Thalidomide

Thalidomide
Clinical data
Pregnancy; category	Known Teratogenicity;
Routes of; administration	Oral
ATC code	L04AX02 (WHO) ;
Legal status
Legal status	FDA Jul 1998 (Erythema Nodosum Leprosum); TGA Oct-2003, FDA Oct-2004 (multiple myeloma);
Pharmacokinetic data
Metabolism	Exact metabolic pathway currently not known in humans, but the safer version (R)-Thalidomide is converted to (S)-Thalidomide in the liver.
Elimination half-life	5 to 7 hours (single dose between 50 and 400 mg)
Identifiers
	IUPAC name 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione;
CAS Number	50-35-1;
PubChem CID	5426;
DrugBank	APRD01251;
CompTox Dashboard (EPA)	DTXSID9022524 ;
ECHA InfoCard	100.000.029
Chemical and physical data
Formula	C13H10N2O4
Molar mass	258.2

Thalidomide is a drug that was sold during the late 1950s and 1960s as a sleeping aid and to pregnant women as an antiemetic to combat morning sickness and other symptoms. It was synthesized in West Germany in 1953 and marketed by the Stolberg-near-Aachen-based pharmaceutical company Grünenthal from October 1, 1957 to 1961, mainly in Germany and Britain. It was available in almost fifty countries, although not in the United States, under at least forty names (such as Distaval, Talimol, Kevadon, Nibrol, Sedimide, Quietoplex, Contergan, Neurosedyn, Softenon, etc.).

It was later (1960–61) found to be teratogenic in fetal development, most visibly as a cause of amelia or phocomelia, especially if taken during the first 25 to 50 days of pregnancy. Around 15,000 children were affected by thalidomide, of whom about 12,000 in 46 countries were born with birth defects, with only 8,000 of them surviving past the first year of life. Many of these survivors are still alive, nearly all with disabilities caused by the drug. In 2003, a World Health Organization newsletter cited evidence that the disabilities and deformities in many thalidomide survivors may be passed on to the survivor's own children through DNA, but many discount this as scientifically unfounded. Those deformed by thalidomide are sometimes referred to (or self-described) as thalidomiders or the derogatory abbreviative, "Flids". In Germany, where it was marketed as Contergan, the term Contergankind was coined to describe affected children.

Thalidomide was banned for its initial intended use as sedative. However, it has been found to be effective for other indications such as for leprosy and multiple myeloma. As a result thalidomide analogs are being developed with the intent to offer effective drugs that are safe.

Alan Pharmaceuticals is a key supplier of thalidomide worldwide. It cooperates closely with Thalidomide UK, the advisory and campaign organization run by the survivors of the thalidomide tragedy. Also, it is marketed by Celgene as Thalomid with standard warnings for pregnant women to avoid taking it.

The thalidomide tragedy

Thalidomide had 'passed' safety tests performed on animals, primarily because the proper tests — particularly those involving pregnant animals — had not been done. A court trial revealed that some tests were either conducted inadequately, or the results were faked.

There is also some evidence that the tests were carried out on a particular isomer of the drug, which forms a racemic mixture in the body. One element of this mixture has the intended beneficial action, while the other creates the undesirable side effects.

The failure of these tests to discover the drug's disastrous consequences highlighted the inadequacy of testing methodologies in use at that time. This resulted in a dramatic increase in animal testing across a broad range of species in varying stages of pregnancy and lifecycle. In fact, later tests did demonstrate that administering thalidomide to rabbits and mice produces characteristic deformities in the offspring, although thalidomide has no effect on pregnant rats' offspring, (see Blake DA, Gordon GB, Spielberg SP. The role of metabolic activation in thalidomide teratogenesis. Teratology 1982;25(2):28A-29A.). If adequate testing had been done, thalidomide would never have been approved for pregnant women.

In 1960, Chemie Grünenthal decided to expand into the United States through the US marketer Richardson-Merrell pharmaceutical company of Cincinnati. Richardson-Merrell applied to the Food and Drug Administration (FDA) for approval to sell the drug under the brand name Kevadon. This approval was not expected to be controversial, and the case was given to the agency's newest reviewer, Frances Oldham Kelsey. Kelsey had previously done animal toxicity research (including effects in pregnancy), and refused to clear thalidomide for sale until she obtained better documentation of its effects, especially in light of some unusual neurological side effects being reported in Britain. In fact, the testing had not been performed adequately, and satisfactory documentation was not forthcoming.

In December 1961, Dr. William McBride, an Australian gynaecologist and obstetrictrician, published a letter in The Lancet in which he noted a large number of birth defects in the children of patients who were prescribed thalidomide. Pediatric specialist Dr. Helen B. Taussig travelled to Europe to study the rising incidence of phocomelia, and also made a strong recommendation to the FDA not to bring this drug to market in the United States.

Despite increasing pressure from Richardson-Merrell to have Kevadon cleared for sale, Kelsey held out for more toxicity data before coming to a decision. The decision was pre-empted by births throughout the world giving evidence of thalidomide's effect on the embryo, and the manufacturers quickly withdrew their application.

In 2003, the Swedish government authorized an ex gratia compensation of SEK 250,000 for each of the 150 individuals that were subjected to Neurosedyn. According to a widely disputed investigation by the Swedish Office of the Chancellor of Justice (Justitiekanslern), no blame falls on the Swedish government. On October 26, the government decided to raise the compensation to SEK 500,000 each.

Clinical uses

The FDA approved thalidomide in 1998, under a restricted access system, for the treatment of erythema nodosum leprosum associated with leprosy (Hansen's disease). It also was found to be effective for multiple myeloma, and is now standard first line therapy for this disease in combination with dexamethasone.

On October 13, 2003 thalidomide received its first approval for the treatment of multiple myeloma from the Therapeutic Goods Administration of Australia where it is marketed by Pharmion Corp. of Boulder, Colorado. Thalidomide received federal approval on May 25, 2006 for treatment of multiple myeloma, a form of bone marrow cancer, bringing its total number of approvals for multiple myeloma to five. Thalidomide, made by Celgene Corp. of Summit, N.J., and sold as Thalomid in the US, is to be used in treating multiple myeloma in conjunction with dexamethasone, a standard chemotherapy treatment.

Because of thalidomide's teratogenicity, its distribution is closely regulated by the FDA and Celgene through the System for Thalidomide Education and Prescribing Safety (STEPS) program.

Thalidomide is also being investigated in HIV-related symptoms by reducing inflammation (blocking TNF), prostate cancer, glioblastoma, lymphoma, and Crohn's disease. Australian researchers began a trial of thalidomide in April 2002 involving 224 cancer patients over a two-year period. The study found thalidomide sparked a doubling of the number of T cells in patients, allowing the patients' own immune system to attack cancer cells. Thalidomide also shows anti-angiogenic activity and has been shown to have activity in Kaposi's sarcoma, although it is not approved by the FDA or generally used for this condition because of the availability of better and safer drugs. It has been used in Behçet's disease.

Side effects

Apart from its infamous tendency to induce birth defects, the main side effects of thalidomide include fatigue, constipation and peripheral neuropathy. It also is associated with an increased risk of deep vein thrombosis, especially when combined with dexamethasone. Excessive dosages can lead to pulmonary edema, atelectasis or aspiration pneumonia, and refractory hypotension.

Technical details

Thalidomide (C₁₃H₁₀N₂O₄; phthalimido-glutarimide; one of a number of systematic names is 2-(2,6-dioxo-3-piperidinyl)-1H-isoindole-1,3(2H)-dione) is a sedative and hypnotic drug. Thalidomide was synthesized at Chemie Grünenthal in West Germany in 1953.

Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: one enantiomer is effective against morning sickness, and the other is teratogenic. The enantiomers are converted to each other in vivo. That is, if a human is given (R)-thalidomide or (S)-thalidomide, both isomers can be found in the serum. Hence, administering only one enantiomer will not prevent the teratogenic effect in humans.

In order for "second generation" birth defects from thalidomide to occur, thalidomide would need to behave as a mutagen, in addition to its obvious behavior as a teratogen. In other words, second-generation birth defects occur when there is damage to a gene in a parent's DNA. There does not seem to be any convincing data showing that thalidomide acts as a mutagen. There are a few case reports of individuals with thalidomide-like defects having children with thalidomide-like defects. The problem is that it was not possible in every case of phocomelia to definitively establish whether or not the mother had been exposed to thalidomide. The defects seen in "thalidomide babies" are not unique to thalidomide. Thus, some individuals whose congenital defects have been blamed on thalidomide may have those defects as the result of some unrelated gene. Those individuals (with a gene causing these defects) would indeed have a higher risk of having offspring with similar defects.

If thalidomide exposure has in fact caused second-generation defects (something which has not been established), the rate of occurrence must be much lower than seen in the first generation, as the majority of thalidomiders who have had children do not exhibit thalidomide-like defects. See the article Does Thalidomide Cause Second Generation Birth Defects? for more information and cause phocomelia(flipper limbs) or no limbs at all.

Teratogenic mechanism

The mechanism by which thalidomide causes birth defects is not completely understood, although recent papers suggest that it alters TNF-alpha production, modulates integrins, alters T-cell ratios and inhibits angiogenesis. It is known to intercalate into DNA at guanine sites which may be responsible for some of these effects by altering expression of certain genes.

Thalidomide analogs

The antiangiogenetic and immunomodulatory activity of thalidomide has been further explored and given rise to the study of thalidomide analogs. Celgene, maker of Thalomid (thalidomide), received in 2005 FDA approval for the use of lenalidomide (Revlimid) as the first commercially useful derivative. This agent is only available in a restriced distribution setting to avoid its use during pregnancy. Further studies are conducted to find safer compounds with useful qualities. Still in clinical trials is Actimid. These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight one.

Famous children of thalidomide

Mat Fraser [1] A comedian and actor who is a co-presenter of the BBC's "Ouch Podcast" [2]
Brett Nielsen is a musician. His career in sound began over 25 years ago in commercial radio and television. He lives in Mullumbimbi, Australia with his wife and 3 children. Brett was the first Australian thalidomide child.
Terry Wiles' life was documented in the book "On Giant's Shoulders: The Story of Terry Wiles" (ISBN 0723001464) by Marjorie Wallace, as well as in a movie by the same name adapted from the book.
Tony Melendez is a guitarist who was born without arms. He plays only with his feet.
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."
Prof. Theresia Degener was born without arms. She is a prominent human rights lawyer with a special interest in the rights of the disabled.
Antje Kratz is an artist and a member of the Association of Mouth and Foot Painting Artists of the World.
Paul the Thalidomide Comic recently made an appearance on the Howard Stern Show

Thalidomide in fiction

Peter Milligan and Brendan McCarthy's short graphic novel Skin (1992) features a teenage skinhead who is a child of thalidomide.
Ecstasy, a Chemical Romance is a trilogy of short stories by Irving Welsh. The first story, Fortune's Always Hiding, features a thalidomide woman born without arms, who seeks revenge on the marketing director of the company which produced it [3].
In The Girl With the Silver Eyes, by Willo Davis Roberts a girl receives supernatural powers because of her mother taking Thalidomide during her pregnancy.

References

Robert Nilsson, Henning Sjostrom (1972), Thalidomide and the Power of the Drug Companies, Penguin Publishing ISBN 0140522980.

Trent D. Stephens, Rock Brynner (2001-12-24), Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine, Perseus Publishing ISBN 0738205907.

External links

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