出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2013/03/03 07:01:43」(JST)[Wiki en表示]
|This article may contain unsourced predictions, speculative material or accounts of events that might not occur. Please help improve it by removing unsourced speculative content. (February 2012)|
|Systematic (IUPAC) name|
|Pregnancy cat.||X (AU) X (US)|
|Legal status||℞ Prescription only|
|Protein binding||55% and 66% for the (+)-R and (–)-S enantiomers, respectively|
|Half-life||mean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses|
|Mol. mass||258.23 g/mol–|
| N (what is this?)
Thalidomide (pron.: //) is an anti-nausea and sedative drug that was introduced in the late 1950s to be used as a sleeping pill, and was quickly discovered to help pregnant women with the effects of morning sickness. It was sold from 1957 until 1962, when it was withdrawn after being found to be a teratogen, which caused many different forms of birth defects.
The negative effects of thalidomide led to the development of more structured drug regulations and control over drug use and development. Modern uses of thalidomide (trademarked as Thalomid, according to FDA Orange Book) include treating multiple myeloma in combination with dexamethasone, treating erythema nodosum leprosum, and alleviating symptoms of HIV, with strict controls to prevent birth defects. Research is ongoing in its use to treat other cancers and autoimmune conditions, although its use is controversial.
Thalidomide was developed by German pharmaceutical company Grünenthal, who obtained a patent for it in 1954. It was prescribed as a sedative, tranquilizer, and antiemetic for morning sickness. Thalidomide, launched by Grünenthal on 1 October 1957, was proclaimed a "wonder drug" for insomnia, coughs, colds, and headaches. It was also found to be an effective antiemetic that had an inhibitory effect on morning sickness. During this time period the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the fetus. 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. There soon appeared reports of findings of abnormalities in children being born, traced back to the use of the drug thalidomide. In late 1959, peripheral neuritis was noticed to develop 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.
In Canada, the history of the drug thalidomide dates back to April 1, 1961. There were many different forms sold, with the most common variant being Talimol. Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects. It was not until March 2, 1962 that both drugs were banned from the Canadian market by the FDD, and soon afterward physicians were warned to destroy their supplies.
Birth defects crisis
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. It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000. Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962; Canada was the last country to end sales of the drug.
In the United Kingdom, the drug was licensed in 1958 and withdrawn in 1961. Of the approximately 2,000 babies born with defects, around half died within a few months and 466 survived to at least 2010.
The Australian obstetrician William McBride and the German pediatrician Widukind Lenz suspected a link between birth defects and the drug, a theory Lenz proved in 1961. McBride was later awarded a number of honors, including a medal and prize money by the prestigious L'Institut de la Vie in Paris.
The East German central pharmacy control also considered the drug. The head of the commission, Friedrich Jung, suspected an antivitaminic effect of thalidomide as derivative of glutamic acid. It took some time before the increase in dysmelia at the end of the 1950s was connected with thalidomide. In 1958 Karl Beck, a former pediatric doctor in Bayreuth wrote an article in a local newspaper claiming a relationship between nuclear weapons testing and cases of dysmelia in children. Based on this, FDP whip Erich Mende requested an official statement from the federal government. For statistical reasons, the main data series used to research dysmelia cases started by chance at the same time as the approval date for thalidomide. After the Nazi regime with its Law for the Prevention of Hereditarily Diseased Offspring used mandatory statistical monitoring to commit various crimes, western Germany had been very reluctant to monitor congenital disorders in a similarly strict way.  The parliamentary report rejected any relation with radioactivity and the abnormal increase of dysmelia. Also the DFG research project installed after the Mende request was not helpful. The project was led by pathologist Franz Büchner who ran the project to propagate his teratological theory. Büchner saw lack of healthy nutrition and behavior of the mothers as being more important than genetic reasons. Furthermore, it took a while to install a Surgeon General in Germany; the Federal Ministry of Health (Germany) was not founded until 1962, some months after thalidomide was banned from the market. In Germany approximately 2,500 thalidomide babies were born.
Several countries either restricted the drug's use or never approved it. Ingeborg Eichler, a member of the Austrian pharmaceutical admission conference enforced thalidomide (tradename Softenon) being sold under the rules of prescription medication and as a result relatively few affected children were born in Austria and Switzerland. In the United States, pharmacologist Frances Oldham Kelsey M.D. withstood pressure from the Richardson-Merrell company and refused Food and Drug Administration (FDA) approval to market thalidomide, saying further studies were needed. This reduced the impact of thalidomide in United States patients. Although thalidomide was never approved for sale in the United States at the time, millions of tablets had been distributed to physicians during a clinical testing program. It was impossible to know how many pregnant women had been given the drug to help alleviate morning sickness or as a sedative.
Aftermath of scandal
For correctly denying the application despite the pressure from Richardson-Merrell, Kelsey eventually received the President's Award for Distinguished Federal Civilian Service at a 1962 ceremony with President John F. Kennedy. In September 2010, the FDA honored Kelsey with the first Kelsey award. The award, given annually to an FDA staff member, came 50 years after Kelsey, then a new medical officer at the agency, first reviewed the application from the William S. Merrell Company of Cincinnati.
The numerous reports of malformations in babies brought about the awareness of the side effects of the drug on pregnant women. The birth defects caused by the drug thalidomide can range from moderate malformation to more severe forms. Possible birth defects include phocomelia, dysmelia, amelia, bone hypo plasticity, and other congenital defects affecting the ear, heart, or internal organs. Franks et al looked at how the drug affected new born babies, the severity of their deformities, and reviewed the drug in its early years. Webb in 1963 also reviewed the history of the drug and the different forms of birth defects it had caused. “The most common form of birth defects from thalidomide is shortened limbs, with the arms being more frequently affected. this syndrome is the presence of deformities of the long bones of the limbs resulting in shortening and other abnormalities.”
In 1968, after a long campaign by The Sunday Times, a compensation settlement for the UK victims was reached with Distillers Company (now part of Diageo), which had distributed the drug in the UK. This compensation, which is distributed by the Thalidomide Trust in the UK, was substantially increased by Diageo in 2005. The UK Government gave survivors a grant of £20 million, to be distributed through the Thalidomide Trust, in December 2009.
Melbourne woman Lynette Rowe, who was born without limbs, is leading an Australian class action lawsuit against the drug's manufacturer, Grünenthal, which fought to have the case heard in Germany. The Victorian Supreme Court dismissed Grünenthal's application in 2012, and the case was heard in Australia. More than a hundred Australian thalidomide survivors are involved in the class action, according to Rowe's lawyer. On 17 July 2012, Lynette Rowe was awarded an out-of-court settlement, believed to be in the millions of dollars and paving the way for class action victims to receive further compensation.
On 31 August 2012, Grünenthal chief executive Harold Stock apologized for the first time for producing the drug and remaining silent about the birth defects. At a ceremony, Stock unveiled a statue of a disabled child to symbolize those harmed by thalidomide and apologized for not trying to reach out to victims for over 50 years. At the time of the apology, there were 5,000 to 6,000 sufferers still alive. Victim advocates called the apology "insulting" and "too little, too late", and criticized the company for not compensating victims. They also criticized the company for their claim that no one could have known the harm the drug caused, arguing that there were plenty of red flags at the time.
Change in drug regulations
|This section requires expansion. (January 2013)|
The drug thalidomide’s birth defects in children affected many people’s lives, and from these events came the formation of the group called The Thalidomide Victims Association of Canada, a group of 120 Canadian survivors. Their goal was to prevent future usage of the drug that could be of potential harm to mothers and babies. The members from the thalidomide victims association were involved in the STEPS program, which aimed to prevent tetrogenicity.
The effects of thalidomide increased the fear of the safety of pharmaceutical drugs. The Society of Toxicology of Canada was formed after the events of thalidomide were made public, focusing on toxicology as a discipline separate from pharmacology. The need for the testing and approval of the toxins in certain pharmaceutical drugs became more important after the disaster. The Society of Toxicology of Canada is responsible for the Conservation Environment Protection Act, focusing on researching the impact to human health of chemical substances. Thalidomide brought on the change in the way drugs are tested, what type of drugs are used during pregnancy, and increasing the awareness of potential side effects of drugs.
After being removed from the pharmaceutical market, thalidomide has been the subject of significant clinical research. To prevent birth defects, Celgene developed the STEPS protocol for clinical trials, which monitors trial participants for signs of pregnancy and requires use of two forms of contraception to prevent birth defects. The drug has since shown promise in the treatment of leprosy and certain forms of cancer.
Research also suggests that thalidomide is useful in treating complications of infection with HIV, such as wasting syndrome, nausea, and prurigo nodularis. However, it was also found that thalidomide's toxic side-effects are less well-tolerated in HIV patients, requiring caution during treatment.
Thalidomide has also been found to be effective in treating actinic prurigo, an autoimmune skin disease. Thalidomide has been used in chronic bullous dermatosis of childhood (CBDC) with encouraging results. Peripheral neuritis may be a limiting factor for long term use of thalidomide.
Studies carried out in animal models have suggested the use of combined therapy with thalidomide and glucantime could have a therapeutic benefit in the treatment of visceral leshmaniasis.
A study published in April 2010 discussed the ability of thalidomide to induce vessel maturation, which may be useful as a therapeutic strategy for the treatment of vascular malformations. The research was conducted in an experimental model of the genetic disease hereditary hemorrhagic telangiectasia.
In 1964 Jacob Sheskin, biology professor at the Hebrew University of Jerusalem and chief of staff of the Hansen Leper Hospital, Jerusalem, administered thalidomide to a patient critically ill with leprosy. The patient exhibited erythema nodosum leprosum (ENL), a painful skin condition, one of the complications of leprosy. This was attempted despite the ban on thalidomide's use, but results were favorable: 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.
Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965, resulting in 33 cases of thalidomide embryopathy in people born in Brazil after 1965. In 1990 a group of researchers in Brazil noted that TNF alpha levels went up in leprosy reactional states  and observed that TNF levels decreased in some patients on treatment with thalidomide. A research fellow was sent to explore the mechanism of this effect to the lab of Dr. Kaplan at Rockefeller university. Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, but cases of thalidomide embryopathy continue.
Further work conducted in 1991 by Gilla Kaplan and the brazilian fellow at Rockefeller University in New York City showed that thalidomide decreased TNF alpha levels in leprosy by enhancing the degradation of its mRNA. Kaplan believed thalidomide could be an effective treatment for AIDS given the cachectic effects of TNF alpha in this disease. She partnered with Celgene to further develop the potential for thalidomide in AIDS and tuberculosis. However, clinical trials for AIDS proved disappointing.
In 1998 the FDA approved the drug's use in the treatment of ENL. 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 only to authorized prescribers and pharmacies, keeping a registry of all patients prescribed thalidomide, providing extensive patient education about the risks associated with the drug, and providing periodic pregnancy tests for women who take the drug.
More recently, the World Health Organisation (WHO) has stated:
"The WHO does not recommend the use of thalidomide in leprosy as experience has shown that it is virtually impossible to develop and implement a fool-proof surveillance mechanism to combat misuse of the drug. The drug clofazimine is now a component of the multidrug therapy (MDT), introduced by WHO in 1981 as the standard treatment for leprosy and now supplied free of charge to all patients worldwide."
In 1994 Harvard Professor Robert D'Amato at Boston Children's Hospital discovered that thalidomide was a potent inhibitor of new blood vessel growth (angiogenesis), which is required for tumor growth. He then showed in a rabbit cancer model that thalidomide suppressed tumor growth in animals. Interestingly, he also found that a subset of anti-inflammatory drugs, such as sulindac and dexamethasone, had moderate anti-angiogenic activity. When these anti-inflammatory anti-angiogenic drugs were combined with thalidomide they increased both thalidomide's anti-angiogenic and anti-tumor activity. Based on these discoveries, numerous cancer clinical trials for thalidomide were initiated with and without dexamethasone.
Thalidomide was initially tested in humans as a single agent for the treatment of multiple myeloma due to its anti-angiogenic activity. Since then, many studies have shown that thalidomide, in combination with dexamethasone, has increased the survival of multiple myeloma patients. The combination of thalidomide and dexamethasone, often in combination with melphalan, is now one of the most common regimens for patients with newly diagnosed multiple myeloma, with an improved response rate of up to 60-70%. Thalidomide may also cause side effects, such as polyneuropathy, fatigue, skin rash, and venous thromboembolism (VTE), or blood clots, which could lead to stroke or myocardial infarction. Because of the high incidence of VTEs—as high as 26%—a black box warning was added in the United States in 2006 to the package insert for thalidomide, indicating that patients with multiple myeloma who receive thalidomide-dexamethasone may benefit from concurrent thromboembolism prophylaxis or aspirin.
In 2006 the U.S. Food and Drug Administration granted accelerated approval for thalidomide in combination with dexamethasone for the treatment of newly diagnosed multiple myeloma patients. The FDA approval came seven years after the first reports of efficacy in the medical literature and Celgene took advantage of "off-label" marketing opportunities to promote the drug in advance of its FDA approval for the myeloma indication. Over $300 million worth of Thalomid, as the drug is commercially known, was sold in 2004, while approved only for leprosy.
Thalidomide appears to inhibit disease progression in multiple myeloma by several mechanisms:
- Inhibition of angiogenesis in the bone marrow, which is needed for myeloma cell proliferation.
- Inhibition of the production of interleukin-6 (IL‑6), which is a growth factor for the proliferation of myeloma cells
- Activation of apoptotic pathways through caspase 8-mediated cell death
- At the mitochondrial level, thalidomide results in induction of c-jun terminal kinase (JNK).
- Activation of T cells to produce IL‑2, thereby altering the amount and function of natural killer cells (NK cells), thus augmenting the activity of NK‑dependent cytotoxicity
All physicians prescribing and patients receiving thalidomide must go through the STEPS process to ensure that no more children are born with birth defects traceable to the medication. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression.
Thalidomide is also being investigated for treating prostate cancer, glioblastoma, lymphoma, arachnoiditis, Behçet's disease, and Crohn's disease. In a small trial, Australian researchers found thalidomide caused a doubling of the number of T cells in patients, allowing the patients' own immune system to attack cancer cells.
The mechanism of thalidomide's teratogenic action has led to over 2000 research papers and the proposal of 15 or 16 plausible mechanisms. A theoretical synthesis in 2000 suggested the following mechanism: thalidomide intercalates (inserts itself) into DNA in guanine-cytosine-rich regions. Owing to its glutarimide part, (S) thalidomide fits neatly into the major groove of DNA at purine sites. Such intercalation impacts upon the promoter regions of the genes controlling the development of limbs, ears, and eyes, such as IGF-I and FGF-2. These normally activate the production of the cell surface attachment integrin αvβ3, with the resulting αvβ3 integrin dimer stimulating angiogenesis in developing limb buds. This then promotes the outgrowth of the bud (IGF-I and FGF-2 are also both known to stimulate angiogenesis). Therefore, by inhibiting the chain of events, thalidomide causes the truncation of limb development. In 2009, this theory received strong support, with research showing "conclusively that loss of newly formed blood vessels is the primary cause of thalidomide teratogenesis, and developing limbs are particularly susceptible because of their relatively immature, highly angiogenic vessel network". The inhibition of the growth of blood vessels, once understood, is beneficial in treating some disorders in patients who are definitively known not to be pregnant.
Thalidomide is racemic – it contains both left- and right-handed isomers in equal amounts. The enantiomers can interconvert (racemize) in vivo   – that is, inside the body of a human male.  The mechanism (eg. organ) for this phenomenon is apparently ill-understood. The study of Eriksson et al  could be cemented by an investigation of racemization in post-menopausal women.
Inactivation of the protein cereblon
Thalidomide binds to and inactivates the protein cereblon, which is important in limb formation and leads to a teratogenic effect on fetal development. This was confirmed in studies that reduced the production of cereblon in developing chick and zebrafish embryos using genetic techniques. These embryos had defects similar to those treated with thalidomide. While the mechanism that causes teratogenicity has been established, the mechanism for therapeutic effects remains unclear.
The exploration of the antiangiogenic and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analogs. 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 analog, pomalidomide, is in the clinical trial phase. These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.
Notable people affected
- Mat Fraser, musician, actor and performance artist born with phocomelia of both arms
- Alvin Law, radio broadcaster, born without arms
- Louise Medus Mansell, daughter of David Mason, campaigner for increased compensation for thalidomide children, born with no arms or legs.
- Tony Meléndez, award-winning singer and guitarist who plays with his feet and recognized by Pope John Paul II and U.S. President Ronald Reagan
- Thomas Quasthoff, 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"
- 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
- Terry Wiles, born with phocomelia of both arms and legs, has become known internationally through the television drama On Giant's Shoulders and the best-selling book of the same name
- Discovery and development of thalidomide and its analogs
- Drug of last resort
- Health crisis
- Category:People with phocomelia
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- The 50-year global cover-up
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- 1. サリドマイドおよびその類似体による多発性骨髄腫治療後の血栓性合併症 thrombotic complications following treatment of multiple myeloma with thalidomide and its analogues
- 2. 資源の乏しい状況での多発性骨髄腫のマネージメント management of multiple myeloma in resource poor settings
- 3. 移植片対宿主病の予防および治療に使用される免疫抑制剤の概要 overview of immunosuppressive agents used for prevention and treatment of graft versus host disease
- 4. 非プラチナ製剤ベースの癌化学療法の神経学的合併症の概要 overview of neurologic complications of non platinum cancer chemotherapy
- 5. 多発性骨髄腫の治療プロトコル treatment protocols for multiple myeloma
- Thalidomide reduces mechanical hyperalgesia and depressive-like behavior induced by peripheral nerve crush in mice.
- Nascimento FP1, Macedo-Júnior SJ2, Borges FR3, Cremonese RP3, da Silva MD4, Luiz-Cerutti M3, Martins DF5, Rodrigues AL6, Santos AR7.
- Neuroscience.Neuroscience.2015 Sep 10;303:51-8. doi: 10.1016/j.neuroscience.2015.06.044. Epub 2015 Jun 27.
- BACKGROUND: It has been shown that chronic pain is able to induce depressive disorders in humans, in part, due to peripheral inflammation that reaches the central nervous system. However, the mechanisms involved remain to be established. The purpose of this study was to investigate whether sciatic n
- PMID 26126925
- Improvement of in vivo anticancer and antiangiogenic potential of thalidomide derivatives.
- da Costa PM1, da Costa MP2, Carvalho AA3, Cavalcanti SM4, de Oliveira Cardoso MV4, de Oliveira Filho GB4, de Araújo Viana D5, Fechine-Jamacaru FV1, Leite AC4, de Moraes MO1, Pessoa C6, Ferreira PM7.
- Chemico-biological interactions.Chem Biol Interact.2015 Sep 5;239:174-83. doi: 10.1016/j.cbi.2015.06.037. Epub 2015 Jun 29.
- The strategy of antiangiogenic drugs is based on inhibiting formation of new blood vessels as alternative to limit cancer progression. In this work, we investigated the antitumor and antiangiogenic potential of eight thalidomide derivatives. Most of the molecules was not cytotoxic but 2a, 2d and 3d
- PMID 26134001
- Induction therapy alters plasma fibrin clot properties in multiple myeloma patients: association with thromboembolic complications.
- Undas A1, Zubkiewicz-Usnarska L, Helbig G, Woszczyk D, Kozińska J, Dmoszyńska A, Dębski J, Podolak-Dawidziak M, Kuliczkowski K.
- Blood coagulation & fibrinolysis : an international journal in haemostasis and thrombosis.Blood Coagul Fibrinolysis.2015 Sep;26(6):621-7. doi: 10.1097/MBC.0000000000000315.
- Induction therapy in patients with multiple myeloma increases the risk of thromboembolism. We have recently shown that multiple myeloma patients tend to form denser fibrin clots displaying poor lysability. We investigated the effect of induction therapy on fibrin clot properties in multiple myeloma
- PMID 26083985
- 高橋 正知
- 東京女子医科大学雑誌 83(E2), E476-E484, 2013-03-31
- 多発性骨髄腫(以下MM)は形質細胞の腫瘍性増殖による疾患で、一時的には治療に反応するものの再発が必須である。サリドマイドがMMに有効であることが明らかとなり、その後ボルテゾミブおよびレナリドマイドが治療に用いられ、これまでの標準治療とされてきたメルファラン、プレドニゾンによるMP療法からMMに対する治療が大きく変わりつつある。これまで予後不良因子としての染色体異常、例えば13番異常を持つMM患者は …
- NAID 110009575055
- 和田 眞紀夫
- 東京女子医科大学雑誌 83(E2), E470-E475, 2013-03-31
- 現在、米国、英国などから、多発性骨髄腫および類縁疾患の包括的な診療ガイドラインが公表されている。共通していることは、それぞれ独自に世界の臨床研究データを収集・分析して、高いエビデンスの得られた事項を中心に「根拠に基づいた治療ガイドライン」を組み立てていることである。具体的には(1)無症候性の骨髄腫にはすぐには治療をしないこと、(2)可能な症例では自家幹細胞移植を行う方がよいことなどがエビデンスレベ …
- NAID 110009575054
- サリドマイド・IMiDsの作用とユビキチンリガーゼ (AYUMI ユビキチン修飾系の分子機構と疾患)
- 伊藤 拓水,半田 宏
- 医学のあゆみ 243(6), 503-507, 2012-11-10
- NAID 40019469120
- Thalidomide was developed by German pharmaceutical company Grünenthal in Stolberg near Aachen. Heinrich Mückter, a former Nazi Party member and army physician, had headed Grünenthal's research department since the foundation of ...
- サリドマイド（thalidomide）は、1957年にグリュネンタール社（西ドイツ）が開発・発売 した睡眠薬の名称である。サリドマイドは、睡眠薬として即効性があるなど優れた特長を 持っていたため、世界各国で販売（米国を除く）されていた。しかし、サリドマイドを妊婦が ...
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