Thalidomide_History

The Ever-Changing Identity of Thalidomide and its Impact on Society The thalidomide catastrophe shocked the world and its devastating effects coupled with its high profile in the media have ensured that, despite taking place fifty years ago, it is still a mainstream topic, discussed by the general public as well as being the subject of much interest and debate in the medical world. It was responsible for limb defects and a whole host of other abnormalities in thousands of babies born in the 1950s and early 1960s. The effects of this tragedy have been far-reaching and the question has to be raised: how could one molecule cause so much damage' Thalidomide, or α-phthalimidoglutarimide (derma rediscovering), is an analogue of glutamic acid. It is a racemic mixture consisting of S(-) and R(+) enantiomers - under physiological conditions, these enantiomers readily interconvert. It is thought that the R(+) form is responsible for the sedative effects of thalidomide via, it has been suggested, sleep receptors in the forebrain. The S(-) enantiomer is considered to be responsible for the birth defects in the children of women who took it.1 Fig. 1: Enantiomers of thalidomide readily interconvert.1 This molecule has had many identities since its original development in 1954. Its first intended use was as an antibiotic when Chemie Grunenthal, a small pharmaceutical company in West Germany, manufactured it by chance as part of their quest to develop an inexpensive method of producing antibiotics from peptides. They heated phthaloyisoglutamine and produced α-phthalimidoglutarimide, coining the name ‘thalidomide’. Disappointingly, it showed no antibiotic properties but, casting dreams of Thalidomide the Antibiotic aside, Chemie Grunenthal did not give up hope, encouraged by the fact it seemed to be harmless – they did not detect any side-effects and even the highest doses did not kill the lab animals.2 The company’s management saw a gap in the market for a non-lethal sedative and, despite thalidomide not showing any sedative properties in animals, began in 1955 distributing free samples to doctors, advising them to prescribe it as a sedative for the prevention of epileptic seizures. Thalidomide now took on the role of anticonvulsant though, unsurprisingly since there was no clinical evidence from trials, it had no anti-epileptic effect so this identity was short-lived. However, patients reported that the drug had soothing and sleep-inducing effects: Thalidomide the Sedative was born.2 With only anecdotal evidence from a handful of patients, the manufacturers proved, somewhat dubiously, that thalidomide was worthy of this title by issuing results indicating reduced movements of the ‘jiggle cage’ by mice given thalidomide compared to mice given other sedatives. And so, from 1957 the drug was marketed over-the-counter – the makers had found it to be completely safe – and by the next year Grunenthal were recommending it for pregnant and nursing mothers. Soon, thalidomide was not just a sedative but also acquired the identity of anti-sickness drug for pregnant women.2 Alarmingly, before it was even marketed, thalidomide had begun to show its dangerous potential: the child of an employee of Grunenthal was born without ears. Shortly after its release into the public domain, questions were raised as to a possible association between thalidomide and peripheral neuritis. However, Grunenthal ignored these reports and maintained their claims that this drug was totally safe. Thalidomide was selling phenomenally well in forty-six countries and clinical trials were underway in America.2 Before long, reports of severe abnormalities in babies whose mothers had taken thalidomide were appearing around the world: McBride in Australia and Lenz in Germany were among the first to link thalidomide and the abnormalities3. Fig. 2: McBride’s letter to the Lancet, 1962, positing a link between thalidomide and abnormalities in children. The effects of thalidomide on the children of the women who took it were wide-ranging, with an estimated 40% mortality rate due to thalidomide-induced embryopathy4. In some countries, the survival rates are reported to be lower but Lenz suggested that this may be due to superstitious attitudes towards birth defects, explaining that the babies may have been “left to die because of the belief that they were something devilish, created by bad demons.”4 Perhaps thalidomide’s most obvious impact is that of the limb defects it can cause. Most commonly, it can lead to phocomelia – characterised by the absence of the proximal part of the limb so that hands and feet are attached to stumps, forming flipper-like limbs. In more severe cases, amelia (complete absence of limbs) may occur.5 Limb defects are usually bilateral and grossly symmetrical6. Abnormalities include: aplasia of the bones e.g. radius, humerus; synostosis (fusion of the bones), syndactyly and many other defects4. Though there is no comprehensive catalogue of the birth defects directly attributed to thalidomide, it is clear that the effects of thalidomide on the foetus are not limited to the limbs. From a number of reports detailing the types of malformations caused by thalidomide, it has been found that there no area of the developing foetus exposed to thalidomide can be sure to go unscathed by this destructive drug: other skeletal defects can occur, for example involving the spine; craniofacial effects can be so severe as to cause blindness and/or deafness; systems affected include: central nervous system, respiratory, cardiovascular, gastrointestinal, renal and genitourinary.6 System Affected | Abnormality | Central nervous system | Facial nerve palsySpina bifida occultaMeningomyelocoeleAutismEpilepsyHydrocephalus | Respiratory | Abnormal lung lobulationLaryngeal and tracheal abnormalities | Cardiovascular | Atrial and ventricular septal defectsPericardial effusionHypertrophySystolic murmurs | Gastrointestinal | Oesophogeal, duodenal, common bile duct and anal atresias and stenosisAplasia of gall bladder and appendixFistulasAbnormal liver lobulation | Genitourinary | Duplex ureters, aplasia of fallopian tube, penile maldevelopment | Craniofacial | Eyes (microphthalmos, cataracts, glaucoma), ears (anotia, microtia, deafness), nose (hypoplastic nasal bridge), teeth abnormalities, abnormal face/skull shape | Table 1: Examples of non-limb abnormalities illustrating the extensive effects of thalidomide6 Some have argued that it is possible to match up the birth defects present in the foetus or baby with the days on which the mother took - and, therefore, the foetus was exposed to - thalidomide. Exposure to thalidomide seems to only cause defects when taken during a ‘critical period’, that is 34-50 days after the mother’s last menstrual period (LPM) began6. Thus, the babies of women who took the drug only in the later stages of pregnancy largely produced unaffected children7. The attempts to pinpoint the abnormalities and the precise days of exposure have become quite specific e.g. thumb duplication, 35-38 days after LPM; lower limb amelia, 41-45 days after LPM6. However, there are some cases that do not seem to fit this pattern such as a set of twins were that born in the USA, having been exposed to thalidomide, with very different abnormalities: one had significant gastrointestinal malformations but largely normal limbs while the other had phocomelia of the upper limbs but the gut was unaffected8. Clearly, the effects of thalidomide vary between individuals and the hypothesis that timing of exposure directly correlates with the type of malformation cannot be totally relied upon; thalidomide’s mechanism of action is still, to an extent, a mystery. Various suggestions to explain the manner in which thalidomide exerts its teratogenic effects have been put forward over the years subsequent to its recognition as a teratogen, one hypothesis being that it acts by disrupting the BMP/Dkk1/Wnt signalling pathway9. Wnt refers to a family of genes involved in patterning in embryogenesis. BMPs (bone morphogenic proteins) are a group of growth factors and cytokines that induce the formation of bone and cartilage10. BMPs 2,4,5 and 7 are important in limb development. The idea proposed is that thalidomide effects oxidative stress on the developing embryo, causing increased BMP signalling. BMP 4 and 5 induce Dkk1 (Dickkopf1) expression and Dkk1 inhibits Wnt signalling and promotes programmed cell death in the developing limb. With enhanced BMP and therefore enhanced Dkk1 signalling, Wnt expression was blocked and programmed cell death increased. This pathway has also been implicated as the cause of eye defects in embryos exposed to thalidomide. Furthermore, inhibition of the BMPs, Dkk1 and other downstream signalling molecules was found to partially counteract the effects of thalidomide and reduce cell death and limb truncations9. It is generally accepted that thalidomide acts by a variety of mechanisms. Most evidence so far indicates the creation of oxidative stress by thalidomide as the trigger factor, with many studies turning to Wnt and Akt gene signalling pathways to explain the ensuing events: the oxidative stress down-regulates these pathways leading to apoptosis and limb truncations. More recently, stress responsive and pro-apoptotic transcription factors, such as Tbx5 and Sall4, have also been investigated, heightening our understanding of the complex nature of thalidomide’s mechanism of action. Evidently, there is still a long way to go before its teratogenic action is fully understood11. As the scale of the tragedy began to be realised – an estimated 10,000 babies were born affected by thalidomide worldwide – people questioned how society would care for these children and manage their condition. While the thoughts of the medical world turned to immediate practicalities such as whether to amputate and how to achieve the best functional outcomes through splints etc19 to make their bodies appear normal, others considered how these children could be supported socially to make their lives more normal. The Thalidomide Trust was set up in 1974 and focused on supporting family life for the victims, many of whom had grown up in institutions such as Chailey Heritage and had received a lot of media and medical attention throughout their childhood. The Trust felt it was time to give these children a break and set about providing home adaptations, cars and specialist equipment to improve their quality of life on a day-to-day basis. They encourage the thalidomide victims to lead active and independent lives7. The thalidomide generation initiated a turning point in the management of the disabled, refusing to accept the limited lifestyles offered and low expectations society had of them that were typical treatment of the disabled at that time7. These people strived to achieve normal lifestyles and maintain their own identity beyond their disability, many of them seeking employment and having families7. Additionally, there is the Thalidomide Society that supports its members more with emotional support than practical assistance, arranging meetings to enable members to share experiences and exchange information regarding the latest research. They also encourage others with similar disabilities, not caused by thalidomide, to join12. At one point, there were some tentative suggestions that thalidomide might be a mutagen, able to change the DNA of its users, and therefore the possibility of its effects being passed on to the next generation was explored. This was brought up by McBride in the light of some children, born of thalidomide parents, exhibiting limb defects13. According to McBride, 10 out of 380 children with thalidomide parents (in 1998) exhibited thalidomide-like limb deformities14. However, by 2002 these ideas were overturned once and for all following a Swedish retrospective study producing data showing that thalidomide is devoid of mutagenic activity15. Nevertheless, despite its negative history, thalidomide is now being used to treat a multitude of conditions. In particular, it is used to target diseases with an autoimmune or inflammatory basis16 as it is thought to have immunomodulatory and anti-inflammatory properties17. The first turning point for thalidomide’s clinical applications came with the realisation of its potential to treat dermatological conditions; it can be used now to treat aphthous stomatitis, Behcet’s syndrome, certain forms of lupus erythmatosus and many more17. Thalidomide’s immunomodulatory function is as a result of its ability to inhibit TNFα. Because of this, it can be used to treat patients with lepromatous leprosy who typically have elevated levels of TNFα. Thalidomide is also being trialled as a treatment for conditions associated with HIV infection such as wasting, diarrhoea and ulcers and it seems to be effective without impairing immunocompetence. Moreover, it is being considered as a treatment for the primary HIV infection itself as studies are ongoing to assess the effect of thalidomide on viral load in patients receiving combination antiretroviral therapy17. Thalidomide has also been added to the treatment regime for patients with refractory multiple myeloma17, illustrating further its extensive range of uses many of which are probably yet to be discovered. Some have questioned whether the thalidomide tragedy was preventable, pointing out that evidence of drugs being able to overcome the barrier of the placenta and exert teratogenic activity of the foetus was ignored. Dally has implicated a resistance to cast aside traditional attitudes such as the idealisation of the womb as a reason why such evidence was ignored18. We might hope that the thalidomide tragedy has gone some way to reducing the stigma towards people with limb anomalies and other birth defects. Certainly, we have come a long way since Lenz’s account of leaving deformed babies to die or hiding them away in institutions. Additionally, teratologists and clinicians have learnt a lot, with the events with thalidomide in the ‘50s and ‘60s accelerating advances in prosthetics and triggering ideas for better practical and emotional support for people with disability7. Though thalidomide is a relatively simple molecule in terms of structure, it is obviously complex and very powerful with devastating effects on the developing embryo. Although it has been argued that this catastrophe could have been averted, the manufacturing of the thalidomide drug was not in itself a mistake; this drug has a lot to offer the medical world. However, clearly the myriad identities of thalidomide are still being uncovered as our understanding of its therapeutic potential is still in its infancy. References 1. Figg W, Franks ME, Macpherson GR. Thalidomide. Lancet. 2004 May 29; 363:1802-11. 2. Silverman WA. The Schizophrenic Career of a “Monster Drug”. Pediatrics. 2002 Aug; 110(2): 404-6. Available from: http://pediatrics.aappublications.org/cgi/content/full/110/2/404 3. McBride WG. Thalidomide and congenital abnormalities. Lancet. 1961 Dec; 2:1358. Available from: http://www.jameslindlibrary.org/trial_records/20th_Century/1960s/mcbride/mcbride_whole.html 4. Lenz W. A short history of thalidomide embryopathy. Teratology. 1988; 38: 203-15 5. Perri AJ, Hsu Sylvia. A review of thalidomide’s history and current dermatological applications. Dermatology Online Journal. 2003; 9(3): 5. Available from: http://dermatology.cdlib.org/93/reviews/thalidomide/hsu.html 6. Thalidomide. Drugs in pregnancy and lactation. DrugSafetySite.com. Available from: http://drugsafetysite.com/thalidomide 7. The Thalidomide Trust. 2008 Jun 3. Available from: http://www.thalidomide.org.uk/home.aspx 8. Katzenstein M, Mellin GW. The saga of thalidomide. Neuropathy to embryopathy, with case reports of congenital anomalies. N Engl J Med. 1962; 267:1184–93. 9. Knobloch J, Shaughnessy JD, Ruther U. Thalidomide induces limb deformities by perturbing the Bmp/Dkk1/Wnt signaling pathway. FASEB. 2007; 21:1410-21. Available from: http://www.fasebj.org/cgi/content/full/21/7/1410 10. Bone morphogenic protein. The Free Dictionary. 2008. Available from: http://encyclopedia.thefreedictionary.com/Bone+Morphogenic+Proteins 11. Knobloch J, Ruther U. Shedding light on an old mystery: Thalidomide suppresses survival pathways to induce limb defects. Cell Cycle. 2008 May 1; 7(9):1122-28. Available from: http://www.landesbioscience.com/journals/cc/abstract.php'id=5793 12. The Thalidomide Society. 2006. Available from: http://www.thalidomidesociety.co.uk/index.htm 13. McBride WG, Read AP. Thalidomide may be a mutagen. BMJ 1994 Jun 18;308:1635-1636. Available from: http://bmj.bmjjournals.com/cgi/content/full/308/6944/1635/b 14. Holliday R. The possibility of epigenetic transmission of defects induced by teratogens. Mutation Research. 1998; 422:203-5 15. Ashby J. Thalidomide is not a human mutagen. BMJ. 2002 November 23; 325(7374): 1245. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi'artid=1124708 16. Tseng S, Pak G, Washenik K, Keltz Pomeranz M, Shupack JL. Rediscovering thalidomide: A review of its mechanism of action, side effects and potential uses. J Am Acad Dermatol. 1996 Dec; 35(6):969-979 17. Calabrese L, Fleischer AB. Thalidomide: Current and potential clinical applications. Am J Med. 2000; 108:487-95 18. Dally A. Thalidomide: was the tragedy preventable' Lancet. 1998 April 18; 351:1197-99 19. Gillis L. Thalidomide babies: management of limb defects. BMJ. 1962 Sep 8; 2(5305):647-51