In 1954 the German pharmaceutical company Chemie Grünenthal has been conducting research to develop an inexpensive way to produce antibiotics from peptides. In the course of research, the company's employees obtained a drug they called thalidomide (thalidomide), after which they began to study its properties to determine the scope of its application.
Initially, thalidomide was supposed to be used as an anticonvulsant, but the first experiments on animals showed that such properties new drug does not possess. However, it was found that an overdose of the drug did not kill the experimental animals, which gave reason to consider the drug harmless.
In 1955, Chemie Grünenthal informally sent free samples of the drug to various doctors in Germany and Switzerland.
People who took the drug noted that although it does not show anticonvulsant properties, it has a calming and hypnotic effect. People who took the drug reported that they experienced deep "natural" sleep that lasted all night.
The effect of the drug impressed many therapists, a safe sedative and hypnotic agent stood out against the background of existing sleeping pills. The safety of overdose (accidental or suicide attempt) of the drug was emphasized further when promoting this product on the market.
Even though the drug had similar effects in humans, it needed to be shown to be effective in order to be licensed. However, the drug did not have a sedative effect on animals, so representatives of Chemie Grünenthal had to make a special cage for the demonstration, which served to measure the slightest movements of experimental animals. Thus, representatives of Chemie Grünenthal were able to convince the commission that, despite the fact that the mice were awake after taking the drug, their movements slowed down to a greater extent than in animals that were injected with other drugs. sedatives. During the demonstration, the representatives of the company made the main emphasis on the fact that the drug is absolutely safe, which made it possible to obtain a license for the production and distribution of the drug.
In 1957, the drug was officially released for sale in Germany under the name Contergan, in April 1958 in the UK it was released by the Distillers Company under the name Distaval. In addition, thalidomide has been marketed as part of medicines for the most different cases, for example, Asmaval - against asthma, Tensival - against increased blood pressure, Valgraine - against migraine. In total, thalidomide went on sale in 46 countries in Europe, Scandinavia, Asia, Africa, South America, where it was produced under 37 different names. No additional independent studies of the drug in any country have been conducted.
In August 1958, a letter was sent to someone from Grünenthal stating that "thalidomide - the best medicine for pregnant and lactating mothers. This point was almost immediately reflected in the advertising of the drug in the UK by Distiller, despite the fact that studies of the effect of the drug on the fetus were not carried out by either the German company Grünenthal or the English Distiller. Thalidomide has been successfully used to eliminate unpleasant symptoms associated with pregnancy such as insomnia, anxiety, morning sickness.
Beginning in 1959, Grünenthal began to receive letters about peripheral neuritis and other side effects from drug use. There were opinions that the drug should be sold only on prescription. Despite this, thalidomide continued to dominate sales and in some countries fell behind only aspirin in terms of sales. Company policy has been to deny the association of Contergan with peripheral neuritis, and Grünenthal has stubbornly resisted attempts to limit sales of the drug.
Francis O. Kelsey
On September 8, 1960, the US Richardson-Merrell Company submitted thalidomide to the US Food and Drug Administration under the name Kevadon. American laws of the time for licensing medicinal product demanded only the safety of its use. The same laws allowed for clinical trial use of a drug prior to licensing, allowing Richardson-Merrell to distribute more than 2,500,000 tablets to 20,000 patients through 1,267 physicians. The drug was approved by a majority of physicians who considered it safe and useful, which they reflected in their reports. However, Dr. Francis O. Kelsey, appointed by the FDA to oversee licensing of the drug, was unimpressed with the results of this test. One of the main factors that influenced Kelsey's decision was that Richardson-Merrell knew about the risk of developing neuritis, but kept silent about it in the report to the FDA. Francis O. Kelsey, despite strong pressure from Richardson-Merrell, did not approve Kevadon and it was not placed on the US market. Of course, at that moment she did not yet suspect how many lives she had saved by making such a decision.
On December 25, 1956, in the city of Stolberg, a daughter without ears was born in the family of an employee of Chemie Grünenthal. This employee was giving his pregnant wife an unofficial thalidomide he had taken at work. At that time, no one saw a connection between taking the drug and a malformation of the fetus, the appearance of children with congenital physical defects was repeatedly observed earlier. However, after the introduction of thalidomide on the market, the number of children born with congenital malformations increased dramatically. In 1961, the German pediatrician Hans-Rudolf Wiedemann drew public attention to this problem, describing it as an epidemic.
At the end of 1961, almost at the same time, Professor W. Lenz in Germany and Dr. McBride in Australia discovered an association between an increased number of birth defects in newborns and the fact that the mothers of these children were taking thalidomide. on early dates pregnancy.
On November 16, 1961, Lenz reported his suspicions to Chemie Grünenthal by telephone. On November 18, the newspaper Welt am Sonntag published his letter in which he described more than 150 cases of birth defects in newborns and associated them with the intake of thalidomide by mothers on early stages. On November 26, under pressure from the press and German authorities, Chemie Grünenthal began withdrawing thalidomide from the German market, notifying Richardson-Merrell, whose products had already spread to South America. At the same time, Chemie Grünenthal continued to deny the connection between the epidemic and its drug.
On December 2, Distillers announced the withdrawal of the drug from the markets in an open letter published in the English journals The Lancet and the British Medical Journal.
In December 1961, a letter from William McBride was published in The Lancet, in which he also described his observations regarding the association of thalidomide with birth defects in babies. After that, the drug began to be removed from the shelves in other countries. Confirmation of the words of Lenz and McBride began to come from different countries, the situation received wide publicity in newspapers, on radio and on television, however, despite this, the drug was available for purchase in some pharmacies even six months after the first reports. In Italy and Japan, the drug was sold even 9 months after the publicity.
In early 1962, Lenz speculated that since 1959, between 2,000 and 3,000 thalidomide-victim children had been born in West Germany. Total, by various estimates, as a result of the use of thalidomide, about 40,000 people received peripheral neuritis, from 8,000 to 12,000 newborns were born with physical deformities, of which only about 5,000 did not die in early age remaining disabled for life.
Teratogenic effects of thalidomide
As it turned out, thalidomide has teratogenic (from the Greek. τέρας - a monster, a freak; and other Greek. γεννάω - I give birth) properties and poses the greatest danger in the early stages of pregnancy. The critical period for the fetus is 34-50 days after the woman's last menstrual period (20 to 36 days after conception). The likelihood of a child with physical deformities appears after taking just one tablet of thalidomide in this period of time.
Fetal damage caused by thalidomide affects a wide variety of body parts. Among the most common external manifestations defects or absence of upper or lower extremities, absence auricles, defects of the eyes and mimic muscles. In addition, thalidomide affects the formation internal organs, destructively affecting the heart, liver, kidneys, digestive and genitourinary system, and can also lead in some cases to the birth of children with deviations in mental development, epilepsy, autism. Limb defects are called phocomelia and amelia (the literal translation from Latin is “seal limb” and “lack of limb”, respectively), which appear as a kind of seal flippers instead of a limb or their almost complete absence.
According to the data collected by Lenz, about 40% of newborns exposed to the drug during the fetal stage died before their first birthday. Some destructive influences (particularly those affecting the child's reproductive system) may not become apparent until many years after birth and can only be revealed as a result of careful analysis.
No less horrific is the fact that these physical deformities can be inherited. This was stated by representatives of the English Society of Victims of Thalidomide. As evidence, they cited the story of 15-year-old Rebecca, the granddaughter of a woman who was taking thalidomide. The girl was born with shortened hands and three fingers on each hand, a typical deformity associated with this drug.
The mechanism of teratogenic effects
Schematic representation of thalidomide enantiomers
The thalidomide molecule can exist in the form of two optical isomers - dextrorotatory and levorotatory. One of them provides therapeutic effect drug, while the second is the cause of its teratogenic effects. This isomer is wedged into cellular DNA at sites rich G-C bonds, and interferes with the normal process of DNA replication necessary for cell division and embryonic development.
Since the enantiomers of thalidomide are able to pass into each other in the body, a preparation consisting of a single purified isomer does not solve the problem of teratogenic effects.
thalidomide victims
Monument to the victims of thalidomide in London, erected in 2005. The model was Alison Lepper, who was pregnant at the time of the creation of the sculpture. Her child grew up healthy.
In 2012, the German pharmaceutical concern Gruenenthal opened a bronze monument in the city of Stolberg to children affected by the drug thalidomide.
"Thalidomide tragedy" - the beginning of a modern era in drug safety already used in medical practice. In 1954, employees of the German pharmaceutical company Chemie Grünenthal, while searching for an inexpensive way to produce antibiotics from peptides, obtained a drug called thalidomide. To study the properties and determine the scope of the new drug, free samples were informally donated to doctors of various specialties in Germany and Switzerland. Patients taking the drug noted its calming and hypnotic effect (after taking it, a deep "natural" sleep occurred that lasted all night). To obtain permission for medical application The drug needed to be tested on animals. However, in laboratory mice, thalidomide did not have a sedative effect. Nevertheless, Chemie Grünenthal was able to convince the commission that, compared to other sedatives, the new drug slowed down the movements of mice to a greater extent. The main emphasis of the company was on the fact that the drug is absolutely safe. As a result, a license for the production and distribution of the drug was issued, and in 1957 it went on sale in Germany under trade name Contergan. In 1958, Thalidomide appeared in the UK, manufactured by Distillers under the name Distraval. In addition, thalidomide was part of combined drugs for the treatment of asthma, migraine, to reduce blood pressure. In total, thalidomide was used in 46 countries in Europe, Asia, Africa, South America under 37 different names. However, no additional independent studies of the drug in any country have been conducted. By 1961, thalidomide had become the best-selling sedative in Germany. In August 1958, Chemie Grünenthal reported that "thalidomide is the best medicine for pregnant and nursing mothers." And this information was immediately included in the advertising of the drug in the UK by Distiller. Thalidomide has been successfully used to eliminate unpleasant symptoms associated with pregnancy, such as insomnia, anxiety, morning sickness, despite the fact that studies of the effect of the drug on the fetus have not been conducted by either the German company Chemie Grünenthal or the English Distiller. Since 1959, Chemie Grünenthal has been receiving reports of peripheral neuritis and other side effects from thalidomide, and proposals to move it to the prescription-only category. The company resisted attempts to restrict sales of the drug, denying the connection of thalidomide with peripheral neuritis and ignoring the fact that in December 1956 a daughter without auricles was born in the family of a company employee (this employee gave his pregnant wife not yet officially released thalidomide, which he took at work ). As a result, thalidomide continued to be the top seller in many countries, second only to aspirin. In 1960, Richardson Merrel submitted its thalidomide drug, Kevadon, to the US Food and Drug Administration (FDA). Under the laws of the United States of that time, only data on the safety of its use were required for registration of a drug. Trial was allowed clinical application drug before it was licensed, allowing Richardson-Merrell to distribute more than 2.5 million tablets to 20,000 patients through 1,267 physicians. The drug was approved by most doctors - they considered it safe and useful, which they reflected in their reports. However, Dr. Francis O. Kelsey, appointed by the FDA to oversee the drug's registration, was not satisfied with the results. She was particularly alarmed by the fact that Richardson-Merrell, knowing about the risk of developing neuritis, kept silent about this in a report to the FDA. Despite strong pressure from Richardson Merrell, Frances O. Kelsey did not approve of Kevadon. Thus, thalidomide was not approved for the US market. Meanwhile, only in West Germany in 1959-1962, from 2000 to 3000 children were born with deformities that arose as a result of their mothers taking thalidomide during pregnancy. Francis O. Kelsey's integrity and professionalism were appreciated by the US authorities: in 1962, US President John F. Kennedy presented her with the Order of Distinguished Service to the Fatherland, the highest award that civil servants can receive. The first accusations against Chemie Grünenthal began to arrive at the end of 1961, and only 7 years later, in 1968, the case materials were finally prepared and the trial began against seven workers of Chemie Grünenthal. They were accused of allowing dangerous goods to enter the market. medicinal product, which has not passed due diligence and caused bodily harm to a significant number of children. Two and a half years later, the court ruled to close the case due to the obligation of Chemie Grünenthal to pay compensation of DM 100 million to children affected by thalidomide. In 1971, the German Ministry of Health established a fund whose task was to compensate victims of thalidomide. By the beginning of 1992, 2,866 people in Germany alone had received a total compensation of more than 538 million marks from the fund. Thalidomide poses the greatest risk to the fetus in the early stages of pregnancy, between 20 and 36 days after conception. There is a possibility of a child with physical defects even after taking only one tablet of thalidomide in this period of time. The most common external manifestations are defects in the upper or lower extremities or their absence, the absence of auricles, defects in the eyes and mimic muscles. In addition, thalidomide affects the formation of internal organs (heart, liver, kidneys, digestive and genitourinary systems), in some cases it can lead to the birth of children with mental retardation, epilepsy, autism. According to the data collected by Professor W. Lenz (Germany), about 40% of newborns exposed to the drug at the stage of fetal development died before the age of 1 year. Some destructive influences (in particular, concerning the reproductive system) may appear many years after birth. The thalidomide molecule can exist as two optical isomers, dextrorotatory and levorotatory. The first provides the therapeutic effect of the drug, the second has a teratogenic effect (integrating into certain regions of DNA and interfering with the normal transcription process, thereby disrupting the process of cell division and embryo development). Moreover, the purification of the substance from the teratogenic isomer does not solve the problem of the safety of thalidomide, since in the body the dextrorotatory isomer can turn into a levorotatory one and vice versa. Thalidomide negatively affects not only the fetus, but also the body of an adult, causing weakness, headache, drowsiness, dizziness, menstrual cycle, temperature increase. In some cases, taking thalidomide can lead to the development of peripheral neuritis. In total, in the world in 1956-1962, according to various estimates, from 8,000 to 12,000 children were born with congenital deformities caused by thalidomide. This tragedy has forced many countries to reconsider existing practices state registration medicines, tighten the requirements for their safety. Half a century has passed since then, but children are still occasionally born with limb defects after their mothers took thalidomide during pregnancy. In 1995, thalidomide was secretly returned to the market in the UK and Brazil; in some countries, this drug is still given to pregnant women. So, the use of thalidomide has been abandoned worldwide for the indications that were established for this drug when it first appeared on the market. However, it turned out that there is a field of medicine in which the use of thalidomide is justified and necessary. In 1964, Jacob Sheskin, a doctor at the Jerusalem Hadassah Hospital, was looking for a drug that could help a terminally ill patient with leprosy (he suffered from unbearable pain couldn't sleep for weeks). Among the hospital supplies, the doctor found thalidomide. Knowing that the drug was prohibited, Sheskin nevertheless gave it to the patient. After taking the first dose of thalidomide, the patient slept for 20 hours, and then he was able to stand up on his own. After further administration of thalidomide, his health began to improve. The same effect was obtained in six other patients with similar symptoms. Sheskin later conducted studies in Venezuela that showed that out of 173 leprosy patients treated with thalidomide, 92% were completely cured. Further studies by the World Health Organization on 4552 patients with leprosy showed that thalidomide was effective in 99% of cases. This was a prerequisite for the return of the drug to the market. The American scientist Judah Folkman was one of the first to suggest that in order to stop the development of a malignant tumor, it is necessary, first of all, to disrupt its blood supply, i.e. suppress the formation of tumor vessels (angiogenesis). For a long time, the scientist worked on the creation of an effective oral drug that suppresses angiogenesis. Folkman's colleague, professor of ophthalmology Robert D'Amatov, suggested in the early 1990s that the teratogenicity of thalidomide was due to its ability to suppress angiogenesis. The assumption was confirmed in experiments on chickens and rabbits, which gave grounds for considering the possibility of using the drug in the treatment oncological diseases. In 1997, Professor Bart Barlogi (USA) tested the effectiveness of thalidomide in malignant tumors in clinical trials at the Arkansas Cancer Research Center. 169 patients with multiple myeloma (a type of leukemia) who failed chemotherapy and transplant bone marrow received thalidomide. As a result, most of them slowed down the development malignant tumors. At 18 months after the start of the studies, half of these patients were still alive, contrary to the usual statistics. After two years of research, Barlogi made an official statement that thalidomide can help patients who are ineffective standard methods treatment. In the 1990s, thalidomide was investigated by scientists at an American laboratory headed by Professor Jilla Kaplan and Dr. David Stirling. It has been found that thalidomide and its analogues can be effectively used in the treatment of many serious illnesses, including tuberculosis and AIDS. On July 16, 1998, the FDA approved thalidomide as a treatment for leprosy. As the FDA imposed additional drug registration requirements in the aftermath of the thalidomide tragedy, thalidomide manufacturers had to develop a robust safety system that included training and strict supervision of prescribers and patients taking the drug. In particular, patients are required to take the correct dose of the drug and are prohibited from donating blood and sperm. Thalidomide is currently used to treat leprosy, multiple myeloma, and other cancers. The use of the drug is regulated by the Pharmion Risk Management Program (PRMP). The thalidomide tragedy produced a shock in society. Three novels were written under the impression of this event (Arthur Hailey "Strong Medicine", Douglas Copeland " normal families it doesn’t happen”, Frederick Forsyth “Dogs of War”, etc.), films were made (“Private Affair”, “Contergan: One Single Pill”), songs were written. In London, a monument to the disabled - the victims of thalidomide. Prepared by Larisa SKRIPACHEVA based on materials from foreign publications (bulletin "MEDEX" of the Coalition for Rational and safe application drugs, Bulletin "Drugs and Medicine" Science Center drug testing and medical technologies Ministry of Health of Armenia)
This is scary. Much more terrible is what medicines they can be cured of. Today, we will tell you about thalidomide. At the beginning of its existence, it was known as a sleeping pill and sedative, but it carried a living hell for the future of patients. The birth of freaks, but not moral ones, although judging by your mother, anything can happen. Mistakes in medicine, pain, torment, crippled destinies and other frightening facts. Read, turn gray and learn another stupidity of people.
The infamous sedative and hypnotic drug - thalidomide, invented by German (and what else?) Pharmacologists after the Second World War, and manifested itself as a teratogenic agent, or a drug that disrupted human embryonic development. Naturally, about side properties they didn’t recognize it right away, and the Germans in that century loved surprise. And the peak of fame came in 1962, when it was revealed that over the past six years, about 12,000 people were born with congenital defects due to their mothers taking thalidomide during pregnancy.
Half of the victims did not live even a year. After a long ban, thalidomide began to be used to cure the most severe diseases, such as: leprosy, severe oncological diseases, etc. Do you think that's all? No, here's hell in all its glory!
1. Origin and start of sales of thalomid. The German pharmaceutical company Chemie Grünenthal in 1954 worked on the creation of affordable technologies for the production of antibiotics and peptides. As a result of the work, a drug called thalidomide (thalidomide) was obtained, and pharmacologists studied the finished drug to determine the beneficial field of application.
The first direction of application was anticonvulsant action, but experience with animals did not confirm hopes. However, the drug did not kill animals when overdosed. Scientists have decided that it is not dangerous.
Before even registering thalidomide, already in 1955 Chemie Grünenthal sent the drug to various clinics in Germany and Switzerland. Patients confirmed that the drug does not have anticonvulsant properties, but calms and has a hypnotic effect. People suffering from insomnia have confirmed that thalidomide helps them sleep naturally and deep sleep. Such indicators impressed many therapists, because the drug is safe in case of overdose, which means it is not suitable for suicides, which was later reminded in advertising.
Mild side effects were not noticed, it was time to bring the drug to the market and license, proving the effectiveness of the application. Chemie Grunenthal proved that laboratory mice after the first doses of the drug did not cover sleep, but their movement became lethargic. At the same time, the inventors of the drug constantly remind that the drug is harmless. And all together helped to finally obtain a license for the production and sale of the drug.
And in 1957, the drug went on sale in Germany under the name Contergan, and in the spring of 1958 it came out in England, from the manufacturer Distillers Company with the name Distaval. In general, thalidomide was taken as a panacea for everything - from impotence to diarrhea, the whole world began to teem with drugs, which included this not harmless ancestor of Herbalife. While in the USSR everything was made from Khrushchev's corn and they did not hear about tolidamide, the capitalists are trying to treat it dangerous diseases, Asmaval - against asthma, Tensival - against high blood pressure, Valgraine - against migraine. But treating a disease with thalidomide is like treating a headache with a guillotine. Well, let's not get ahead of ourselves.
Relax before we show you the hell that comes with thalidomide.
So, thalidomide appeared in 46 countries of Europe, Scandinavia, Asia, Africa, South America, where 37 different names were invented for it. At the same time, the laws of that hippy era allowed no checks to be made, and no one did them anywhere. Only business, yopta.
In the summer of 1958, Grunenthal spams dealers with his potion - "thalidomide is the best medicine for pregnant and nursing mothers". Marketing geniuses, this cry was picked up in an advertisement in England by the manufacturer Distiller. At the same time, not a single person in a white coat from Germany or England tested the effect of this muck on future fetus person. They just attracted a new consumer - pregnant women. And expectant mothers were offered to eat a miracle pill for nausea or insomnia.
At the same time, quite comrades from Grunenthal in 1959 receive complaints about the side effect of the drug, peripheral neuritis ( inflammatory disease peripheral nerves, in which, along with pain, symptoms of loss or decrease in sensitivity, and paralysis are detected). A trifle, but unpleasant, and not treated. Actually, the dog barks, the caravan moves on. Pharmacologists from Grunenthal not only do not respond in response, they themselves have hidden the complaints. And thalidomide is second only to aspirin in terms of sales.
Pindos surprised. In September 1960, in the US, the local Richardson-Merrell Company submits thalidomide to the US Food and Drug Administration under the name Kevadon. American drug licensing laws only required proof of safety. And the same laws allowed clinical trials, which resulted in the sale of 25,000,000 tablets in the United States to 20,000 patients through 1,267 physicians.
The same therapists approved the drug and found it effective. Damn, were there really kickbacks then? But, such a grymza on guard of Pindos health, Dr. Francis O. Kelsey, who is in charge of the FDA for the control of licensed drugs, did not find the results of the use of the drug so impressive. And the main factor for the negative decision on the drug was the fact that Richardson-Merrell, knowing about the risk of developing neuritis, did not mention this in the report to the FDA. Thanks to the negative opinion of Francis O. Kelsey, the drug did not go on sale in the United States. Pindos very lucky. VERY.
2. The tragedy of thalidomide. In 1961, thalidomide becomes the best-selling sedative drug in Germany. And rushed!
First reported case side effects thalidomide was the birth of a daughter in the family of an employee of Chemie Grunentha on December 25, 1956 in Stolberg, a girl without ears. The employee's wife received from him not yet registered thalidomide, which he had taken at work. However, the people poked about what was the connection between an unlicensed drug and between the birth of a child with a deviation.
And when thalidomide became available in pharmacies, the fool had shag, the growth of newborns with deviations began. All over the world.
In 1961, German pediatrician Hans-Rudolf Wiedemann called it an epidemic. Already at the end of 1961, at the same time, Dr. McBride in Australia and Professor Lenz in Germany discovered a connection between an increase in the number of birth defects in newborns and the intake of thalidomide in early pregnancy by their mothers.
On November 16, 1961, Lenz called Chemie Grunenthal and said something bad about thalidomide. Already on November 18, in the newspaper Welt am Sonntag, his article was published describing more than 150 cases of congenital malformations in newborns and the relationship with mothers taking thalidomide in the early stages. Under pressure from the authorities and the press, on November 26, 1961, Chemie Grunenthal begins recalling thalidomide from the German market, but does not recognize the connection between the outbreak and the drug being produced. At the same time, products with thalidomide in the composition are successfully sold throughout South America. However, even then Chemie Grunenthal does not recognize the connection of the epidemic with its drug. (National socialists and capitalists rolled into one. Germany, keep it up).
Inflated in England, on December 2, 1961, Distillers withdraws the drug from the markets through an open letter published in the English journals The Lancet and the British Medical Journal.
The Lancet magazine in December of the same 1961 publishes a letter from William McBride, which deals with the connection of thalidomide with congenital malformations in infants. The drug is no longer sold in other countries. Reviews with confirmations from different countries began to pour into the publication of Lenz and McBride, the situation made a fuss around the world, in all the media, but even after that the drug was still sold for six months in some pharmacies, even after the first reports. And in Italy and Japan, the drug was sold for another 9 months. The axis of evil, it is always the axis of evil.
All the same, Germany got decently. In early 1962 Lenz writes about 2000-3000 child victims of thalidomide since 1959, in West Germany alone. According to various estimates, about 40,000 people got peripheral neuritis from thalidomide, and from 8,000 to 12,000 babies were born with physical abnormalities, and of these, only about 5,000 did not die at an early age, becoming disabled for life.
3. The most humane court in the world. Germany. At the end of 1961, the first accusations against Chemie Grunenthal reached the prosecutor's office of Aachen, but only by 1968 did the Germans prepare all the case materials that fit on 972 pages. On May 27, 1968, the first court session was held, there were as many as seven representatives of Chemie Grunenthal in the dock, on charges of having put on the market dangerous drug, untested and causing great bodily harm in a significant number of children. The entire company was accused of hushing up complaints and not responding to incoming complaints.
On December 18, 1970, the last meeting of the court was held, it was decided to close the prosecution, in response to the proposal by Chemie Grunenthal published on April 10, 1970, about the obligation to pay compensation of 100,000,000 German marks to affected children from the use of thalidomide. The court decided that, given the entire system for the production and distribution of drugs, this could happen to any company, and the main task will be to build new system drug licensing, not blaming all seven people. How the hell is it, no one sat down at all, and thousands of babies died or were left crippled.
The amount of the payment to the child was measured as the damage received from the drug. Every month, from 100 to 450 marks were paid per child, over time, the monthly payment was revised upwards in 1976, 1977, 1980 and 1991. By the beginning of 1992, DM 538,000,000 had left the fund for compensation, for 2,866 people from Germany. And payments to Chemie Grünenthal were already going not only to German citizens. Germany is again mired in debt to the world.
4. England and thalidomide. From 1962 to 1966, 70 parents and guardians of thalidomide victim children sued the Distillers Company for negligence seeking damages. Also filed a lawsuit and suffering from peripheral neuritis, who claimed that they fell ill with it after the use of thalidomide. The manufacturing company, shouting "in line, sons of bitches", decided not to bring matters to meetings and agreed with 65 of the 70 applicants. The representatives of the affected children were offered to withdraw the negligence claim in exchange for 40% of the amount for which they wanted to sue the company. In this way, 58 claims were withdrawn, in which the company paid 1,000,000 pounds. From people who know how to bargain. Interestingly, did you manage to bargain with your conscience?
However, the court did not share in the share, and allowed the filing of claims in this case, even after the limitation period of three years, and new claims began to come in. Of these, 389 were not closed in 1971. In each case, the people at Distillers continue to negotiate, avoiding going to court. Lists of suers were developed: list X with evidence that they were a victim of thalidomide, and list Y with no such evidence.
As early as 1971, Distillers was under pressure to create a trust fund to help children with congenital physical deformities, and by early autumn the fund was ready to start working with a volume of 3,250,000 for ten years, while not taking into account the amount paid to persons on list X .
However, on September 24, 1972, The Sunday Times published an article "Our thalidomide children are the cause of national disgrace", where he provocatively jacked up payments to the Distillers company. After all, the amounts of payments are incomparable with the amount of damage caused English families, compensation of 3,250,000 pounds, against the background of the company's annual turnover of 64.8 million pounds and assets of 421 million, are weightless. And such milking of money can be understood:
The article went through the society, and everyone attacked the innocent manufacturer, Distillers. And after that, they increase the capital of the fund to 5,000,000 pounds. At the same time, the merchants of death give up, Distillers appealed to the Prosecutor General, with a statement about the illegitimacy and disrespect of the author of the article to the court, because the trial is not over yet, they say the noise around the article may affect the decision of the judges. In November 1972, under a lawsuit Attorney General The Supreme Court banned the publication. Times Newspapers Ltd, in turn, filed an appeal, arguing that the ban on the work of a journalist is unfair. Court of Appeal overturned the decision of the Supreme Court, but on July 18, 1973, the House of Lords again passed a ban on publications, which was in effect until June 23, 1976.
At the same time, everyone throws shovels at Distillers, and they gritting their teeth create a fund project in the amount of 20,000,000 pounds in December 1972, with payments over 7 years.
August 10, 1973 already public organizations The Thalidomide Children's Trust was founded to support disabled children whose mothers took thalidomide during pregnancy. The government of England exempted payments to child victims of the thalidomide tragedy from taxation.
Considering the fact that the claims were mostly withdrawn and the compensation paid before the trial, the criminal case was not opened and none of the Distillers sat down. Total fucked up! Sorry, it's somehow like that - "Well, your child is disabled, well, he died in agony, well, we established the fund, that's all, what other claims to us?" Money rules this world.
5. Proceedings in other countries. In the United States, the thalidomide scandal prompted new and tougher drug licensing regulations, leading to the 1962 Food, Drug, and Cosmetic Act requiring proof of the effectiveness of the licensed product. Pindos straight talking.
In Japan, the product was completely withdrawn from the shelves only on September 13, 1962, and this is almost 10 months after Contergan was recalled in Germany. 309 children have been identified as victims of thalidomide in Japan. During the trial, the parties were Dainippon and the Ministry of Health of Japan, on October 26, 1974, a decision was made to pay monetary compensation families with children with disabilities due to the use of thalidomide. Based on the calculations of Dr. Lentz, who spoke at the trial, payments to Japanese families are much higher than payments to families in other countries. Well, cross-eyed, they didn’t jail anyone either.
In all countries where thalidomide was sold, except Italy, funds were set up to compensate victims of thalidomide. Italy is not without reason the birthplace of fascism and Celentano.
By the way, less than 50 years later, representatives of the prosperous German Gruenenthal apologized, noting that the possible side effects of the drug could not be identified before it entered the market. Here, well done, the main thing is not to admit guilt.
6. Return of thalidomide to the counter! In 1964, a certain doctor Hadassah Yakov Sheskin, (an Armenian or what?), in a Jerusalem hospital, (for sure an Armenian), picked up a medicine for a terminally ill patient who suffered from severe inflammation due to leprosy. It was thalidomidol. They started talking about bringing the drug back to the market.
Cytologist Judah Folkman from the United States was one of the first to suggest that in order to stop the development of a malignant tumor, it is necessary to stop its blood supply. For a very long time, the scientist worked on the creation of an effective oral drug that stops angiogenesis. This is the very development of the tumor that needs to be stopped.
Ophthalmologist Professor Robert D'Amato of the Folkman Laboratory at Harvard University proposed from 1992 to 1994 that the teratogenicity of thalidomide was due to its anti-angiogenesis properties.
Did everyone understand? A man at Harvard learns to say that, so don't worry, the uncle said that thalidomide is good in severe cases because it is bad in the lungs. In experiments on chickens and rabbits, thalidomide proved to be a drug capable of significantly reducing angiogenesis (see above), which gave grounds to consider the possibility of using the drug in the treatment of severe oncological diseases.
Already in 1997, Professor Bart Barlogi experimentally tested how effectively thalidomide fights against malignant tumors. He gave thalidomide to 169 doomed patients who had the disease and failed chemotherapy and bone marrow transplants from the Arkansas Cancer Research Center. In many patients, the development of tumors slowed down, but 18 months after the start of the experiment, half of the patients were still alive, contrary to statistics. After a two-year study of the drug, in 1999 Barlogi made an official statement about thalidomide as a means of combating multiple myeloma (it is better not to know what it is), in those severe cases when conventional methods of treatment no longer work.
In parallel with the above facts, in the 90s, scientists from the laboratory of the American professor Jilla Kaplan, together with Dr. David Stirling, actively studied thalidomide. They found that yes, thalidomide can effectively treat many terrible diseases including tuberculosis and AIDS. NOT INSSON IN PREGNANT WOMEN!
7. Negative effect of thalidomide on the body. What exactly is terrible in Talidome. Apart from the fools who decide to sell it to pregnant women, the danger of its use in initial stages pregnancy. The most critical period for the fetus is 34-50 days after the last menstruation or 20 to 36 days after conception. At this time, there is a 100% chance of a child with deformities after taking one tablet of thalidomide.
Damage to the fetus by thalidomide affects all parts of the body. The most frequent were defects or absence of the upper and lower extremities, the absence of auricles, defects in the eyes and mimic muscles (facial muscles, yes, poker face). Also, thalidomide changes the formation of internal organs, destroying the heart, liver, kidneys, digestive and genitourinary systems, and leads to the birth of children with a very strong mental retardation, of course, epilepsy and autism.
Based on Dr. Lenz's statistics, about 40% of newborn victims of the drug died before their first birthday. And sometimes dangerous diseases, for example, concerning the reproductive system, can manifest themselves many years after birth and are revealed as a result of in-depth research.
Recall none of the perpetrators were put in jail. Nowhere. However, there is a rumor that Irwin Welsh wrote his "Ecstasy" not only under ecstasy. But also impressed by the story about how a baby was stolen from one of the creators of thalidomide, and then his hands were sent by mail.
8. How thalidomide works. The thalidomide molecule consists of two optical isomers - dextrorotatory and levorotatory. One gives the therapeutic effect of the drug, while the second is the terrible cause of its teratogenic effects. This isomer enters the cellular DNA at sites rich in G-C bonds and interferes with the normal process of DNA replication necessary for cell division and embryo development. In short, one side heals, the other cripples.
And due to the cunning property of thalidomil isomers in the body - to pass into each other, at any moment, the purification of one of them does not have an effect and, as a result, kills the therapeutic effect of the drug. He is like a drunken soldier on the attack - he will either shoot his own or close the embrasure with his chest. Or fall asleep under a bush and not touch anyone.
We decided to insert this picture to distract you a little from what you read.
In addition to the main effect - on the fetus, the use of thalidomide has a negative effect on the adult. Side effects there are just childish pranks: dizziness, menstrual irregularities, weakness, headache, drowsiness, fever. Or peripheral neuritis.
P.s.
Before, there were no pills, and people were healthy and ruddy on one potato with bacon. Not like you, pale and skinny, jerky primates.
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This story is more like a movie script, but it's true nonetheless. Perhaps it should be learned by heart when entering the civil service and any responsible position in principle. It tells the story of a female scientist who managed to resist the pressure of a pharmaceutical corporation and save thousands of children from disability, and reminds us of how far the consequences of our decisions can spread.
We are in website We believe that some stories have no statute of limitations, and the lessons that history teaches need to be reminded so as not to repeat the same mistakes.
About Frances' life before the "thalidomide scandal"
Frances O. Kelsey dreamed of becoming a scientist since childhood (which was not easy for a woman at that time), and at 21 she already received degree in pharmacology. And then the stars aligned happy way: famous explorer Geilling of the University of Chicago, when reviewing the resumes of applicants, assumed that Francis was the name of a man, and took Kelsey to his team.
The irony is that here Kelsey was able to find the cause of the mass poisoning of people with an antibiotic solution that was not tested before being put on the market. After 30 years, having joined the FDA, she will partially repeat this experience, but not as a scientist, but as an official: Kelsey will not let thalidomide enter the US market.
About thalidomide
Thalidomide was first synthesized in the middle of the 20th century during the research of the Chemie Grünenthal company for the production of antibiotics. For several years of work, conclusions were drawn, which later became fatal.
- Even when overdosed, thalidomide did not kill the test animals. From this, it was concluded that the drug was harmless, and the manufacturer sent free samples to doctors from Germany and Switzerland for the treatment of patients.
- The drug had a noticeable sedative (calming) effect.
What happened in 1960
“Distaval (thalidomide) is not a barbiturate, a sedative and sleeping pill. Safe calm and healthy sleep.
In September 1960, thalidomide reached the United States. Richardson-Merrell has submitted it to the FDA for review. food products and US Medicines) called Kevadon. The approval seemed to be just a formality. However, the new employee, Frances O. Kelsey, unexpectedly turned down the application.
What confused her?
- Studies of the safety of the drug gave strange results: an absolute absence of toxicity was noted. But what if the body of experimental animals simply could not absorb the drug? This version has not been tested. On the contrary, when the first experiment showed that the animals hardly calmed down when taking thalidomide, the scientists rearranged the test conditions so that they gave the desired result, so strong was the desire to quickly release the drug to the market. Frances considered such safety evidence insufficient.
- Richardson-Merrell was aware of the risk of developing neuritis (these reports began to come in a year ago), but did not mention this in the report to the FDA. In February 1961, there were more such messages.
- No one conducted tests on the effect of the drug on the developing fetus, and in fact at that time it was already known about the permeability of the placental barrier. Frances theorized that thalidomide caused peripheral nerve palsies and suggested that the damage to the embryo could be even greater.
"Rot Your Line"
Frances asked for more detailed information and the result was a conflict. She received responses from the US manufacturer, the William S. Merrell Company, waited the required 60 days, and made new requests. They put pressure on her, tried to act through the leadership, reproached her for incompetence and complained about the bureaucracy. Kelsey insisted that the safety evidence was inconclusive and pressed Merrell to do her own research.
“Richardson-Merrell were just on edge,” Kelsey noted. “They were very disappointed because Christmas is the season for sedatives and sleeping pills. They kept calling me and paying me visits, saying:“ We want to see this drug on the market before Christmas, because it's our best selling time."
She lasted until the end of 1961, until finally scientists from Germany and Australia did not reveal a link between taking thalidomide and numerous cases of deformities in children born after taking it during pregnancy. Only under pressure from the press after the publications, Chemie Grünenthal began withdrawing the drug from the market, notifying its American partners as well.
What was the cost of Kelsey's decision
In order to appreciate how difficult it was for this woman to make such a decision, you need to realize several facts.
- At that time, thalidomide had been sold for several years in more than 40 countries. There was an aggressive marketing campaign. It seemed that the signature on the authorization for sale in the US was just a formality.
The only requirement of American laws was the safety of the drug. In addition, it has already been trialed: Richardson-Merrell has distributed more than 2.5 million tablets through physicians, and most physicians have found it effective and beneficial, as confirmed by their reports. There were already tons of Kevadon ready for sale in the warehouses.
At that time, Kelsey worked at the FDA for about a month, and this was one of her first assignments. We can only guess how much strength it took her to resist the numerous accusations of incompetence. The pressure on Kelsey was enormous.
What happened after?
- On August 8, 1962, President John F. Kennedy presented Frances O. Kelsey with the Distinguished Civilian Service Award, the highest non-military honor in the United States. She became the second woman in history to receive such an award.
The thalidomide tragedy has forced many countries to review and tighten licensing policies for many drugs. For example, requirements were added to provide evidence of the effectiveness of a licensed drug, and close monitoring was introduced for both patients receiving the drug and prescribing doctors.
In total, according to rough estimates, over 6 years of the drug's presence on the market, up to 12,000 children were born with deviations due to their mothers taking a "harmless sedative." About 40% of these babies did not live up to 1 year. To understand how hard the survivors had in life, just look at the photos of the most famous victims - the star of German documentary Niko von Glazov and bass-baritone from Germany Thomas Quasthoff.
In 1954, the German pharmaceutical company Chemie Grünenthal was conducting research to develop an inexpensive way to produce antibiotics from peptides. In the course of research, the company's employees obtained a drug they called thalidomide (thalidomide), after which they began to study its properties to determine the scope of its application.
Initially, thalidomide was supposed to be used as an anticonvulsant, but the first experiments on animals showed that the new drug does not have such properties. However, it was found that an overdose of the drug did not kill the experimental animals, which gave reason to consider the drug harmless.
In 1955, Chemie Grünenthal informally sent free samples of the drug to various doctors in Germany and Switzerland.
People who took the drug noted that although it does not show anticonvulsant properties, it has a calming and hypnotic effect. People who took the drug reported that they experienced deep "natural" sleep that lasted all night.
The effect of the drug impressed many therapists, a safe sedative and hypnotic agent stood out against the background of existing sleeping pills. The safety of overdose (accidental or suicide attempt) of the drug was emphasized further when promoting this product on the market.
Even though the drug had similar effects in humans, it needed to be shown to be effective in order to be licensed. However, the drug did not have a sedative effect on animals, so representatives of Chemie Grünenthal had to make a special cage for the demonstration, which served to measure the slightest movements of experimental animals. In this way, Chemie Grünenthal representatives were able to convince the commission that, despite the fact that the mice were awake after taking the drug, their movements slowed down to a greater extent than in animals that were given other sedatives. During the demonstration, the representatives of the company made the main emphasis on the fact that the drug is absolutely safe, which made it possible to obtain a license for the production and distribution of the drug.
In 1957, the drug was officially released for sale in Germany under the name Contergan, in April 1958 in the UK it was released by the Distillers Company under the name Distaval. In addition, thalidomide has been marketed in medicines for a wide variety of conditions, such as Asmaval for asthma, Tensival for high blood pressure, Valgraine for migraine. In total, thalidomide went on sale in 46 countries in Europe, Scandinavia, Asia, Africa, South America, where it was produced under 37 different names. No additional independent studies of the drug in any country have been conducted.
In August 1958, a letter was received from Grünenthal to someone noting that "thalidomide is the best medicine for pregnant and nursing mothers." This point was almost immediately reflected in the advertising of the drug in the UK by Distiller, despite the fact that studies of the effect of the drug on the fetus were not carried out by either the German company Grünenthal or the English Distiller. Thalidomide has been successfully used to eliminate unpleasant symptoms associated with pregnancy, such as insomnia, anxiety, and morning sickness.
Beginning in 1959, Grünenthal began receiving letters of reports of peripheral neuritis and other side effects from the drug. There were opinions that the drug should be sold only on prescription. Despite this, thalidomide continued to dominate sales and in some countries fell behind only aspirin in terms of sales. Company policy has been to deny the association of Contergan with peripheral neuritis, and Grünenthal has stubbornly resisted attempts to limit sales of the drug.
On September 8, 1960, the US Richardson-Merrell Company submitted thalidomide to the US Food and Drug Administration under the name Kevadon. The American laws of the time for drug licensing required only the safety of its use. The same laws allowed for clinical trial use of a drug prior to licensing, allowing Richardson-Merrell to distribute more than 2,500,000 tablets to 20,000 patients through 1,267 physicians. The drug was approved by a majority of physicians who considered it safe and useful, which they reflected in their reports. However, Dr. Francis O. Kelsey, appointed by the FDA to oversee licensing of the drug, was unimpressed with the results of this test. One of the main factors that influenced Kelsey's decision was that Richardson-Merrell knew about the risk of developing neuritis, but kept silent about it in the report to the FDA. Francis O. Kelsey, despite strong pressure from Richardson-Merrell, did not approve Kevadon and it was not placed on the US market. Of course, at that moment she did not yet suspect how many lives she had saved by making such a decision.
On December 25, 1956, in the city of Stolberg, a daughter without ears was born in the family of an employee of Chemie Grünenthal. This employee was giving his pregnant wife an unofficial thalidomide he had taken at work. At that time, no one saw a connection between taking the drug and a malformation of the fetus, the appearance of children with congenital physical defects was repeatedly observed earlier. However, after the introduction of thalidomide on the market, the number of children born with congenital malformations increased dramatically. In 1961, the German pediatrician Hans-Rudolf Wiedemann drew public attention to this problem, describing it as an epidemic.
At the end of 1961, almost at the same time, Professor W. Lenz in Germany and Dr. McBride in Australia discovered an association between an increased number of birth defects in newborns and the fact that the mothers of these children were taking thalidomide. in early pregnancy.
On November 16, 1961, Lenz reported his suspicions to Chemie Grünenthal by telephone. On November 18, a letter was published in the Welt am Sonntag newspaper in which he described more than 150 cases of birth defects in newborns and linked them to early mothers taking thalidomide. On November 26, under pressure from the press and German authorities, Chemie Grünenthal began withdrawing thalidomide from the German market, notifying Richardson-Merrell, whose products had already spread to South America. At the same time, Chemie Grünenthal continued to deny the connection between the epidemic and its drug.
On December 2, Distillers announced the withdrawal of the drug from the markets in an open letter published in the English journals The Lancet and the British Medical Journal.
In December 1961, a letter from William McBride was published in The Lancet, in which he also described his observations regarding the association of thalidomide with birth defects in infants. After that, the drug began to be removed from the shelves in other countries. Confirmation of the words of Lenz and McBride began to come from different countries, the situation received wide publicity in newspapers, on radio and on television, however, despite this, the drug was available for purchase in some pharmacies even six months after the first reports. In Italy and Japan, the drug was sold even 9 months after the publicity.
In early 1962, Lenz speculated that since 1959, between 2,000 and 3,000 thalidomide-victim children had been born in West Germany. In total, according to various estimates, as a result of the use of thalidomide, about 40,000 people received peripheral neuritis, from 8,000 to 12,000 newborns were born with physical deformities, of which only about 5,000 did not die at an early age, remaining disabled for life.
Teratogenic effects of thalidomide
As it turned out, thalidomide has teratogenic (from the Greek. τέρας - a monster, a freak; and other Greek. γεννάω - I give birth) properties and poses the greatest danger in the early stages of pregnancy. The critical period for the fetus is 34-50 days after the woman's last menstrual period (20 to 36 days after conception). The likelihood of a child with physical deformities appears after taking just one tablet of thalidomide in this period of time.
Fetal damage caused by thalidomide affects a wide variety of body parts. Among the most common external manifestations are defects or absence of the upper or lower extremities, the absence of auricles, defects in the eyes and mimic muscles. In addition, thalidomide affects the formation of internal organs, damaging the heart, liver, kidneys, digestive and genitourinary systems, and can also lead in some cases to the birth of children with mental retardation, epilepsy, autism. Limb defects are called phocomelia and amelia (the literal translation from Latin is “seal limb” and “lack of limb”, respectively), which appear as a kind of seal flippers instead of a limb or their almost complete absence.
According to the data collected by Lenz, about 40% of newborns exposed to the drug during the fetal stage died before their first birthday. Some destructive influences (particularly those affecting the child's reproductive system) may not become apparent until many years after birth and can only be revealed as a result of careful analysis.
No less horrific is the fact that these physical deformities can be inherited. This was stated by representatives of the English Society of Victims of Thalidomide. As evidence, they cited the story of 15-year-old Rebecca, the granddaughter of a woman who was taking thalidomide. The girl was born with shortened hands and three fingers on each hand, a typical deformity associated with this drug.
The mechanism of teratogenic effects
The thalidomide molecule can exist in the form of two optical isomers - dextrorotatory and levorotatory. One of them provides the therapeutic effect of the drug, while the second is the cause of its teratogenic effects. This isomer wedged into cellular DNA at sites rich in G-C bonds and interferes with the normal process of DNA replication necessary for cell division and embryonic development.
Since the enantiomers of thalidomide are able to pass into each other in the body, a preparation consisting of a single purified isomer does not solve the problem of teratogenic effects.
In 2012, the German pharmaceutical concern Gruenenthal opened a bronze monument in the city of Stolberg to children affected by the drug thalidomide.
