Thalidomide
Thalidomide, sold under the brand names Contergan, Distaval and Thalomid among others, is an oral administered medication used to treat a number of cancers, graft-versus-host disease, and many skin disorders. 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 bones, and phocomelia. 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 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.The bacterium that causes tuberculosis 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. The U.S. Food and Drug Administration 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 adverse effects include tremor, dizziness, tingling, numbness, constipation, and peripheral edema.
Common adverse effects 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 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 -enantiomer has the desired sedative effect while the -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 - to.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 can react with L-glutamine to yield N-phthaloyl-L-glutamine. Cyclization of N-phthaloyl-L-glutamine occurs using carbonyldiimidazole, which then yields thalidomide. 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. It was proclaimed a "wonder drug" for insomnia, coughs, colds and headaches.
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.
While initially considered safe, the drug was responsible for teratogenic deformities in children born after their mothers used it during pregnancies, prior to the third trimester. In November 1961, thalidomide was taken off the market due to massive pressure from the press and public. Experts estimate that thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, with over half of them in West Germany. The regulatory authorities in East Germany never approved thalidomide. One reason for the initially unobserved side effects of the drug and the subsequent approval in West Germany was that at that time drugs did not have to be tested for teratogenic effects. They were tested for toxicity on rodents only, as was usual at the time.
In the UK, the British pharmaceutical company The Distillers Company Ltd, a subsidiary of Distillers Co. Ltd, marketed thalidomide throughout the UK, Australia, and New Zealand, under the brand name Distaval, as a remedy for morning sickness. Their advertisement claimed that "Distaval can be given with complete safety to pregnant women and nursing mothers without adverse effect on mother or child... Outstandingly safe Distaval has been prescribed for nearly three years in this country." Globally, more pharmaceutical companies started to produce and market the drug under license from Chemie Grünenthal. Thalidomide was available in 46 countries under many different brand names.
In the US, representatives from Chemie Grünenthal approached Smith, Kline & French, now GlaxoSmithKline, with a request to market and distribute the drug in North America. A memorandum, rediscovered in 2010 in the archives of the FDA, shows that in 1956–57, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women. In 1956, researchers involved in clinical trials at SKF noted that, even when used in very high doses, thalidomide could not induce sleep in mice. When administered at doses 50 to 650 times larger than that claimed by Chemie Grünenthal to be "sleep-inducing", the researchers could still not achieve the hypnotic effect in animals that it had on humans. After completion of the trial, and based on reasons kept hidden for decades, SKF declined to commercialize the drug. In 1958, Chemie Grünenthal reached an agreement with the William S. Merrell Company in Cincinnati, Ohio, to market and distribute thalidomide throughout the US.
The US FDA refused to approve thalidomide for marketing and distribution. However, the drug was distributed without approval in large quantities for testing purposes, after the American distributor and manufacturer Richardson-Merrell had applied for its approval in September 1960. The official in charge of the FDA review, Frances Oldham Kelsey, did not rely on information from the company, which did not include any test results. Richardson-Merrell was called on to perform tests and report the results. The company demanded approval six times and was refused each time. The unapproved distribution for "testing" resulted in 17 children born in the US with thalidomide-induced malformations. Oldham Kelsey was awarded the President's Award for Distinguished Federal Civilian Service by President Kennedy in 1962 for not allowing thalidomide to be approved for sale in the US. She was also inducted into the National Women's Hall of Fame in 2000.
Canada's Food and Drug Directorate approved the sale of thalidomide by prescription in November 1960. There were many different forms sold: Kevadon, produced by the William S. Merrell Company seeking approval for its thalidomide product, was released on the market in April 1961, and the most common variant was put on the market on October 23 of the same year. Two months after Talimol went on sale, pharmaceutical companies sent physicians letters warning about the risk of birth defects. It was not until March 1962 that both drugs were banned from the Canadian market by the directorate, and soon afterward physicians were warned to destroy their supplies.