Thalicsimidine
From DrugPedia: A Wikipedia for Drug discovery
| Image:Thalidomide-2D-skeletal-wavy.svg | |
| Thalicsimidine
| |
| Systematic (IUPAC) name | |
| 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione | |
| Identifiers | |
| CAS number | |
| ATC code | L04 |
| PubChem | |
| DrugBank | |
| ChemSpider | |
| Chemical data | |
| Formula | ? |
| Mol. mass | 258.23 g/mol |
| SMILES | & |
| Pharmacokinetic data | |
| Bioavailability | ? |
| Protein binding | 55% and 66% for the (+)-R and (–)-S enantiomers, respectively |
| Metabolism | Hepatic |
| Half life | mean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses |
| Excretion | ? |
| Therapeutic considerations | |
| Pregnancy cat. |
? |
| Legal status |
Template:Unicode Prescription only |
| Routes | oral |
Thalidomide' is a sedative-hypnotic, and multiple myeloma medication. The drug is a potent teratogen in rabbits and primates including humans: severe birth defects may result if the drug is taken during pregnancy.
Contents |
[edit] History
[edit] Development
Thalidomide was thought to have been developed by German pharmaceutical company Grünenthal in Stolberg (Rhineland) near Aachen although this has recently been challenged by Dr Martin W Johnson, director of the Thalidomide Trust in the UK<ref>http://www.timesonline.co.uk/tol/life_and_style/health/article5683577.ece</ref>. It is thought that thalidomide was developed by the Nazis as an antidote to nerve gas such as sarin.
It was sold from 1957 to 1961 in almost 100 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.
[edit] Birth defects
From 1956 to 1962, over 9000 children in Africa and Europe were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy.<ref name =Bren> The Australian obstetrician William McBride discovered the link between birth defects and the drug, and was awarded a medal and prize money by the prestigious L'Institut de la Vie in Paris.<ref>Report of Thalidomide at University of New South Wales. See also main William McBride article.</ref>
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. 17 children in the U.S. were born with the defects.<ref>Thalidomide - medic8.com - Retrieved August 25, 2008</ref>
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.<ref name =Burkholz>Template:Cite news</ref> Other countries enacted similar legislation, and thalidomide was not prescribed or sold for decades.
However, it was soon found that it was only one particular optical isomer of thalidomide which caused the teratogenicity. The pair of enantiomers, although mirror images of each other, cause different effects<ref>Chemistry 2, published by Cambridge University Press 2001. ISBN 0-521-79882-5</ref> (see Teratogenic mechanism section for details).
[edit] Revived interest
Researchers, however, continued to work with the drug. Soon after its banishment, an Israeli doctor discovered anti-inflammatory effects of thalidomide and began to look for uses of the medication despite its teratogenic effects.
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 then 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.<ref name =Silverman>Silverman, MD, William (2002-04-22). "The Schizophrenic Career of a "Monster Drug"". Pediatrics 110 (2): 404–406. doi:. PMID 12165600. Retrieved on 2006-09-21.</cite></ref>
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.<ref>http://www.medscape.com/viewarticle/562417_3</ref>
[edit] FDA approval
On July 16, 1998, the FDA approved the use of thalidomide for the treatment of lesions associated with Erythema Nodosum Leprosum (ENL). Because of thalidomide’s potential for causing birth defects, the distribution of thalidomide was permitted only under tightly controlled conditions. The FDA required that Celgene Corporation, which planned to market thalidomide under the brand name Thalomid, establish a System for Thalidomide Education and Prescribing Safety (S.T.E.P.S) oversight program. The S.T.E.P.S program includes limiting prescription and dispensing rights only to authorized prescribers and pharmacies, extensive patient education about the risks associated with thalidomide, periodic pregnancy tests, and a patient registry.<ref>FDA, Center for Drug Evaluation and Research, July 16, 1998</ref>
"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."<ref>FDA Approves Thalomid (thalidomide) to Treat Multiple Myeloma</ref> The FDA approval came seven years after the first reports of efficacy in the medical literature<ref name=Desikan><cite style="font-style:normal">Desikan, R; N. Munsi, J. Zeldis et al. (1999). "Activity of thalidomide (THAL) in multiple myeloma (MM) confirmed in 180 patients with advanced disease". Blood 94 (Suppl. 1): 603a-603a.</cite></ref> 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.<ref>Pushing Prescriptions - The Center for Public Integrity</ref>
Thalidomide was and, as of 2009, still is an important advance in the treatment of multiple myeloma, ever since news of its efficacy appeared in the Desikan et al. report.<ref name =Desikan /> 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.
[edit] 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.
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.<ref name =Burkholz />
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.<ref name =Chem>Template:Cite web</ref> 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.<ref name =Burkholz />
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.<ref>Reuters, Thalidomide helps elderly cancer patients: study</ref>
[edit] Teratogenic mechanism
Left: (S)-thalidomide
Right: (R)-thalidomide
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<ref><cite style="font-style:normal">Teo SK, Colburn WA, Tracewell WG, Kook KA, Stirling DI, Jaworsky MS, Scheffler MA, Thomas SD, Laskin OL (2004). "Clinical pharmacokinetics of thalidomide". Clin Pharmacokinet. 43 (5): 311–327. doi:. PMID 15080764.</cite></ref> – 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.
[edit] Thalidomide and multiple myeloma
Thalidomide was first tested as a single agent for the treatment of multiple myeloma in 1999 due to its antiangiogenesis activity. <ref>Singhal S, Mehta J, Desikan R, et al. Antitumor activity of thalidomide in refractory multiple myeloma. N Engl J Med. 1999;341(21):1565–71. [PubMed]</ref> Since then many studies have shown that thalidomide in combination with dexamethasone has increased the survival of multiple myeloma patients. The combination of thalidomide and dexamethasone, often in combination with melphalan, is now one of the most common regimens for patients with newly diagnosed multiple myeloma, with an improved response rate of up to 60-70%. <ref>Gieseler, F. Pathophysiological consideration to thrombophilia in the treatment of multiple myeloma with thalidomide and derivative. Thromb Haemost 2008;99:1001-1007.</ref><ref>Denz, U et al State of the art of therapy in multiple myeloma and future perspectives. Eur J. Cancer 2006; 42:1591-1600</ref> However, thalidomide may also cause side effects such as polyneuropathy, fatigue, skin rash, and venous thromboembolism (VTE), or blood clots which could lead to stroke or myocardial infarction.<ref name="pmid18182082"><cite style="font-style:normal">Haas PS, Denz U, Ihorst G, Engelhardt M (April 2008). "Thalidomide in consecutive multiple myeloma patients: single-center analysis on practical aspects, efficacy, side effects and prognostic factors with lower thalidomide doses". Eur. J. Haematol. 80 (4): 303–9. doi:. PMID 18182082.</cite></ref> Bennett et al. have conducted a systematic review of VTE associated with thalidomide in multiple myeloma patients. <ref>Bennett et al Thalidomide- and lenalidomide- associated thromboembolism among patients with cancer 2006;296(21):2558-2560</ref>They have found that when Thalidomide was administered without prophylaxis, VTE rates reached as high as 26%. Due to the high rates of VTE associated with thalidomide in combination with dexamethasone or doxorubicin, a black box warning was added in 2006 to the package insert for thalidomide, indicating that patients with multiple myeloma who receive thalidomide-dexamethasone may benefit from concurrent thromboembolism prophylaxis or aspirin. In addition, due to these side effects, newer drugs, such as a thalidomide derivative lenalidomide (marketed as Revlimid) and bortezomib (marketed as Velcade) have increased in popularity, and use of thalidomide may be on a decline.
[edit] Other 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 is also 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.
[edit] 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.<ref>Search of: pomalidomide - ClinicalTrials.gov</ref> These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.
[edit] Notable children affected
- Mat Fraser, a comedian, actor, co-presenter of the BBC's Ouch Podcast.
- Alvin Law, a motivational speaker and former radio broadcaster.
- Tony Meléndez is a guitarist who was born without arms. He plays only with his feet.
- Terry Wiles internationally known through On Giants' Shoulders, a book and film about his life.
- Brett Nielsen, a musician , was the first Australian thalidomide child.
- Louise Medus Mansell, daughter of David Mason, campaigner for increased compensation for Thalidomide children, born with no arms or legs.<ref>Daily Mail article on Louise Medus Mansell</ref>
- Thomas Quasthoff is an internationally acclaimed bass-baritone who describes himself: "1.34 meters tall, short arms, seven fingers - four right, three left - no large, relatively well formed head, brown eyes, distinctive lips; profession: singer."<ref>Orpheus lives: A small good thing in Quastoff Retrieved on 2008-10-22</ref>
- Matthias Berg is a lawyer, renowned hornist and multiple Paralympics gold medalist.
- Melody Potter Native Alabamian disability activist, severe deformities, no arms or legs.
- Giancarlo Cosio, Italian Waterski World disabled Champion.
- David Lega, Swedish swimmer. Paralympian and current holder of 5 world records. <ref>David Lega personal website</ref>
- Gary Skyner, a comedian and motivational speaker.
[edit] General Properties
*Molecular Weight
385.45348
*Molecular Formula
C22H27NO5
*IUPAC NAME
N/A
*Canonical Smiles
CN1CCC2=C(C(=C(C3=C2C1CC4=CC(=C(C=C43)OC)OC)OC)OC)OC
*Isomeric Smiles
N/A
*XLogP
2.4
*Topological Polar Surface Area
49.4
[edit] External Links
[edit] References
[edit] Further reading
[edit] External links
- Thalidomide product monograph (Needs registration)
- Multiple Myeloma Research Foundation article on Thalidomide
- International Myeloma Foundation article on Thalidomide
- Thalidomide — Annotated List of Links (covering English and German pages)
- WHO Pharmaceuticals Newsletter No. 2, 2003 - See page 11, Feature Article
- Grünenthal GmbH - Thalidomide
- Celgene website on Thalomid
- The Return of Thalidomide - BBC
- CBC Digital Archives – Thalidomide: Bitter Pills, Broken Promises
- Thalidomide UK
- The Thalidomide Trust
- "The Big Pitch: How would you conduct a campaign for the new Thalidomide Drugs?", forum of pharmaceutical and medical marketing professionals commenting on how they would address the Thalidomine controversies.
