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Thalidomide chemical structure
Thalidomide

2-(2,6-dioxopiperidin-3-yl) isoindoline-1,3-dione
IUPAC name
CAS number
50-35-1
ATC code

L04AX02

PubChem
5426
DrugBank
APRD01251
Chemical formula {{{chemical_formula}}}
Molecular weight 258.23 g/mol
Bioavailability
Metabolism
Elimination half-life mean ranges from approximately 5 to 7 hours following a single dose; not altered with multiple doses
Excretion
Pregnancy category
Legal status Rx-only
Routes of administration oral
File:Thalidomide Baby.jpg
File:Kelsey 01.jpg

Thalidomide is a sedative-hypnotic, and multiple myeloma medication. The drug is a potent teratogen in rabbits and primates including humans: this means that severe birth defects may result if the drug is taken during pregnancy.[1]

HistoryEdit

DevelopmentEdit

Thalidomide was developed by German pharmaceutical company Grünenthal in Stolberg near Aachen. It was sold from 1957 to 1961 in almost 50 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.

Birth defectsEdit

From 1956 to 1962, approximately 10,000 children in Africa and Europe were born with severe malformities, including phocomelia, because their mothers had taken thalidomide during pregnancy.[2]

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.[3]

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.[4] 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.[5]

Revived interestEdit

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 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.[6]

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.[7]

FDA approvalEdit

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, to 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.[8]

"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."[9] The FDA approval came seven years after the first reports of efficacy in the medical literature[10] 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.[11]

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.[10] 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.

Possible indicationsEdit

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.[4]

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.[12] 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.[4]

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.[13]

Teratogenic mechanismEdit

File:Thalidomide-structures.png

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[14] – 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.

Thalidomide and multiple myelomaEdit

Thalidomide was first tested as a single agent for the treatment of multiple myeloma in 1999 due to its antiangiogenesis activity. [15] 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%. [16][17] 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. [18] Bennett et al have conducted a systematic review of VTE associated with thalidomide in multiple myeloma patients. [19]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.

Other side effectsEdit

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.

Thalidomide analogsEdit

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.[20] These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.

See alsoEdit

ReferencesEdit

  1. Thalidomide: Drug safety during pregnancy and breastfeeding / DRUGSAFETYSITE.COM
  2. includeonly>Bren, Linda. "Frances Oldham Kelsey: FDA Medical Reviewer Leaves Her Mark on History", FDA Consumer, US Food and Drug Administration, 2001-02-28. Retrieved on 2006-09-21.
  3. Thalidomide - medic8.com - Retrieved August 25, 2008
  4. 4.0 4.1 4.2 includeonly>Burkholz, Herbert. "Giving Thalidomide a Second Chance", FDA Consumer, US Food and Drug Administration, 1997-09-01. Retrieved on 2006-09-21.
  5. Chemistry 2, published by Cambridge University Press 2001. ISBN 0-521-79882-5
  6. Silverman, MD, William (2002-04-22). The Schizophrenic Career of a "Monster Drug". Pediatrics 110 (2): 404–406.
  7. http://www.medscape.com/viewarticle/562417_3
  8. FDA, Center for Drug Evaluation and Research, July 16, 1998
  9. FDA Approves Thalomid (thalidomide) to Treat Multiple Myeloma
  10. 10.0 10.1 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.
  11. Pushing Prescriptions - The Center for Public Integrity
  12. Rouhi, Maureen Thalidomide. Chemical & Engineering News. American Chemical Society. URL accessed on 2006-09-21.
  13. Reuters, Thalidomide helps elderly cancer patients: study
  14. 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.
  15. 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]
  16. Gieseler, F. Pathophysiological consideration to thrombophilia in the treatment of multiple myeloma with thalidomide and derivative. Thromb Haemost 2008;99:1001-1007.
  17. Denz, U et al State of the art of therapy in multiple myeloma and future perspectives. Eur J. Cancer 2006; 42:1591-1600
  18. Haas, PS et al. Thalidomide in consecutive multiple myeloma patients: single-center analysis on practical aspects, efficacy, side effects and prognostic factors with lower thalidomide doses. 2007;80:303-309
  19. Bennett et al Thalidomide- and lenalidomide- associated thromboembolism among patients with cancer 2006;296(21):2558-2560
  20. Search of: Actimid - List Results - ClinicalTrials.gov

Further readingEdit

BooksEdit

  • Fish, J. M., Serrat, S. M., & Elias, M. E. T. (1989). Thalidomide adolescents and preadolescents in Brazil. New York, NY, England: Praeger Publishers.
  • Knightley, Phillip; Evans, Harold. Potter, Elaine. Wallace, Marjorie. (1979). Suffer The Children: The Story of Thalidomide, New York: The Viking Press.
  • Schonberger, F. (1971). The so called contergan-(thalidomide) children. Oxford, England: Kosel.
  • Stephens, Trent; Brynner, Rock (2001-12-24). Dark Remedy: The Impact of Thalidomide and Its Revival as a Vital Medicine, Perseus.

PapersEdit

Alkam, T., Nitta, A., Mizoguchi, H., Saito, K., Seshima, M., Itoh, A., et al. (2008). Restraining tumor necrosis factor-alpha by thalidomide prevents the amyloid beta-induced impairment of recognition memory in mice: Behavioural Brain Research Vol 189(1) May 2008, 100-106.

  • Armstrong, K. S. (1973). Forgotten children: Some notes on "abnormality and normality." Canadian Psychologist/Psychologie canadienne Vol 14(4) Oct 1973, 374-375.
  • Brent, R. L. (2004). Comment. Teratology in the 20th Century. Environmental Causes of Congenital Malformations in Humans and how they were established: Neurotoxicology and Teratology Vol 26(1) Jan-Feb 2004, 1-12.
  • Cata, J. P., Weng, H.-R., & Dougherty, P. M. (2008). The effects of thalidomide and minocycline on taxol-induced hyperalgesia in rats: Brain Research Vol 1229 Sep 2008, 100-110.
  • Chaudhry, V., Cornblath, D. R., Corse, A., Freimer, M., Simmons-O'Brien, E., & Vogelsang, G. (2002). Thalidomide-induced neuropathy: Neurology Vol 59(12) Dec 2002, 1872-1875.
  • Croisiaux, C., & Blomart, J. (1985). A tentative approach to the self-image of young adult thalidomide victims with congenital malformations: Revue Belge de Psychologie et de Pedagogie Vol 47(189) Mar 1985, 17-25.
  • Enomoto, N., Takei, Y., Hirose, M., Kitamura, T., Ikejima, K., & Sato, N. (2003). Protective effect of thalidomide on endotoxin-induced liver injury: Alcoholism: Clinical and Experimental Research Vol 27(Suppl8) Aug 2003, 2S-6S.
  • Frederickson, R. C., & et al. (1977). A comparison of thalidomide and pentobarbital: New methods for identifying novel hypnotic drugs: Journal of Pharmacology and Experimental Therapeutics Vol 203(1) Oct 1977, 240-251.
  • George, A., Marziniak, M., Schafers, M., Toyka, K. V., & Sommer, C. (2000). Thaliomide treatment in chronic constrictive neuropathy decreases endoneurial tumor necrosis factor-alpha , increases interleukin-10 and has long-term effects on spinal cord dorsal horn met-enkephalin: Pain Vol 88(3) Dec 2000, 267-275.
  • Gordinier, M. E., Dizon, D. S., Weitzen, S., Disilvestro, P. A., Moore, R. G., & Granai, C. O. (2007). Oral Thalidomide as Palliative Chemotherapy in Women with Advanced Ovarian Cancer: Journal of Palliative Medicine Vol 10(1) Feb 2007, 61-66.
  • Gouin-Decarie, T., & O'Neill, M. (1973). Some aspects of cognitive development among children suffering from malformations due to thalidomide: Bulletin de Psychologie Vol 27(5-9) 1973-1974, 286-303.
  • Greig, N. H., Giordano, T., Zhu, X., Yu, Q.-S., Perry, T. A., Holloway, H. W., et al. (2004). Thalidomide-based TNF-alpha inhibitors for neurodegenerative diseases: Acta Neurobiologiae Experimentalis Vol 64(1) 2004, 1-9.
  • Gupta, A., Cohen, B. H., Ruggieri, P., Packer, R. J., & Phillips, P. C. (2003). Phase I study of thalidomide for the treatment of plexiform neurofibroma in neurofibromatosis 1: Neurology Vol 60(1) Jan 2003, 130-132.
  • Hetherington, E. M. (1972). Review of Abnormality and Normality: The Mothering of Thalidomide Children: PsycCRITIQUES Vol 17 (12), Dec, 1972.
  • Isoardo, G., Bergui, M., Durelli, L., Barbero, P., Boccadoro, M., Bertola, A., et al. (2004). Thalidomide neuropathy: Clinical, electrophysiological and neuroradiological features: Acta Neurologica Scandinavica Vol 109(3) Mar 2004, 188-193.
  • Jonsson, B. G. (1972). Effects of thalidomide on the embryonic development of the axolotl (Ambystoma mexicanum): Acta Pharmacologica et Toxicologica Vol 31(1-2) 1972, 27-32.
  • Jonsson, B. G. (1972). Teratological studies on thalidomide in rabbits: Acta Pharmacologica et Toxicologica Vol 31(1-2) 1972, 17-23.
  • Jonsson, B. G. (1972). Teratological studies on thalidomide in rats: Acta Pharmacologica et Toxicologica Vol 31(1-2) 1972, 11-16.
  • Kaitin, K. I. (1985). Effects of thalidomide and pentobarbital on neuronal activity in the preoptic area during sleep and wakefulness in the cat: Psychopharmacology Vol 85(1) Jan 1985, 47-50.
  • Kalter, H. (2003). Teratology in the 20th century Environmental causes of Congenital malformations in humans and how their environmental causes were established: Neurotoxicology and Teratology Vol 25(2) Mar-Apr 2003, 131-282.
  • Kanbayashi, T., Shimizu, T., Takahashi, Y., Kitajima, T., Takahashi, K.-i., Saito, Y., et al. (1999). Thalidomide increases both REM and stage 3-4 sleep in human adults: A preliminary study: Sleep: Journal of Sleep Research & Sleep Medicine Vol 22(1) Feb 1999, 113-115.
  • Kuwabara, S., Misawa, S., Kanai, K., Sawai, S., Hattori, T., Nishimura, M., et al. (2008). Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome: Journal of Neurology, Neurosurgery & Psychiatry Vol 79(11) Nov 2008, 1255-1257.
  • McBride, W. (2004). Health of thalidomide victims and their progeny: Lancet Vol 363(9403) Jan 2004, 169.
  • McFie, J., & Robertson, J. (1973). Psychological test results of children with thalidomide deformities: Developmental Medicine & Child Neurology Vol 15(6) Dec 1973, 719-727.
  • Miyazaki, K., Narita, N., & Narita, M. (2005). Maternal administration of thalidomide or valproic acid causes abnormal serotonergic neurons in the offspring: Implication for pathogenesis of autism: International Journal of Developmental Neuroscience Vol 23(2-3) Apr-May 2005, 287-297.
  • Sommer, C., Marziniak, M., & Myers, R. R. (1998). The effect of thalidomide treatment on vascular pathology and hyperalgesia caused by chronic constriction injury of rat nerve: Pain Vol 74(1) Jan 1998, 83-91.
  • Stoeckel, M. C., Jorgens, S., Witte, O. W., & Seitz, R. J. (2005). Reduced somatosensory hand representation in thalidomide-induced dysmelia as revealed by fMRI: European Journal of Neuroscience Vol 21(2) Jan 2005, 556-562.
  • Stromland, K., Nordin, V., Miller, M., Akerstrom, B., & et al. (1994). Autism in thalidomide embryopathy: A population study: Developmental Medicine & Child Neurology Vol 36(4) Apr 1994, 351-356.
  • Teitelbaum, P. (2003). A proposed primate animal model of autism: European Child & Adolescent Psychiatry Vol 12(1) Mar 2003, 48-49.
  • Tweedie, D., Sambamurti, K., & Greig, N. H. (2007). TNF-alpha inhibition as a treatment strategy for neurodegenerative disorders: New drug candidates and targets: Current Alzheimer Research Vol 4(4) Sep 2007, 378-385.
  • Vincent, H., & Chaibi, P. (2008). Treatment of myeloma in the elderly: Contribution of new compounds: NPG Neurologie, Psychiatrie, Geriatrie Vol 8(44) Apr 2008, 10-18.
  • Vorhees, C. V., Weisenburger, W. P., & Minck, D. R. (2001). Neurobehavioral teratogenic effects of thalidomide in rats: Neurotoxicology and Teratology Vol 23(3) May-Jun 2001, 255-264.
  • Zara, G., Ermani, M., Rondinone, R., Arienti, S., & Doria, A. (2008). Thalidomide and sensory neurotoxicity: A neurophysiological study: Journal of Neurology, Neurosurgery & Psychiatry Vol 79(11) Nov 2008, 1258-1261.

DissertationsEdit

  • Kaitin, K. I. (1982). Neuronal activity in the preoptic area of the hypothalamus during sleep and wakefulness in the drug-free cat and after administration of thalidomide and pentobarbital: Dissertation Abstracts International.


External linksEdit


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