Thalidomide


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Thalidomide, 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione, is a sedative, hypnotic, and multiple myeloma medication. The drug is a potent teratogen in rats, rabbits, and primates.[http://drugsafetysite.com/thalidomide] Thalidomide was developed by German pharmaceutical company Grünenthal. 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. 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. 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, a 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 showed that it was effective in multiple myeloma, and it is now approved by the FDA for use in this malignancy. There are studies underway to determine the drug's effects on arachnoiditis, Crohn's disease, and several types of cancers. However, physicians and patients alike must go through a special process to prescribe and receive thalidomide to ensure no more children are born with birth defects traceable to the medication.

History

Discovery and introduction

A German pharmaceutical company, Chemie Grünenthal at Stolberg, synthesized thalidomide in West Germany in 1953 while searching for an inexpensive method of manufacturing antibiotics from peptides. By heating phthaloylisoglutamine, the company's chief researcher produced phthalimidoglutarimide, which they soon labeled 'thalidomide'. Chemie Grünenthal patented the molecule and began searching for a disease thalidomide could cure.The Grünenthal scientists could not find any antibiotic activity, or any other encouraging effects, in mice and rats. However, the new chemical seemed to be harmless; high doses did not kill rodents, rabbits, cats or dogs, nor show any other side effects. The research team began to describe thalidomide as "nontoxic" and Grünenthal began to consider the lucrative prospects of their new find. Although no sedative or tranquilizing effects were observed in animals, Grünenthal management considered "a nonlethal sedative would have enormous market potential".With no teratogenicity tests (tests on pregnant animals), no clinical trial plans, and no scientific rationale, Grünenthal began distributing free samples of thalidomide to doctors in Switzerland and West Germany in 1955. It was first recommended for the prevention of seizures in patients with epilepsy; although no anticonvulsant effect was found, patients reported experiencing a deep sleep. Other patients said they felt calming and soothing effects. Some reported side effects, but they were not believed to be serious. One author later said that "Thalidomide was introduced by the method of Russian Roulette. Practically nothing was known about the drug at the time of its marketing".Thalidomide could not be sold in West Germany until its effects on animals were documented – usually effects of a drug are demonstrated on animals before the drug is administered to humans, but thalidomide was not tested that way. The sedative effects had not been seen in animals, so the Grünenthal scientists came up with a "jiggle cage" to measure the movements of mice to see if treated mice "jiggled" the cage less than non-treated mice. Grünenthal also pointed out that their "powerful hypnotic drug was completely safe".An employee of Chemie Grünenthal brought home samples of the new drug for his pregnant wife and ten months before thalidomide was put on the market in Germany, on Christmas Day in 1956, their child was born without ears. Years later, the father learned that his daughter was the first living victim of the epidemic of thalidomide-induced infant malformations and deaths.The company began selling the drug over the counter in Germany in October 1957, under the brand name Contergan. The company claimed that "Even a determined suicide could not take enough Contergan to cause death" and "accidental overdoses by children would be unheard of with this drug". Not one of those statements turned out to be true. Soon the drug was being sold in 46 countries under "at least 37 names", without any additional independent testing, and was the drug of choice for pregnant women with morning sickness.

Frances Kelsey

By 1960, Grünenthal was selling thalidomide worldwide – except in the United States. In September 1960 Richardson-Merrell applied for Food and Drug Administration (FDA) approval to sell thalidomide in the United States under the brand name Kevadon. The company wanted to begin selling Kevadon in early 1961. This approval was not expected to be controversial, and the case was given to the agency's newest reviewer, Frances Oldham Kelsey, who had joined the FDA one month before.At the time, the prevailing US law was the 1938 Federal Food, Drug, and Cosmetic Act, which required proof of safety be sent to the FDA before a medication could be approved for sale in the United States. The law did not require demonstration of efficacy for approval. It also allowed "investigational" or "experimental" use of a drug while approval for its sale was being sought, allowing a medication to be widely distributed prior to approval. The law gave the FDA 60 days to review a drug application. If the FDA reviewer told a drug company that its application for a medication was incomplete, it was considered withdrawn and the company would have to submit more data when it resubmitted the application. With each resubmission, the 60 days started anew. Kelsey was interested in fetal safety because in the 1940s she had studied quinine, including its effects in pregnancy, while she was part of a team that was trying to find a synthetic to treat malaria. In particular, she recalled a study she conducted on rabbits at the University of Chicago. In that study, she noted that adult rabbits metabolized quinine rapidly, but pregnant rabbits were less able to metabolize it and embryonic rabbits could not metabolize it at all. Contrary to the prevailing theories of the time, Kelsey found that the drug passed through the placental barrier between mother and fetus. Recalling her work with quinine, Kelsey thought that perhaps thalidomide acted the same way. If so, thalidomide might be safe for older, non-pregnant patients, but could be toxic to children, pregnant women and their fetuses.In addition to the lack of teratogenicity data, Kelsey had other worries about thalidomide. She wanted to know about the drug's mechanism of action – its effects on human metabolism, its chemistry and pharmacology and its stability. None of this data had been provided by Richardson-Merrell. There had been no chronic toxicity studies, excretion and absorption data was inadequate and there were few manufacturing controls to assure quality. Kelsey rejected the application and requested the aforementioned data from the company in a letter. Richardson-Merrell resubmitted the application, but with no new information, and Kelsey turned it down again. She continued to request more data from the company and with each request the 60 day clock started again. As the end of 1960 approached and with it the holiday season (the best time for selling sedatives), Richardson-Merrell began increasing the pressure on the FDA and Kelsey. Executives and scientists telephoned and personally visited Kelsey, and executives complained to her superiors that she was nit-picking and unreasonable.Kelsey refused to clear Kevadon for sale in the United States until she could review satisfactory studies. She later said that the reports submitted by Grünenthal and Richardson-Merrell were more like testimonials than results of well-designed, controlled studies. (One possible reason for the lack of data could be that Richardson-Merrell's "investigation" of thalidomide for its FDA application was organized and implemented not by scientists, but by the company's sales and marketing division.) Kelsey had also heard anecdotal reports of peripheral neuropathy as a side effect, which increased her concern about possible effects on a fetus. She continued to reject the Kevadon application. In total, the company resubmitted its Kevadon application to the FDA six times, but with no new evidence in those applications Kelsey refused approval.

Side Effects: Birth Defects

Side effects had been reported by patients taking thalidomide in the UK, including peripheral neuropathy. Worse, pregnant women who had taken the drug were giving birth to babies with a condition called phocomelia – abnormally short limbs with toes sprouting from the hips and flipper-like arms. Other infants had eye and ear defects or malformed internal organs such as unsegmented small or large intestines. Chemie Grünenthal denied that thalidomide was responsible for any of these problems. In 1959, Grünenthal responded to one doctor's inquiry by saying, "We have no idea how these cases... could have been caused by Contergan".Under US law at the time, Richardson-Merrell had been legally distributing Kevadon on an "investigational" basis since early 1960 and pregnant women were included as patients after the first three months of the trial. American doctors were told,
"We have firmly established the safety, dosage, and usefulness of Kevadon by both foreign and US laboratory and clinical studies. This program is designed to obtain widespread confirmation of its usefulness in a variety of hospitalized patients. Doctors need not report results if they don't want to..."
In December 1960, three months after Richardson-Merrell applied for FDA approval of Kevadon, the British Medical Journal published a letter from a British physician who reported cases of peripheral neuropathy, or painful extremities, in patients who had taken thalidomide over a long period of time. Kelsey read this letter, and she believed it was the first indication of toxicity effects. It increased her misgivings about approving the application, and she immediately requested information from Richardson-Merrell about the problem. The company denied knowing about harmful side effects. Years later, it was shown that Richardson-Merrell knew about the risk of nerve damage but failed to disclose the fact to the FDA. Throughout 1961, more unofficial, anecdotal reports of thalidomide side effects surfaced in Europe and Australia. On November 18 1961, the German paper Welt am Sonntag published a letter by German pediatrician Widukind Lenz. Lenz described more than 150 infants with malformations, including phocomelia, and associated them with thalidomide given to their mothers. A stunning statistic was that 50 percent of the mothers with deformed children had taken thalidomide during the first trimester of pregnancy. The limits of danger were narrow: women who took even one tablet of thalidomide between the 20th and 36th day after conception were at risk for delivering malformed infants. After that point, the drug caused no deformities. Lenz notified Chemie Grünenthal about the dangers of its flagship product. Ten days later, German authorities removed thalidomide from the market against Grünenthal's wishes. Grünenthal withdrew thalidomide soon afterward from the market and notified Richardson-Merrell of its decision. In December, The Lancet, one of the oldest peer-reviewed medical journals in the world, published a letter by William McBride, an Australian physician, who noted large numbers of birth defects in the children of women who had taken thalidomide. Other countries quickly removed the drug from distribution. Grünenthal continued to dispute the claims that thalidomide was responsible for the defects, saying that their action was "merely a response to the sensationalism". Richardson-Merrill withdrew its Kevadon application in March 1962, but the sheer number and variety of brand names meant the drug remained available in some countries. Thalidomide could be found in Brazil, Italy, and Japan as long as nine months after the German withdrawal.Grünenthal's decision was too late for thousands of families. An estimated 8,000 to 12,000 infants were born with deformities caused by thalidomide, and of those only about 5,000 survived beyond childhood. The medication never received approval for sale in the United States, but 2.5 million tablets had been given to more than 1,200 American doctors during Richardson-Merrell's "investigation" and nearly 20,000 patients received thalidomide, including several hundred pregnant women. In the end, 17 American children were born with thalidomide-related deformities. An estimated 40,000 people developed drug-induced peripheral neuropathy. Exact numbers will never be known because the companies and doctors kept incomplete and inaccurate records. No thalidomide victims have passed defects to their children, because thalidomide is not a mutagen.The American media coverage of thalidomide children and the woman who refused to approve the drug for use in the US enveloped Kelsey and the FDA. Kelsey was praised in a story by Morton Mintz in The Washington Post on July 15 1962. The headline read, " 'Heroine' of FDA Keeps Bad Drug Off of Market". Follow up articles appeared in The New York Times, Life magazine, Saturday Review and other publications. A controversial bill by U.S. Senator Estes Kefauver, of Tennessee, was resurrected and rewritten, passed by Congress, and signed by President John F. Kennedy on October 10 1962. The Kefauver Harris Amendment strengthened the FDA's control of experimentation on humans and changed the way new drugs were approved and regulated. Before the thalidomide scandal, US drug companies only had to show their new products were safe. Now they would have to show their new drugs were safe and effective. Informed consent was required of patients participating in clinical trials, and adverse drug reactions were required to be reported to the FDA.The legal mess caused by the effects of thalidomide and Chemie Grünenthal's shoddy testing and approval procedures, is still winding its way through courts worldwide 50 years later. In connection with one of the first lawsuits, a court-ordered gag rule prohibited all mention of the thalidomide effects for ten years, from 1962 to 1972. In one of the more recent developments in 2003, the Swedish government authorized an ex gratia compensation of SEK 250,000 for each of the 150 individuals that were subjected to thalidomide (marketed in Sweden as Neurosedyn). According to a widely disputed investigation by the Swedish Office of the Chancellor of Justice (Justitiekanslern), no blame falls on the Swedish government. The Swedish government later decided to raise the compensation to SEK 500,000 each.

Thalidomide today

FDA Approval

"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." [http://www.fda.gov/cder/Offices/OODP/whatsnew/thalidomide.htm] The FDA approval came seven years after the first reports of efficacy in the medical literature (Desikan R, Munshi N, Zeldis J, et al. Activity of thalidomide (THAL) in multiple myeloma (MM) confirmed in 180 patients with advanced disease. Blood 1999;94:Suppl 1:603a-603a.abstract), 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. [http://www.publicintegrity.org/rx/report.aspx?aid=722]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 medical literature in 2000. 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 dangerous stem cell transplants 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.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. 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. 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.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 cells 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. Reuters, Thalidomide helps elderly cancer patients: study

Teratogenic mechanism

Thalidomide is racemic – it contains both left- and right-handed isomers in equal amounts. One enantiomer is effective against morning sickness. The other is 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 serum – therefore, administering only one enantiomer will not prevent the teratogenic effect in humans. The mechanism is being debated, with current literature that suggests that it intercalates into the DNA in G-C rich regions.

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 edema, atelectasis, aspiration pneumonia and refractory hypotension.

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 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.[http://clinicaltrials.gov/ct/search?term=Actimid&submit=Search] These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.

Notable children of those who took thalidomide

  • Theresia Degener, a prominent human rights lawyer with a special interest in the rights of the disabled.
  • Gregor Wolbring, a biochemist and well known bioethicist and disabled peoples' rights scholar.
  • Mat Fraser, a comedian, actor, co-presenter of the BBC's Ouch Podcast.
  • Alvin Law, a motivational speaker and former radio broadcaster.
  • Tony Melendez is a guitarist who was born without arms. He plays only with his feet.
  • 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.
  • Giancarlo Cosio, Italian Waterski World disabled Champion.
  • Terry Wiles internationally known through On Giants Shoulders''', a book and film about his life.
  • Thalidomide in literature, music and arts

  • On Giants Shoulders: The Story of Terry Wiles'' (ISBN 0-7230-0146-4) by Marjorie Wallace, a book & movie about the life of Terry Wiles.
  • Peter Milligan and Brendan McCarthy's short graphic novel 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 horror movie Scanners and its subsequent sequels deal with children whose mothers took a similar "wonder drug" during their pregnancy with even more dramatic side effects.
  • The Punk rock band NOFX wrote a song entitled "Thalidomide Child". Another song referencing thalidomide is "She's Nubs". NOFX sing about their love for a girl with no arms or legs, just "Nubs" as they put it.
  • 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 (1996) is a story of revenge-seeking thalidomide victims.
  • "Left Behind" by 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".
  • In the computer game Scratches, it is revealed that one of the characters took 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 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.



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