a fictional drug named "ephemerol" while they were pregnant. The effects of the drug caused the unborn children to develop powerful psychic abilities.
* Prince Charles has raised controversy by warning of the use of nanotechnology, saying it would be "surprising" if it did not "offer similar upsets" to thalidomide.<ref>"Prince warns of science 'risks.'" BCC News. 11 July
2004.</ref>
* In an episode of [[Breaking Bad]], Walter White explains the concept of [[chirality]] to his high school chemistry class by describing both isomers of thalidomide and their vastly different effects.
==References==
{{reflist|2}}
==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= |id=ISBN 0-7382-0590-7 }}
* {{cite book | last=Knightley |first=Phillip |coauthors=Evans, Harold. Potter, Elaine. Wallace, Marjorie. |title=Suffer The Children: The Story of Thalidomide |date=1979| publisher=The Viking Press|location=New York|id=ISBN 0-670-68114-8}}
==External links==
*[http://www.thalidomide.com.au/corporateweb/thalidomideau/home.nsf/Content/ThalidomideMonograph.pdf/$FILE/ThalidomideMonograph.pdf Thalidomide product monograph ] (Needs registration)
*[http://www.multiplemyeloma.org/treatments/3.04.html Multiple Myeloma Research Foundation article on Thalidomide]
*[http://www.myeloma.org/main.jsp?source=link&source_link_id=45&type=article&tab_id=13&menu_id=94&id=1070 International Myeloma Foundation article on Thalidomide]
*[http://www.k-faktor.com/thalidomide/ Thalidomide — Annotated List of Links (covering English and German pages)]
*[http://www.who.int/entity/medicines/publications/newsletter/en/news2003_2.pdf WHO Pharmaceuticals Newsletter No. 2, 2003 - See page 11, Feature Article]
*[http://www.contergan.grunenthal.info/ctg/en_EN/html/ctg_en_en_history.jhtml?CatId=ctg_en_en_history Grünenthal GmbH - Thalidomide]
*[http://www.thalomid.com Celgene website on Thalomid]
*[http://www.bbc.co.uk/insideout/southwest/series7/thalidomide.shtml The Return of Thalidomide - BBC]
*[http://archives.cbc.ca/IDD-1-75-88/science_technology/thalidomide/ CBC Digital Archives – Thalidomide: Bitter Pills, Broken Promises]
*[http://www.thalidomideuk.com Thalidomide UK]
*[http://www.thalidomide.org.uk The Thalidomide Trust]
*[http://www.prweekus.com/THE-BIG-PITCH-How-would-you-conduct-a-PR-campaign-for-the-newThalidomide-drugs/article/41655/ "The Big Pitch: How would you conduct a campaign for the new Thalidomide Drugs?"], forum of pharmaceutical and medical marketing professionals commenting on how they would address the Thalidomine controversies.
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[[Category:Teratogens]]
[[Category:Carcinogens]]
[[Category:Medical disasters]]
[[Category:Leprosy]]
[[Category:Withdrawn drugs]]
[[Category:Imides]]
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