Thalidomide, sold under the brand names Contergan, Distaval and Thalomid among others, is an oral administered medication currently used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complications of leprosy such as skin lesions). Updated as required. Thalidomide has been used to treat conditions associated with HIV: aphthous ulcers, HIV-associated wasting syndrome, diarrhea, and Kaposi's sarcoma, but increases in HIV viral load have been reported.
Common side effects include sleepiness, rash, and dizziness. Severe side effects include tumor lysis syndrome, blood clots, and peripheral neuropathy. Thalidomide is a known human teratogen and carries an extremely high risk of severe, life-threatening birth defects if administered or taken during pregnancy. It causes skeletal deformities such as amelia (absence of legs and/or arms), absence of bones, and phocomelia (malformation of the limbs). A single dose of thalidomide, regardless of dosage, is enough to cause teratogenic effects.
Thalidomide was first marketed in 1957 in West Germany, where it was available as an over-the-counter drug. When first released, thalidomide was promoted for anxiety, trouble sleeping, "tension", and morning sickness. While it was initially thought to be safe in pregnancy, thalidomide was found to cause birth defects, resulting in its removal from the market in Europe in 1961. The total number of infants severely harmed by thalidomide use during pregnancy is estimated at over 10,000, possibly 20,000, of whom about 40% died around the time of birth. Those who survived had limb, eye, urinary tract, and heart problems. Its initial entry into the US market was prevented by Frances Oldham Kelsey, a reviewer at the FDA. The birth defects caused by thalidomide led to the development of greater drug regulation and monitoring in many countries.
It was approved in the United States in 1998 for use as a treatment for cancer. It is on the World Health Organization's List of Essential Medicines. It is available as a generic medication.
Medical uses
Thalidomide is used as a first-line treatment for multiple myeloma in combination with dexamethasone or with melphalan and prednisone to treat acute episodes of erythema nodosum leprosum, as well as for maintenance therapy. For label updates see
The bacterium that causes tuberculosis (TB) is related to leprosy. Thalidomide may be helpful in some cases where standard TB drugs and corticosteroids are not sufficient to resolve severe inflammation in the brain.
It is used as a second-line treatment to manage graft-versus-host disease and aphthous stomatitis in children and has been prescribed for other conditions in children, including actinic prurigo and epidermolysis bullosa; the evidence for these uses is weak. It is recommended only as a third line treatment in graft-versus-host-disease in adults because of lack of efficacy and side effects observed in clinical trials.
Contraindications Prescriptions of thalidomide are accompanied by strict measures to avoid any possibility of use during pregnancy, and thalidomide should be avoided in women wanting to conceive. In the United States, the prescribing doctor is required to ensure that contraception is being used and that regular pregnancy tests are taken.
Adverse effects
Thalidomide causes birth defects.Anastas, P. T.; Warner, J. C. Green Chemistry: Theory and Practice, p3 The U.S. Food and Drug Administration (FDA) and other regulatory agencies have approved marketing of the drug only with an auditable risk evaluation and mitigation strategy that ensures that people using the drug are aware of the risks and avoid pregnancy; this applies to both men and women, as the drug can be transmitted in semen.
There is a high risk that thalidomide can cause excessive blood clots. There is also a high risk that thalidomide can interfere with the production of several types of new blood cells, creating a risk of infection via neutropenia, leukopenia, and lymphopenia, and risks that blood will not clot via thrombocytopenia. There is also a risk of anemia via lack of red blood cells. The drug can also damage nerves, causing potentially irreversible peripheral neuropathy.
Thalidomide has several adverse cardiovascular effects, including risk of heart attacks, pulmonary hypertension, and changes in heart rhythm, such as syncope, bradycardia, and atrioventricular block.
Thalidomide can cause liver damage and severe skin reactions like Stevens–Johnson syndrome. It tends to make people sleepy, which creates risk when driving and operating other machinery. As it kills cancer cells, it can cause tumor lysis syndrome. Thalidomide can prevent menstruation.
In addition, very common (reported in more than 10% of people) adverse effects include tremor, dizziness, tingling, numbness, constipation, and peripheral edema.
Common adverse effects (reported by 1–10% of people) include confusion, depressed mood, reduced coordination, heart failure, difficulty breathing, interstitial lung disease, lung inflammation, vomiting, dry mouth, rashes, dry skin, fever, weakness, and a sense of unwellness.
Interactions There are no expected pharmacokinetic interactions between thalidomide and other medicines due to its neutral effects on P-glycoprotein and the cytochrome P450 family. It may interact with sedatives due to its sedative action and bradycardic agents, like beta-blockers, due to its bradycardia-inducing effects. The risk of peripheral neuropathy may be increased by concomitant treatment of thalidomide with other agents known to cause peripheral neuropathy. The risk of venous thromboembolisms with thalidomide seems to be increased when patients are treated with oral contraceptives or other cytotoxic agents (including doxorubicin and melphalan) concurrently. Thalidomide may interfere with various contraceptives, and hence it is advised that women of reproductive age use at least two different means of contraception to ensure that no child will be conceived while they are taking thalidomide.
Overdose As of 2013, eighteen cases of overdoses had been reported with doses of up to 14.4 grams, none of them fatal. No specific antidote for overdose exists and treatment is purely supportive.
Pharmacology The precise mechanism of action for thalidomide was not known until the twenty-first century, although efforts to identify thalidomide's teratogenic action generated more than 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000. The primary mechanism of action of thalidomide and its analogs in both their anti-cancer and teratogenic effects is now known to be as cereblon E3 ligase modulators.
Thalidomide also binds to and acts as an antagonist of the androgen receptor and hence is a nonsteroidal antiandrogen of some capacity. In accordance, it can produce gynecomastia and sexual dysfunction as side effects in men.
Chirality and biological activity Thalidomide is provided as a racemic mixture of two enantiomers; while there are reports that only one of the enantiomers may cause birth defects, the body converts each enantiomer into the other through mechanisms that are not well understood. The (R)-enantiomer has the desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effects. The use of R-thalidomide does not remove the risk of birth defects, as it was demonstrated that the "safe" R-thalidomide undergoes an in vivo chiral inversion to the teratogenic S-thalidomide. Under biological conditions, the enantiomers interconvert (bidirectional chiral inversion – (R)- to (S)- and vice versa).
Chemistry
Thalidomide is a chiral molecule, and when synthesized is formed as racemic; while S-thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize to each other due to the acidic hydrogen at the chiral centre, which is the carbon of the glutarimide ring bonded to the phthalimide substituent. The racemization process can occur in vivo. The process of conversion of one enantiomer to its mirror-image version with no other change in the molecule is called chiral inversion.
Celgene Corporation originally synthesized thalidomide using a three-step sequence starting with L-glutamic acid treatment, but this has since been reformed by the use of L-glutamine. As shown in the image below, N-carbethoxyphthalimide (1) can react with L-glutamine to yield N-phthaloyl-L-glutamine (2). Cyclization of N-phthaloyl-L-glutamine occurs using carbonyldiimidazole, which then yields thalidomide (3). Celgene Corporation's original method resulted in a 31% yield of S-thalidomide, whereas the two-step synthesis yields 85–93% product that is 99% pure.
In 2023, it is reported that phthalic anhydride and L-glutamine under suitable conditions can react directly to form thalidomide. In the procedure, phthalic anhydride and L-glutamine are grounded and added into toluene solvent. The solution, along with triethylamine and acetic anhydride, is refluxed at ~110°C for 9 hours; after that the solution goes through a simple vacuum filtration procedure to obtain the product.
History
In 1952, thalidomide was synthesised by Chemical Industry Basel, but was found "to have no effect on animals" and was discarded on that basis. In 1957, it was acquired by Chemie Grünenthal in Germany. The German company had been established as a soap maker after World War II ended, to address the urgent market need for antibiotics. Heinrich Mückter was appointed to head the discovery program based on his experience working with the German army's antiviral research. While preparing reagents for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of glutethimide, a sedative. The medicinal chemistry work turned to improving the lead compound into a suitable drug: the result was thalidomide. The toxicity was examined in several animals, and the drug was introduced in 1956 as a sedative, but it was never tested on pregnant women.
Researchers at Chemie Grünenthal found that thalidomide was a particularly effective antiemetic that had an inhibitory effect on morning sickness. On 1 October 1957, the company launched thalidomide and began marketing it under the trade name Contergan. See also It was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches.Campbell, Denis. "'Wonder drug' left babies with deformed limbs." The Guardian. 29 July 2009.
During that 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 abnormalities in children being born to mothers using thalidomide. In late 1959, it was noticed that peripheral neuritis developed 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.