Thalidomide

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Thalidomide
Systematic (IUPAC) name
(RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione
Clinical data
Trade namesThalomid
AHFS/Drugs.commonograph
MedlinePlusa699032
Pregnancy cat.X (AU) X (US)
Legal status Prescription only
Routesoral
Pharmacokinetic data
Protein binding55% and 66% for the (+)-R and (–)-S enantiomers, respectively
MetabolismHepatic (CYP2C19)[1]
Half-lifemean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses
Identifiers
CAS number50-35-1 YesY
ATC codeL04AX02
PubChemCID 5426
DrugBankDB01041
ChemSpider5233 YesY
UNII4Z8R6ORS6L YesY
KEGGD00754 YesY
ChEBICHEBI:9513 N
ChEMBLCHEMBL468 YesY
Chemical data
FormulaC13H10N2O4 
Mol. mass258.23 g/mol–
 N (what is this?)  (verify)
 
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Thalidomide
Systematic (IUPAC) name
(RS)-2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione
Clinical data
Trade namesThalomid
AHFS/Drugs.commonograph
MedlinePlusa699032
Pregnancy cat.X (AU) X (US)
Legal status Prescription only
Routesoral
Pharmacokinetic data
Protein binding55% and 66% for the (+)-R and (–)-S enantiomers, respectively
MetabolismHepatic (CYP2C19)[1]
Half-lifemean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses
Identifiers
CAS number50-35-1 YesY
ATC codeL04AX02
PubChemCID 5426
DrugBankDB01041
ChemSpider5233 YesY
UNII4Z8R6ORS6L YesY
KEGGD00754 YesY
ChEBICHEBI:9513 N
ChEMBLCHEMBL468 YesY
Chemical data
FormulaC13H10N2O4 
Mol. mass258.23 g/mol–
 N (what is this?)  (verify)

Thalidomide (play /θəˈlɪdəmd/) is a sedative drug introduced in the late 1950s that was used to treat morning sickness and to aid sleep.[2] It was sold from 1957 until 1961, when it was withdrawn after being found to be a teratogen - a cause of birth defects.[3] Modern uses of thalidomide (trademarked as Thalomid, according to FDA Orange Book) include treating multiple myeloma in combination with dexamethasone,[4] and erythema nodosum leprosum, with strict controls on its use to prevent birth defects.[5] Research is ongoing in its use to treat other cancers and autoimmune conditions, although its use is controversial;[6][4][7] the thalidomide tragedy led to much stricter testing being introduced for drug and pesticide licensing.[8]

Contents

History

Development

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 the company and was responsible for inventing thalidomide. During World War II he had been responsible at the German Supreme High Command institute for virus and typhus research in Kraków to produce Rudolf Weigl's vaccine against epidemic typhus.[9]

Thalidomide, launched by Grünenthal on 1 October 1957,[10] was found to act as an effective tranquilizer and painkiller, and was proclaimed a "wonder drug" for insomnia, coughs, colds, and headaches. It was also found to be an effective antiemetic that has an inhibitory effect on morning sickness, so 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.[8]

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.[11] It is not known exactly how many worldwide victims of the drug there have been, although estimates range from 10,000 to 20,000.[12]

In the United Kingdom, the drug was licensed in 1958. Of the approximately 2,000 babies born with defects, around half died within a few months and 466 survived to at least 2010.[13]

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.[14][15] McBride was later awarded a number of honors, including a medal and prize money by the prestigious L'Institut de la Vie in Paris.[16]

The Food and Drug Administration (FDA) of the United States never licensed thalidomide for general use; some of the birth defects caused by thalidomide in the United States were results of the drug being obtained from other countries.[17] However, samples had been distributed to a number of physicians as part of a clinical trial, in which 20,000 patients in the United States received thalidomide.[18]

The drug was withdrawn in 1961 in the United Kingdom. Canada was the last country to stop the sales of the drug, in early 1962.[19]

The East German central pharmacy control also considered the drug. The head of the commission, Friedrich Jung, suspected an antivitaminic effect of thalidomide as derivate of glutamic acid.[20] 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.[21] Based on this, FDP whip Erich Mende requested an official statement from the federal government.[21] 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.[21] 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. [22] The parliamentary report rejected any relation with radioactivity and the abnormal increase of dysmelia.[21] 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.[22] His counterpart, geneticist Hans Nachtsheim was discredited by his Nazi past while Büchner had openly spoken against the regime's Euthanasia policy. 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.[21] In Germany approximately 2,500 thalidomide babies were born.[15]

Several countries never approved the drug, or restricted its use. 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.[23] 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.[11] This reduced the impact of thalidomide in United States patients. Although thalidomide was never approved for sale in the United States, millions of tablets had been distributed to physicians during a clinical testing program. It was impossible to know how many pregnant women had been given the drug to help alleviate morning sickness or as a sedative.[24]

Aftermath of scandal

1962: FDA pharmacologist Frances Oldham Kelsey receives the President's Award for Distinguished Federal Civilian Service from President John F. Kennedy for blocking sale of thalidomide in the United States.

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.[25]

In 1962 the United States Congress enacted laws requiring tests for safety during pregnancy before a drug could receive approval for sale in the United States.[26] Other countries enacted similar legislation[citation needed]

In 1968, after a long campaign by The Sunday Times newspaper, a compensation settlement for the UK victims was reached with Distillers Company (now part of Diageo), which had distributed the drug in the UK.[27][28] This compensation, which is distributed by the Thalidomide Trust in the UK, was substantially increased by Diageo in 2005.[29] The UK Government gave survivors a grant of £20 million, to be distributed through the Thalidomide Trust, in December 2009.[2]

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.[30] 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 31st 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.[31]

Later research

Leprosy treatment

In 1964 Jacob Sheskin, Biology Professor at the Hebrew University of Jerusalem and a Physician at the Hadassah University Hospital, where he is chief of staff and manager of the Hansen Leper Hospital, Jerusalem, administered thalidomide to a patient. The patient was critically ill with leprosy and exhibited erythema nodosum leprosum (ENL), a painful skin condition, one of the complications of leprosy. This attempt to relieve his pain was tried despite the ban. The results were that 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 for the actual leprosy itself, and he followed by getting a Thalidomide clinical trial for leprosy.[32]

Thalidomide has been used by Brazilian physicians as the drug of choice for the treatment of severe ENL since 1965. A study published in 1996 reported 33 people born in Brazil after 1965 with thalidomide embryopathy.[33] Since 1994, the production, dispensing, and prescription of thalidomide have been strictly controlled, but cases of thalidomide embryopathy continue.[34][35]

Further work conducted in 1991 by Gilla Kaplan at Rockefeller University in New York City showed thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha. Kaplan believed thalidomide could be an effective treatment for AIDS. He 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.[5] 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.[5]

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."[36]

Cancer treatment

Studies are underway to determine the drug's effects on arachnoiditis and several types of cancers. However, 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 also developed analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression.[37]

In 1994 Robert D'Amato at Harvard Medical School discovered thalidomide was a potent inhibitor of new blood vessel growth (angiogenesis). Numerous cancer clinical trials for thalidomide began based upon this finding. Thalidomide was later reported to be effective against multiple myeloma,[38] particularly in combination with dexamethasone.[4] Lenalidomide is now more commonly used than thalidomide in the treatment of myeloma.[citation needed]

In 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 patients.[39] The FDA approval came seven years after the first reports of efficacy in the medical literature[40] 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 approved only for leprosy.[41]

Thalidomide is available to only a small number of patients in the UK, in general in specialist cancer treatment centres where research trials are taking place and where specialist doctors have experience in its use.[citation needed]

Possible indications

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 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.[26]

Thalidomide also has potent anti-inflammatory effects that may help ENL patients. In the United States, Celgene distributes 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.[42] Thalomid, in conjunction with dexamethasone, is now standard therapy for multiple myeloma.

Thalidomide has also been found to be effective in treating actinic prurigo, an autoimmune skin disease.[43] Thalidomide has been used in chronic bullous dermatosis of childhood (CBDC) with encouraging results.[44] Peripheral neuritis may be a limiting factor for long term use of thalidomide.

Thalidomide also inhibits the growth of new blood vessels (angiogenesis); this inhibition, which is suspected as a prime cause of the inhibition of normal development and growth of limbs, 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 that 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 thalomide through the STEPS program.[26]

Thalidomide is also being investigated for treating prostate cancer,[45] glioblastoma,[46] lymphoma,[47] arachnoiditis, Behçet's disease, and Crohn's disease.[48] 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.[49]

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.[50]

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.[51]

Thalidomide and multiple myeloma

Thalidomide has been tested in humans as a single agent for the treatment of multiple myeloma due to its antiangiogenic activity.[38] 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%.[52][53] 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.[54][55] 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 addition, owing to these side effects, newer drugs, such as bortezomib (marketed as Velcade) and a thalidomide derivative, lenalidomide (marketed as Revlimid), have increased in popularity.[citation needed]

Teratogenic mechanism

The mechanism of thalidomide's teratogenic action has led to over 2000 research papers and the proposal of 15 or 16 plausible mechanisms.[56] A theoretical synthesis in 2000[56] suggested the following mechanism: thalidomide intercalates (inserts itself) into DNA in guanine-cytosine-rich regions.[57][58] Owing to its glutarimide part, (S) thalidomide fits neatly into the major groove of DNA at purine sites.[56] 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[56] 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".[59] 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.

The two enantiomers of thalidomide:
Left: (S)-thalidomide
Right: (R)-thalidomide

Thalidomide is racemic – it contains both left- and right-handed isomers in equal amounts. The enantiomers can interconvert (racemize) in vivo[60] – that is, if a human is given pure (R)-thalidomide or (S)-thalidomide, both isomers will later be found in the serum – therefore, administering only one enantiomer will not prevent the teratogenic effect.

Inactivation of the protein cereblon

Thalidomide binds to and inactivates the protein cereblon, which is important in limb formation[12] and leads to a teratogenic effect on fetal development. This was confirmed in studies 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.[61]

Mechanism in multiple myeloma

Thalidomide appears to inhibit the disease progression in multiple myeloma by several mechanisms, as resulting mainly from experiments on myeloma cancer cell lines:

Thalidomide analogs

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.[63] These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.[64]

Notable people affected

See also

References

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