Thalidomide never entirely disappeared from use, however, and it was later found to benefit some leprosy patients. In 1998, after a complex safety monitoring system had been established to prevent further birth defects, thalidomide was approved for use in the United States for a complication of leprosy. The drug is also used to treat multiple myeloma, a cancer that affects the bone marrow.
Thalidomide is a sedative-hypnotic, and multiple myeloma medication. The drug is a potent teratogen in rats, rabbits, and primates including humans: this means that severe birth defects may result if the drug is taken during pregnancy.
The impact in the United States was minimized when Frances Oldham Kelsey refused FDA-approval for an application from Richardson Merrell to market it saying it needed more study. Richardson Merrell gave the tablets to doctors with the understanding that it was still under investigation. Only 17 children in the U.S. were born with the defects.
In 1962, 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.
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.
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 conducted in 1991 by Dr. Gilla Kaplan at Rockefeller University in New York City showed that thalidomide worked in leprosy by inhibiting tumor necrosis factor alpha. Kaplan partnered with Celgene Corporation to further develop the potential for thalidomide. Subsequent research has shown that it is effective in multiple myeloma, and it was approved by the FDA for use in this malignancy. The FDA has also since approved the drug's use in the treatment of erythema nodosum leprosum. There are studies underway to determine the drug's effects on arachnoiditis and several types of cancers. However, physicians and patients alike must go through a special process to prescribe and receive thalidomide (S.T.E.P.S and RevAssist) to ensure no more children are born with birth defects traceable to the medication. Celgene Corporation has also developed analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects - except for greater myelosuppression.
"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. The FDA approval came seven years after the first reports of efficacy in the medical literature 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.
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 Desikan et al. report. 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 stem cell transplants may no longer be the standard treatment for this incurable malignancy.
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 is also prescribed for its anti-inflammatory effects in actinic prurigo, an autoimmune skin disease.
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.
Thalidomide is racemic – it contains both left- and right-handed isomers in equal amounts. The (R) enantiomer is effective against morning sickness. The (S) 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 of its biological action is being debated, with current literature that suggests that it intercalates into DNA in G-C rich regions.
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 oedema, atelectasis, aspiration pneumonia and refractory hypotension. In multiple myeloma patients, concomitant use with zoledronic acid may lead to increased incidence of renal dysfunction.
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. These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.