Dissertation Title: Rediscovering Thalidomide: Lessons Learnt and Evolving Indications

Total Word Count: 1959
Abstract: 231
(Dissertations that exceed the allowed word count will be disqualified.)

ABSTRACT
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Thalidomide, perhaps, has the worst reputation among all drugs on the planet. Firstly, the drug was seen as a powerful sedative, as if isolating the nervous system from a variety of unpleasant stimuli. Thus, in contrast to many known drugs, overdose of thalidomide did not result in death, and in general, the side effects during the tests could not be detected. It was believed that very soon this new wonder drug would pave its way to a broad market: thalidomide and its derivatives would be used to relieve the symptoms of colds, migraines, insomnia, etc. However, its widespread use has led to tens of thousands of children born with congenital deformities in the 1950s and 1960s. It was revealed that the wonder drug had a teratogenic effect: one pill taken during early pregnancy dramatically increased the likelihood of significant fetal abnormality. In fact, today thalidomide is not forgotten and continues to be used to treat leprosy. Patients are given specific instructions even regarding their sexual life. In 63% of cases people had a greatly weakened cough, and 20% reported the improved quality of life. Naturally, there were side effects, recorded in 74% of patients: constipation, dizziness, and general malaise with a feeling of discomfort. However, there is no guarantee that the sad story of this drug will not happen again since there is no proof that instructions would be strictly followed.

INTRODUCTION
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On December 25, 1956 in Stolberg in a family of a Chemie Grünenthal member a daughter without ears was born1. This officer gave his pregnant wife not officially released thalidomide which he took from work. What does a person do when he/she gets an unfamiliar drug a doctor? Someone begins to accept it without question, and the more experienced people try to read what is written in a very small font – contraindications and side effects. Sometimes people may refuse medication, fearing that harm from a drug will be incorrigible2. Why does medical practice use things which are supposed to treat, but instead they harm people? Can people eliminate the side effects? Virtually, it is impossible since there is no exact match of a man with a man, so the response to the same things in different people may differ significantly. Overall, drug development is a long business which continues for years before pharmacists have their products released to the market. Even extensive research work carried out on a large number of patients cannot guarantee the absence of adverse effects2. One of such bright examples was the most scandalous story of the side effects – a history of the drug called thalidomide. Being the most burning issue in medicine, thalidomide was supposed to teach people how to prevent such cases in the future and how to treat people, not harm.
In the history of medicine Grünenthal Company is associated with the drug thalidomide (presented on the shelves under the brand name Kontergan and some others). Similarly as it happened with many drugs, it was a random finding: chemists stumbled upon it in the mid-50's, trying to find a way to receive cheap antibiotics. This drug did not have properties of penicillin, but surprisingly it possesses other virtues. The new drug acted as a powerful sedative, as if isolating the nervous system from a variety of unpleasant stimuli2. Thus, in contrast to many known drugs, overdose of thalidomide did not result in death, and in general, the side effects during the tests could not be detected. It was believed that very soon this new wonder drug would pave its way to a broad market: thalidomide and its derivatives would be used to relieve the symptoms of colds, migraines, insomnia, etc. It would also be used to alleviate toxicity of future mothers3. Unfortunately, exactly for them and their children the fate took the gloomiest part4.

THALIDOMIDE HISTORY
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Today, the tragedy seems to be a jumble of accidents, mixed on corporate self-interest, lack of knowledge and irresponsible attitude of regulators. To reconstruct the events which took place fifty years ago in detail is not possible, but, in general, the picture is as follows5. On the one hand, science back then did not recognize that drugs taken by a pregnant woman can seep into a fetus. On the other hand, effects of thalidomide on a body were studied only partly: only forty years later, when the computer technology became powerful enough, the scientists were able to count on digital models and propose a number of possible explanations for the aggressive influence of thalidomide on the DNA molecule6. Finally, the lack of precedents ceased the attention of physicians and opened doors for untested drug pharmacies. Thalidomide was sold in fifty countries around the world from 1957 to 1962, and in most cases it could be purchased without a prescription7. Consequently, by the time the drug was banned everywhere, the list of victims numbered more than ten thousand families. It was revealed that the wonder drug had a teratogenic effect: one pill taken during early pregnancy dramatically increased the likelihood of significant fetal abnormality. Children of mothers who took thalidomide were born with mutilated limbs, mental retardation, and with internal injuries8. Every second of them died in infancy, and to the present day only one in five people managed to survive. The main blow fell on countries which legally allowed the drug: Canada, UK, Japan and Australia9.
Thalidomide was the most dangerous in the early stages of pregnancy. The critical period for the fetus is 34-50 days after the last menstrual period in women (from 20 to 36 days after conception). Just one tablet during this period can lead to having a child with physical deformities. Damage to a fetus can be related to different parts of a body. The most common external manifestations were the absence or defects of upper or lower extremities, no ears, eye and facial muscles defects10. In addition, thalidomide affected the formation of internal organs, destructively acting on the heart, liver, kidneys, digestive and urinary systems. What is more, physical deformities could be inherited. This was stated by the representatives of the English society of thalidomide victims. As evidence, they brought the history of 15-year-old Rebecca, a granddaughter of a woman who took thalidomide. The girl was born with short hands and three fingers on each hand – a typical deformity associated with this drug. Exactly the same changes were observed in children born during the first wave of thalidomide. Experts concluded the possibility of other genetic abnormalities. In fact, this is not the only case11.

GRUNENTHAL COMPANY
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When it became impossible to deny the obvious – a wave of abnormalities became an epidemic – a drug was banned: by 1963 thalidomide was withdrawn from use everywhere. Rare physicians and scientists who refused to recognize the wonder cure harmless without proof were poured with awards. Grünenthal Company and its distributors faced hundreds of lawsuits. The society as a whole has learnt a lesson: in particular, this story was the basis for the widespread tightening of inspection and licensing of medicines. However, Grünenthal Company remained silent until the opening of a memorial to victims of thalidomide when CEO Harald Stoke personally said “Excuse me”12. A London sculptor Marc Quinn created a monument to the victims of thalidomide taking as a model a real woman Alison Lepper who at that time was pregnant (Fig. 1). Luckily, her child grew healthy13.
According to Stoke, the company was silent for fifty years because they were in shock from the created chemical monster. Over the next few days Grünenthal Company was drowned in critical publications where the most characteristic element was usage of “Nazis” word14.
(Fig. 19)
Thalidomide victims, appearing today in the retirement age, describe their life as “a lonely battle of a lifetime”15. Few of them were able to start a family or a career. They need special care, adapted homes and vehicles. All this requires money, but there is no place to find them. Some countries (Germany, England) established special funds for the T-disabled: the major amount was once made by Grünenthal Company, and today government continues to pay16. All others have to settle for standard benefits. Grünenthal Company, according to critics, would do everything to receive a legal immunity (including delaying proceedings) in order to omit any compensation payments.
The other cause for criticism is Grünenthal Company unwillingness to admit their guilt. After all, Stoke apologized just for their silence. His company still does not recognize that fact which brought tens of thousands of lives in sacrifice17. A few days before Stoke’s speech, the Australian journalists published a sensational material from the corporate archive of Grünenthal Company with direct evidence that the company did not conduct tests completely, and later it continued production and sell of thalidomide being already aware of the potential side effects18. An alarm bell rang long before thalidomide came under the ban19. Families of employees who took the drug voluntarily, the flow of messages from doctors, watching young mothers who took prescription warned the company of a possible link between the drug and severe neurological disorders during pregnancy, and mutations in children. This prompted the researchers to conduct separate experiments, in particular testing thalidomide on pregnant animals, but there was no action from Grünenthal Company20.
As it is known now, the company did not study the effect of drugs on pregnancy and silenced reports received from pediatricians. More than that, they deliberately confused the public, insisting on a proven safety of the drug. Congenital malformations of thalidomide victims were attributed to nuclear tests, vitamin deficiency, characteristics of individual patients, even to unlicensed medicines modifications21. Stubbornness of Grünenthal Company stemmed from a simple fact: thalidomide brought a lot of money. Not for nothing it was called wonderful: for its time, it was as good as penicillin for the forties or Viagra for the nineties. Powerful and harmless, this drug easily mastered new territory: distributors supplied doctors with free samples, doctors hooked patients on it, and as a result, a stable demand arose. This was simply business, nothing personal22.
(Fig. 216)
Even today Grünenthal Company lives in the shadow of thalidomide. Critics see the only way out for them: confession23. They need to admit that reports of potential dangers were ignored and hidden from the public. They should recognize that the important internal documents were destroyed in order to prevent a loss in the courts24. However, according to the theory of corporate genetics, even this will not help. Principles underlying the founding of the company continue to define its behavior even when the founders moved away from business. The roots of the same Grünenthal Company (and thalidomide, as some believe) go to the Third Reich, to concentration camps, to experiments on people. After all, the first employees who founded Grünenthal Company in 1946 were the former Nazis. A teratogenic effect was a tragic oversight25. However, in the attitude of Grünenthal Company to their clients an ominous trend is seen26. Only during past five years and only in the UK incriminating evidence of fraud in order to promote their products was
FINAL DISCUSSION
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Thalidomide, perhaps, has the worst reputation among all drugs on the planet. Its widespread use has led to tens of thousands of children born with congenital deformities in the 1950s and 1960s28. However, one might be surprised to know that it is still used in the treatment of certain diseases. Now, there are new findings which suggest that the drug may find mass use. In fact, thalidomide is currently used in the treatment of multiple myeloma and certain symptoms of leprosy29. However, new research published in the journal Annals of Internal Medicine shows that it can be used in the treatment of cough associated with idiopathic pneumosclerosis. Idiopathic pulmonary fibrosis is a progressive and fatal disease, usually associated with debilitating cough that accompanies the seal of the lung tissue and the appearance of scars30. During experiments in the framework of this study patients received this powerful anti-inflammatory drug. In 63% of cases people had a greatly weakened cough, and 20% reported the improved quality of life. Naturally, there were side effects, recorded in 74% of patients: constipation, dizziness, and general malaise with a feeling of discomfort31. However, even despite these shortcomings, this study is an important scientific breakthrough. Consensus about the treatment of idiopathic pneumosclerosis does not exist, especially with regard to the related cough. If thalidomide is used with the same caution and circumspection with which other medicines that can cause birth defects (such as Accutane) are appointed, it will help people who are suffering from this incurable disease32. What is more, it will be an important step forward to making thalidomide less terrible33.
Finally, today thalidomide is not forgotten and continues to be used to treat leprosy. Patients are given specific instructions even regarding their sexual life34. However, there is no guarantee that these instructions would be strictly followed. In fact, nobody can give them35. Therefore, the history of thalidomide is not over and the story continues. Even though thalidomide remains to be the biggest medicine mistake which caused mutation disaster, the name of this drug is being refuted: specialists try to eliminate side effects and help people by treating even incurable diseases.

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