Thalidomide

Topic editor

Steven G. Gilbert
Lead author: Megan Roark

Drug History and Adverse Effects


There is some discussion regarding who first synthesized thalidomide, with some claiming it was synthesized by the German pharmaceutical company CIBA in 1954, the German company Grunenthal in the 1950s, and the Nazis in the 1940s (#Franks, et al, 2004, #Gutierrez, 2009, #Foggo, 2008). The most infamous adverse health effect associated with thalidomide is birth defects. The drug was prescribed in Canada, Europe, Australia, and parts of Asia in the late 1950's-1960's to pregnant women in their first trimester to treat nausea and vomiting caused by morning sickness (#New Zealand Dermatological Society, 2006). It was also prescribed as a sedative and tranquilizer and quickly became a popular drug that was chemically similar to barbiturates with relatively low known toxicity in adults (#Franks, et al, 2004). After the introduction of thalidomide as a pharmaceutical, there was a huge increase in birth defects, especially in Europe and Canada (#FDA). Thalidomide was responsible for these defects, causing children to be born with amelia (absence of limbs), phocomelia (absence of most of the arm with hands extending flipper-like from the shoulders), dysmelia (malformation, missing or extra limbs), bone hypoplasticity (incomplete development/below normal number of cells), and other congenital defects of the ear, heart, and internal organs (#HHS, 2004). The March of Dimes estimates that as many as 10,000 children were born with major malformations due to their mothers taking this drug during pregnancy (#HHS, 2004). Many women who took as little as a single dose gave birth to babies with serious birth defects. The effects of thalidomide have serious implications in the toxicological world. "Before thalidomide, it was assumed that the placenta provided an effective barrier to exogenous substances" (Dr. Rita Loch-Caruso, University of Michigan). It is now known that many toxic substances have chemical structures that give them the ability to penetrate the placenta.

Thalidomide in the US

Dr. Frances Kelsey, the reviewing medical officer for the U.S. Food and Drug Administration in 1960, believed this drug lacked proof of safety in humans and prevented thalidomide to be sold in the U.S. (#Rouhi, 2005). The Center of the Evaluation of Risks to Human Reproduction (CERHR) stated that she "spared the U.S. from the devastating thalidomide tragedy and strengthened drug evaluation in this country." To see more about Dr. Kelsey, see below.

Other Adverse Effects

Aside from the teratogenic effects caused by thalidomide, other side effects include: drowsiness, constipation, rash, nausea, decreased thyroid activity, increased appetite, muscle weakness, and menstrual abnormalities (#FDA).

Common Pharmaceutical Names


  • Thalomid
  • Contergan
  • Actimid
  • CC4047
  • Distaval
  • ImiD 3
  • Kevadon

From (#Rouhi, 2005)

Physical and Chemical Properties


  • Molecular Mass: 258.23 Da
  • Color: white crystalline
  • Odor: Odorless
  • Taste: taste-less
  • Melting point: 271°C.
  • Insoluble in ether and benzene
  • Has a low solubility in water, methanol, ethanol and glacial acetic acid"

All bulleted sources from (#Erkoc, 2004)

Structural Properties

Thalidomide consists of two rings with different chemical makeups. The ring on the left side of the molecule (refer to the picture above) is believed to be responsible for teratogenic effects. The ring on the right resembles a structure similar to hypnotic drugs and is thought to have sedative properties (#Franks, et al, 2004). For these reasons, it was tested on animals with the hope it could treat pregnant women with nausea and vomiting symptoms (#HHS, 2004). The drug was able to pass testing and was made legal to give to human subjects as a treatment for nausea (#Franks, et al, 2004).

The small, yet critical chemical differences between the safe R+ conformation of the molecule (responsible for anti-inflammatory activity) and the dangerous S- conformation are what contribute to thalidomide's toxicity (#Liu, et al, 2004). According to Franks et al. (2004):
"the thalidomide molecule is a racaemic glutamic acid analogue, consisting of S- and R+ enantiomers that interconvert under physiological conditions (#Franks, et al, 2004). The S- form potently inhibits release of tumor necrosis factor (TNF alpha) from peripheral mononuclear blood cells, whereas the R+ form seems to act as a sedative, probably mediated by sleep receptors in the forebrain" (#Franks, et al, 2004).
Liu (2005) also suggests that the S- form of the molecule inhibits TNF alpha, which regulates apoptosis. This seems to promote unregulated cell proliferation that leads to tumor formation (#Liu, et al, 2004). Cytochrome P-450 generates thalidomide metabolites, which leads to adverse health effects (#Liu, et al, 2004). The chemical properties of thalidomide were found to be unstable in solution, because the molecule would spontaneously hydrolyze in physiological conditions over 6.0 pH (#Perri and Hsu, 2005).

Pharmacology and Mechanisms


The mechanism in which thalidomide produces developmental malformations is not completely clear at this point, but various studies are currently underway to investigate many proposed mechanistic pathways.

Recent studies have shown that reactive oxygen species may play a role in embryopathy caused thalidomide intoxication (#Hansem, et al, 2002). One study done at the University of Michigan, "Thalidomide Modulates Nuclear Red-ox Status and Preferentially Depletes Glutathione in Rabbit Limb versus Rat Limb" investigates the mechanistic pathways of thalidomide in two species that differ in thalidomide sensitivity (#Hansem, et al, 2002). Rats are thalidomide resistant and rabbits are thalidomide sensitive. In the study, limb bud cells were removed from rats and rabbits and treated with varying concentrations of thalidomide. Even at low concentrations, thalidomide was found to preferentially increase reactive oxygen species in rabbits as opposed to rats (#Hansem, et al, 2002). Reactive oxygen species (ROS) can cause cellular damage if in large amounts and are reactive because they contain an unbalanced amount of valance shell electrons (#Belozerskaya and Gessler, 2007). Examples of reactive oxygen species are free radicals, oxygen ions, and peroxides (#Belozerskaya and Gessler, 2007). Regulated ROS play a role in apoptosis and many other bodily processes and if levels of ROS are interrupted, it can lead to other damaging effects of the cell (#Belozerskaya and Gessler, 2007).

In other studies, thalidomide is suggested to inhibit angiogenesis. In angiogenesis, new blood vessels form and are crucial for malignant tumors to develop (#Damato, et al, 1994). Some of these studies were done at Harvard Medical School by Judah Folkman, Michael Loughnan, Robert D'Amato, and Evelyn Flynn. They experimented with thalidomide, orally administered the drug to rabbits, and looked at their corneas. They discovered that thalidomide inactivates a protein called fibroblast growth factor type 2 (FGF-2) (#Damato, et al, 1994). The research showed that without thalidomide, this protein attaches to a blood vessel receptor protein and stimulates a cascade of reactions, eventually leading to blood vessel formation (and increased malignant tumors).

!dna damage.gif|thumbnail,align=left!Thalidomide's mechanism in cells are suggested to lead to malignant tumor formation by intercalating into the DNA (#Damato, et al, 1994). In this process, thalidomide plays a role in DNA damage in the developing blood vessel, because thalidomide is alike purine bases (adenine and guanine) structurally and can intercalate itself into DNA or bind to purine bases in the DNA double helix (see picture below) (27). This intercalation is due to the teratogenic form of thalidomide and not the sedative conformation of the molecule. Due to thalidomide's similarity to adenine of guanine, it intercalates itself into G or A rich regions of the FGF-2 gene, but not the T or C rich regions which code for other genes (#Stephens, 2000). For the T or C rich regions, thalidomide does not cause DNA damage and these genes which code for different proteins are unaffected. The Harvard Medical School researchers believed that the birth defects seen in both humans and their experimental pregnant rabbits were a secondary mechanism to blood vessel formation inhibition (#Damato, et al, 1994). They hypothesized that thalidomide intercalates itself into the DNA of the developing blood vessel in the limbs of fetuses, causing DNA damage, and inhibiting normal growth of the arms and legs (#Damato, et al, 1994). These researchers postulated that the arms and legs would be especially vulnerable to thalidomide's toxic effects because normal angiogenesis is important during the limb's development (#Damato, et al, 1994).

From Chemsoc:

Additionally, thalidomide's mechanism is also connected to immunomodulatory, and anti-inflammatory properties (these properties are discussed more in #Present Uses and #Future Therapeutic Uses sections) (#Franks, et al, 2004). Thalidomide can be described as a chemical that undergoes many mechanisms within the human body. Thalidomide has also been shown to slow down integrins (#Stephens, 2000).

When thalidomide was first being tested on animals, the drug exhibited no adverse side effects (#Chung, et al, 2004). Based on these 'safe' tests, it was reasoned that humans might be able to benefit from the possible sedative effects of the drug, however the drug turned out to be toxic (#Chung, et al, 2004). In the clinical trials involving humans, the subjects were observed falling into a deep sleep which led to the conclusions that the drug was successful as a sedative. Unfortunately, after the drug was approved and administered to human mothers, it generated birth defects in fetuses (#Chung, et al, 2004).

Why did the drug only show birth defects and sedative characteristics when given to humans and not in the animals originally used in testing? The reason is unclear as the same mechanism takes place regardless of the host organism. The article titled "Thalidomide Pharmacokinetics and Metabolite Formation in Mice, Rabbits, and Multiple Myeloma Patients" hypothesized that the "major interspecies differences in the Pharmacokinetics of thalidomide were related to the altered degree of metabolism" (#Chung, et al, 2004). "Hydroxylated and glucuronidated metabolites are much more soluble than the parent drug" and "facilitate more rapid elimination of thalidomide from the system" and the results from this study showed that the "hydroxylation of thalidomide occurs extensively in mice, moderately in rabbits, and undetectably in patients", thus providing a reason why thalidomide affects species differently (#Chung, et al, 2004). Or in short, the different species metabolize the drug differently which led to serious differences in effects.

As mentioned above, there are two conformations of thalidomide (the safe R+ form and the unsafe S- form). The obvious answer to change thalidomide into a safe drug would be to only administer the safe R+ conformation to the patients, but this is not what happens in vivo as the liver metabolizes thalidomide with enzymes that turn the R+ into S_ spontaneously using hydrolysis (#Franks, et al, 2004) and (#Stephens, 2000). In the effort to try to separate the two forms, the idea would backfire, because the teratogenic form of the drug is most likely to develop.

Absorption and Elimination

Thalidomide is:

  • Absorbed in gastrointestinal tract, not affected by food consumption
  • Found in a male patients semen, not clear if it is in breast milk
  • Metabolized through a nonenzymatic pathway, undergoing spontaneous hydrolysis in the blood and tissues
  • Eliminated from the body in about 5-7 hours (not through feces) (only a very small amount is metabolized by cytochrome P-450)
  • All bulleted sources from (#FDA), (#Franks, et al, 2004) and (#Stephens, 2000).

Prominent Thalidomide Cases


Frances Kelsey

When it was introduced in the 1950's, drugs containing thalidomide were widely used and marketed as safe in places around the world including Europe, Australia, Japan and Canada (#Franks, et al, 2004). Thalidomide, however, was not approved by the United States Food and Drug Administration (FDA) until 1998. This is largely due to the courageous tenacity of Dr. Frances Kelsey, who in her first month at the FDA, refused to approve the drug without more evidence showing that it was safe in humans (#Rouhi, 2005). She was particularly concerned about what effects the drug could have on the embryo of a pregnant woman taking the drug. Despite the pressures that the drug companies put on her, she was resolved in her decision and would not be moved until sufficient testing had been done (#Rouhi, 2005). Her actions are thought to have saved the United States from a serious medical tragedy that could have potentially affected tens of thousands of lives.

Picture from ChemistryExpliained

Mat Fraser
Mat Fraser is a rock and reggae musician, actor, and screenwriter who was born with phocomelia and resulted in stunted arms whichwas a result of his mother taking thalidomide during her pregnancy with him. Despite his disability, he has made a successful career as a singer, drummer, actor, and performer. Much of his career as an actor is centered around his disability (#Disability World, 2004). He has performed with a disabled European theater company, the Graeae Theatre Company, and has received much praise for his one-man show, "Seal Boy: Freak.' In addition to performing in several productions, he also won much fame for writing "Thalidomide!! A Musical". The story centers around a phocomelic character, Glynn, who falls in love with an able-bodied woman. Fraser describes Glynn as a "cartoon version" of himself. When asked about why he chose to create a story about thalidomide he responded: "I don't believe in turning the other cheek. Yeah, I am angry about the way those corporate bastards got away with it. And finally I'm getting to stick the knife in." Sources: (#Ragged Edge, 2005) & (#Mat Frazer).
Picture from (#National Disability Arts Forum, 2007).

Tony Melendez

Tony Melendez is a singer, songwriter and guitar player who was born without arms. Like Mat Fraser, his mother was prescribed thalidomide while pregnant with him. Melendez, who discarded his artificial arms at the age of 10, uses his feet to do just about everything including playing the guitar (#World Ability Federation, 2005). His most famous performance was when he played in front of an audience that included Pope John Paul II, who embraced him after his performance of a song entitled "Never be the Same"(#World Ability Federation, 2005).

Picture from (#World Ability Federation, 2005).

Inflammatory and Infectious Conditions


Dermatology

!Thalidomide efficacy in ENL patient.jpg|thumbnail,align=right!Thalidomide is a very useful drug to treat the agonizing subcutaneous modules that develop on the skin of a patient with leprosy. In a clinical trial, patients who were administered 100 mg of thalidomide responded positively 70-80% of the time, versus only a 25% positive responds rate in patients who were given a placebo (Aspirin). Fifteen years after thalidomide was discovered to help people fight painful nodules on their skin, over 99% of 4,000 patients have responded to the thalidomide treatment. In other clinical studies, thalidomide has been used as an effective treatment for skin lesions developed in patients with lupus. Although thalidomide is not the primary treatment for cutaneous lesions of lupus due to its neurotoxicity, it is still considered an effective therapy. Treatment for oral and genital lesions related to Behcet's disease can heal wounds in about one month and in a randomized, controlled study, thalidomide performed at a higher level than did the placebo.

Thalidomide is a very useful drug to treat the agonizing subcutaneous modules that develop on the skin of a patient with leprosy. In a clinical trial, patients who were administered 100 mg of thalidomide responded positively 70-80% of the time, versus only a 25% positive responds rate in patients who were given a placebo (Aspirin). Fifteen years after thalidomide was discovered to help people fight painful nodules on their skin, over 99% of 4,000 patients have responded to the thalidomide treatment. In other clinical studies, thalidomide has been used as an effective treatment for skin lesions developed in patients with lupus. Although thalidomide is not the primary treatment for cutaneous lesions of lupus due to its neurotoxicity, it is still considered an effective therapy. Treatment for oral and genital lesions related to Behcet's disease can heal wounds in about one month and in a randomized, controlled study, thalidomide performed at a higher level than did the placebo.

Rheumatological

Many patients with rheumatoid arthritis found joint pain relief (80% complete or partial response) when treated with thalidomide. A combination of many other drug treatments for rheumatoid arthritis with thalidomide also showed strong response rates.

Gastrointestinal

The use of thalidomide as an effective treatment for gastrointestinal diseases, like Crohn's Disease, has let patients decrease their steroid injections by 50%. Thalidomide is a drug that can provide steroid-dependent Crohn's Disease patients with an alternative control. Overall, the clinical response percentage to thalidomide over a placebo (or no thalidomide administered to patients) was from 50%-72%. Additionally, thalidomide is an effective treatment of gastrointestinal lesions.

HIV

HIV is another disease that can benefit by treatment of thalidomide. In one clinical trial (which was randomized and compared with a placebo), thalidomide decreased normal-sized and severe oral lesions in HIV patients with a response rate of 50%. This drug was given to patients on a regular basis in either 100 mg or 200 mg doses, and if the patient discontinued thalidomide treatment, the oral ulcers reappeared shortly after. This strengthens evidence that this drug, once thought to be only associated with tragedy, can be useful if applied to different medical treatment. Also, thalidomide has been shown to help HIV/AIDS patients gain weight within a short period of time when it is grossly important to add on excess body weight.

 

Malignant Disease


Hematological Cancers

Patients with cancer that affects the lymphatic system, the blood, and bone marrow can be treated with thalidomide to decrease the severity of their hematological disorder(s). Thalidomide has a drug derivative called CC-5013 showed that in 24 patients with Cancer of the blood plasma, 71% showed a reduction in paraproteinconcentration. In one clinical trail, patients with Waldenstrom's macroglobulinemia had a response rate of 25% when thalidomide was given daily to them (200-600 mg). Thalidomide has also shown to be effective to help fight against myelofibrosis and thrombocyopenia.

Prostate Cancer

Several studies have been conducted to show the effects of low doses of thalidomide on the treatment of prostate Cancer. One study shows that treatment with thalidomide led to a 50% reduction in prostate Cancer specific antigens in about 20% of patients and measurable improvements based on bone scans. Other studies show similar results for androgen-independent prostate Cancer. When combined with other drugs, thalidomide was shown to improve survival rates by a median of 14 months. Thalidomide has also been investigated as a therapeutic in advanced prostate Cancer. Currently, more studies are being done on this topic.

Renal-Cell Carcinoma

Thalidomide is thought to have an effect on the persistence of renal-cell cancer because it is associated with the secretion of VEGF and TNF-alpha. In a 2000 publication, Eisen and colleagues studied how thalidomide affects several diseases, including breast Cancer, melanoma and renal-cell carcinoma. Of 18 renal-cell carcinoma patients, three responded partially to thalidomide treatment. Unfortunately, these numbers were not found in later trials. The overall response rate was found to be between 0% and 10.

Glioma

Glioma is a tumor that arises from glial cells in the central nervous system. In a non-randomized trial of thalidomide in 36 patients, two patients seemed to respond to the treatment. These patients showed radiographic responses, with a 33% disease stability. This study has, however, been criticized because it does not take into account the various glioma sub-types. Furthermore, the experimenters failed to identify tumor histology at the time of treatment.

Colorectal Cancer

Thalidomide has been shown to improve clinical utility in 29% of chemotherapy-refractory colon Cancer patients when administered nightly in combination with irinotecan. When irinotecan is taken alone, the noted response rate of 12%-21%. Thalidomide has been shown to reduce side effects of irinotecan, making it much easier for all patients to complete therapy.

Melanoma

When thalidomide is used alone, it is ineffective at controlling melanoma when taken at low doses. However, when higher doses are administered (up to 400mg) and when taken in conjunction with temozolamide, 6 of 12 melanoma patients showed at least a partial response. One patient showed a full response. At this point, the data points to the idea that combination therapy is most effective concerning thalidomide in melanoma treatment.

Other Cancers

The use of thalidomide alone has not been proven effective in the treatment of cancers of the breast, ovary, head, or neck. Studies show that in almost all cases of hematological and solid malignant disease, thalidomide is more useful as part of a regimen of several drugs. On the other hand, thalidomide has had a notable effect in the treatment of refractory multiple myeloma. At this point, the efficacy of thalidomide is unproven and few phase III trials have been performed on the drug. More studies are being conducted to determine the optimum dosage and what drug combinations are most effective in the treatment of multiple myeloma and other cancers.

 

Ways to Minimize Risk



For people who are prescribed thalidomide, major precautions must be undertaken. The first and most important preventative measure that doctors must do is to check on a woman's individual health and more specifically, to check if a woman is pregnant (#CDC, 2003). The FDA allowed thalidomide to be put back on the market as they said it is safe for the general public to take as treatment for many of the above conditions (#DA). However, it is not safe for women who are pregnant. Due to the fact that damaging effects of thalidomide can pass from mother to fetus across the placental barrier, it is routine to have women tested regularly to see if they are pregnant. The CDC recommends that women who are of child bearing age use reliable methods of birth control and thalidomide should not be prescribed to women who want to become pregnant (#CDC, 2003). Thalidomide-affected pregnancies can be 100% preventable if certain precautions are used in patients seeking treatment. There are many types of birth control that can be used including pills, vaginal rings, implanted hormone capsules or contraceptives, intrauterine devices, diaphragms, condoms, cervical caps, and abstinence (#CDC, 2003). For men taking thalidomide, it is recommended to use latex condoms when having intercourse, because some studies have revealed that thalidomide can travel through the sperm or semen (#CDC, 2003).

Picture from From FDA.

Doctor/Drug Company Warnings

One way drug companies and doctors can help reduce pregnancy deformity related to thalidomide use is to tell their patients of the risks involved. Only doctors and pharmacies registered with a S.T.E.P.S. thalidomide education program are able to prescribe this drug, which helps to educate patients (#FDA). Other precautions include warning labels on the drug bottles and informational sheets given to the human subjects given this drug. The doctors should educate his/her patients and tell them that around half of pregnancies are not planned and only one dose of thalidomide can cause extreme birth defects in their newborn (#FDA). Women should be taught that if they take the drug, they will have to make sure they are on a reliable birth control method and comply with regular pregnancy testing. For a woman who begins taking thalidomide as a treatment, they must be tested 24 hours before they take their first dose of the drug (#FDA). During the first month of treatment, women are tested for pregnancy weekly until they have regular menstrual cycles and are tested at the beginning of every month (#FDA). It is recommended that women should use contraceptives four weeks before and after their thalidomide treatment and men should continue to use latex condoms four weeks after their treatment (#CDC, 2003). Women should not breast feed (due to its possible side effects on the infant), men should not donate semen, and no one should donate blood if taking this drug (#CDC, 2003).

There are many other complications involved when patients take drugs. For example, all patient's medications should be reviewed by his/her physician to look for possible negative drug interactions, in some cases people develop drug dependency or abuse drugs and in extreme cases, someone might try to harm a fetus with thalidomide pills without a mother's knowledge (of poisoning or of the drug's dangerous implications) (#FDA).

 

References



Erkoc S, Erkoc F. Quantum chemical investigation of thalidomide molecule. Journal of Molecular Structure-Theochem 2005; 719(1-3):1-5.


McBride WG. Thalidomide embryopathy. Teratology 1977;16(1):79-82.


Perri A, Hsu S. A review of thalidomide's history and current dermatological applications. Dermatology Online Journal 2003; 9(3):5


Department of Health and Human Services (HHS, National Toxicology Program). 2005. Thalidomide. (accessed 3 March 2008).


Franks ME, Macpherson GR, Figg WD. Thalidomide. The Lancet 2004; 363:1802-1811.


Liu J, Li LD, Ora A, Heikkila P, Vaheri A, Voutilainen R. cAMP-dependent protein kinase activation inhibits proliferation and enhances apoptotic effect of tumor necrosis factor-alpha in NCI-H295R adrenocortical cells. Journal of Molecular Endocrinology 2004; 33(2):511-522.


Muller GW, Konnecke WE, Smith AM, Khetani VD. A concise two-step synthesis of thalidomide. Organic Process Research & Development 1999; 3(2):139-140.


Rouhi M. Thalidomide. Chemical & Engineering News 2005; 83(25):122-123.


Center for Disease Control. 2003 Available: http://www.cdc.gov/healthmarketing/entertainment_education/tips/thalidom.htm (accessed 20 March 2008)


U.S. Food and Drug Administration & http://www.fda.gov/cder/news/thalidomide.htm (accessed 21 March 2008).


Daniel Foggo, "Thalidomide 'was created by the Nazis'". The Sunday Times, February 8, 2009.


Chung F, Lu J, Palmer BD, Kestell P, Browett P, Baguley BC, Tingle M, Ching LM. Thalidomide pharmacokinetics and metabolite formation in mice, rabbits, and multiple myeloma patients. Clinical Cancer Research 2004; 10(17):5949-5956.


Belozerskaya TA, Gessler NN. Reactive oxygen species and the strategy of antioxidant defense in fungi: A review. Applied Biochemistry and Microbiology 2007; 43(5):506-515.


Damato RJ, Loughnan MS, Flynn E, Folkman J. Thalidomide is an inhibitor of angiogenesis. Proceedings of the National Academy of Sciences of the United States of America 1994; 91(9):4082-4085.


Crossley R. Chirality and aspects of drug development in chirality and the biological activity of drugs. CRC Press Inc. Boca Raton, FL 1995;161-187.


Hansen JM, Harris KK, Philbert MA, Harris C. Thalidomide modulates nuclear redox status and preferentially depletes glutathione in rabbit limb versus rat limb. Journal of Pharmacology and Experimental Therapeutics 2002; 300(3):768-776.


Daniel Gutierrez. "Spanish Thalidomide Babies Still Receive No Compensation from Company or Government". NaturalNews.com, May 8, 2009.


Rebuck JA. Thalidomide revisited. The AIDS Reader 1998;8:7-9.


Sharma A, Raina V, Uppal G, Kumar R, Grover J. Long term use of thalidomide: safe and effective 2007; 44(3):108-110


Tseng S, Pak G, Washenik K, et al. Rediscovering thalidomide: A review of its mechanism of action, side effects, and potential uses. J Am Acad Dermatol. 1996; 35(6):969-79.


New Zealand Dermatological Society 2006. Available: http://dermnetnz.org/treatments/thalidomide.html (accessed 20 March 2008).


Warren, NJ. Celgene Corporation. Thalomid (thalidomide)-overview of potential uses 1998.


USFDA: Center for Drug Evaluation and Research. Thalidomide Information 1998.


World Ability Federation 2005. (accessed 30 March 2008).


National Disability Arts Forum 2007. Available: (accessed 20 March 2008).


Disability World 2004 (accessed 20 March 2008).


Anon. Thalidomide: Facts and Comparisons 1998;744f-744m.


Mat Fraser (accessed 19 March 2008).


Stephens TD, Bunde CJW, Fillmore BJ. Mechanism of action in thalidomide teratogenesis. Biochemical Pharmacology 2000; 59(12):1489-1499.


Ragged Edge Magazine 2005 (accessed 9 March 2008).


Sources:


http://newsimg.bbc.co.uk/media/images/40763000/jpg/_40763931_thalidomide_bottle203.jpg,

All information for Present and Future Uses used source (5).

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