CONTENTS

 1 Introduction
 2 Medical uses
 3 Contraindications
 4 Adverse effects
o 4.1Interactions
o 4.2 Overdose
 5 Pharmacology
 6 Chemistry
 7 History
o 7.1Leprosy treatment
o 7.2Cancer treatment
 8 Society and culture
o 8.1Birth defect crisis
o 8.2Aftermath of scandal
o 8.3Notable cases
o 8.4Change in drug regulations
Thalidomide, sold under the brand name Immunoprin, among
others, is an immunomodulatory drug and the prototype of
the thalidomide class of drugs. Today, thalidomide is used mainly
as a treatment of certain cancers (multiple myeloma) and of a
complication of leprosy.
Thalidomide was first marketed in 1957 in West Germany under
the trade name Contergan. The German drug company Chemie
Grünenthal developed and sold the drug. Primarily prescribed as
a sedative or hypnotic, thalidomide also claimed to cure
"anxiety, insomnia, gastritis, and tension". Afterwards, it was used
against nausea and to alleviate morning sickness in pregnant
women. Thalidomide became an over-the-counter drug in West
Germany on October 1, 1957. Shortly after the drug was sold in
West Germany, between 5,000 and 7,000 infants were born
with phocomelia (malformation of the limbs). Only 40% of these
children survived. Throughout the world, about 10,000 cases were
reported of infants with phocomelia due to thalidomide; only 50%
of the 10,000 survived. Those subjected to thalidomide while in
the womb experienced limb deficiencies in a way that the long
limbs either were not developed or presented themselves as
stumps. Other effects included deformed eyes and hearts,
deformed alimentary and urinary tracts, blindness and deafness.
The negative effects of thalidomide led to the development of
more structured drug regulations and control over drug use and
development.

2. Medical uses

Thalidomide is used as a first-line treatment in multiple

myeloma in combination with dexamethasone or
with melphalan and prednisone, to treat acute episodes
of erythema nodosum leprosum, and for maintenance therapy.
Thalidomide is used off-label in several ways.
The bacterium that causes tuberculosis is related to leprosy.
Thalidomide may be helpful in some cases where standard TB
drugs and corticosteroids are not sufficient to resolve severe
inflammation in the brain.
It is used as a second-line treatment to manage graft versus
host disease and aphthous stomatitis in children and has been
prescribed for other conditions in children including actinic
prurigo and epidermolysis bullosa; the evidence for these uses is
weak.  It is recommended only as a third line treatment in graft
versus host disease in adults, based on lack of efficacy and side
effects observed in clinical trials.

3 Contraindications

Thalidomide should not be used by people who are breast feeding

or pregnant, trying to conceive a child, or cannot or will not follow
the risk management program to prevent pregnancies. The
prescribing doctor is required to ensure that contraception is
being used, and regular pregnancy tests must be administered.
Some people are allergic to thalidomide and should not take it. It
should be used with caution in people with chronic infections like
HIV or hepatitis B.

4 Adverse effects

Thalidomide causes birth defects. The FDA and other regulatory

agencies have approved marketing of the drug only with an
auditable risk evaluation and mitigation strategy that ensures that
people using the drug are aware of the risks and avoid
pregnancy; this applies to men and women both, as the drug can
be transmitted in sperm.

There is a high risk that thalidomide can cause excessive blood

clots. There is also a high risk that thalidomide can interfere with
formation of various kinds of new blood cells, creating a risk of
infection via neutropenia, leukopenia, and lymphopenia, and risks
that blood will not clot via thrombocytopenia. There is also a risk
of anemia via lack of red blood cells. The drug can also damage
nerves, causing peripheral neuropathy that may be irreversible.

Thalidomide has several cardiovascular adverse effects, including

risk of heart attacks, pulmonary hypertension, and changes in
heart rhythm including syncope, bradycardiaand atrioventricular
block.

It can cause liver damage and severe skin reactions like Stevens-

Johnson Syndrome. It tends to make people sleepy, which
creates risk for driving and operating other machinery. As it kills
cancer cells, it can cause tumor lysis syndrome. Thalidomide
can prevent menstruation.

Other than the above, very common (reported in more than 10%
of people) adverse effects include tremor, dizziness, tingling,
numbness, constipation, and peripheral edema.
Common (reported by 1-10% of people) adverse effects include
confusion, depressed mood, reduced coordination, heart failure,
difficulty breathing, interstitial lung disease, lung inflammation,
vomiting, dry mouth, rashes, dry skin, fever, weakness, and a
sense of unwellness.
4.1 Interactions
There are no expected pharmacokinetic interactions between
thalidomide and other medicines due to its neutral effects on p-
glycoprotein and P450 cytochromes. It may interact with
sedatives due to its sedative action. It may also interact with
bradycardic agents due to its bradycardia-inducing effects. The
risk of peripheral neuropathy may be increased by concomitant
treatment with other agents known to cause peripheral
neuropathy. The risk of venous thromboembolisms with
thalidomide seems to be increased when patients are treated with
oral contraceptives or other cytotoxic agents (including
doxorubicin and melphalan) concurrently. Thalidomide may
interfere with various contraceptives, and hence it is advised that
women of reproductive age use at least two different means of
contraception to ensure that no child will be conceived while they
are receiving thalidomide.

4.2 Overdose
As of 2013 eighteen cases of overdoses had been reported with
doses of up to 14.4 g, none of them fatal. No specific antidote for
overdoses exists and treatment is purely supportive.

5 Pharmacology

The precise mechanism of action for thalidomide is unknown

although efforts to identify thalidomide's teratogenic action
generated 2000 research papers and the proposal of 15 or 16
plausible mechanisms by 2000.
As of 2015 the main theories were inhibition of the process
of angiogenesis, its inhibition of cereblon, a ubiquitin ligase, and
its ability to generate reactive oxygen species which in turn kill
cells. 
In 2018, results were first published which suggested that
thalidomide's teratogenic effects are mediated through
degradation of the transcription factor, SALL4, an as yet
unverified finding.
Thalidomide also binds to and acts as an antagonist of
the androgen receptor (AR) and hence is a nonsteroidal
antiandrogen (NSAA) of some capacity. In accordance, it can
produce gynecomastia and sexual dysfunction as side effects in
men.
Thalidomide is provided as a racemic mixture of two enantiomers;
while there are reports that only one of the enantiomers may
cause birth defects, the body converts each enantiomer into the
other through mechanisms that are not well understood.

6. Chemistry
Thalidomide is racemic; while the S-thalidomide is the bioactive
form of the molecule, the individual enantiomers can racemize to
each other due to the acidic hydrogen at the chiral centre, which
is the carbon of the glutarimide ring bonded to the phthalimide
substituent. The racemization process can occur in vivo.
Celgene Corporation originally synthesized thalidomide using a
three-step sequence starting with L-glutamic acid treatment, but
this has since been reformed by the use of L-glutamine.
As shown in the image below, N-carbethoxyphtalimide
(1) can react with L-glutamine to yield N-Phthaloyl-L-glutamine
(2). Cyclization of N-Phthaloyl-L-glutamine occurs
using carbonyldiimidazole, which then yields thalidomide
(3). Celgene Corporation's original method resulted in a 31% yield
of S-thalidomide, whereas the two-step synthesis yields 85-93%
product that is 99% pure.
7 History
Thalidomide was discovered by scientists at the German
pharmaceutical company Chemie Grünenthal (now Grünenthal
GmbH) around 1953. The company had been set up as a soap
maker just after WWII ended, to address the urgent market need
for antibiotics. Heinrich Mueckter was appointed to head the
discovery program based on his experience working with the
German army's antiviral research program. In the course of
preparing reagents for the work, Mueckter's assistant Wilhelm
Kunz isolated a by-product,that was in turn recognized by
pharmacologist Herbert Keller as an analog of glutethimide,
a sedative, and the medicinal chemistry work turned to improving
the lead compound into a suitable drug; the result was
thalidomide. The toxicity was examined in several animals, and
the drug was introduced in 1956 as a sedative.
Researchers at Chemie Grünenthal also found that thalidomide
was a particularly effective antiemetic that had an inhibitory effect
on morning sickness.[27] Hence, on October 1, 1957, the company
launched thalidomide and began marketing it under the trade
name Contergan. It was proclaimed a "wonder drug" for insomnia,
coughs, colds and headaches.
During this time period, the use of medications during pregnancy
was not strictly controlled, and drugs were not thoroughly tested
for potential harm to the fetus.[27] Thousands of pregnant women
took the drug to relieve their symptoms. At the time of the drug's
development, scientists did not believe any drug taken by a
pregnant woman could pass across the placental barrier and
harm the developing fetus,[6] even though the effect of alcohol on
fetal development had been documented by case studies on
alcoholic mothers since at least 1957. There soon appeared
reports of findings of abnormalities in children being born, traced
back to the use of the drug thalidomide. In late 1959, it was
noticed that peripheral neuritis developed in patients who took the
drug over a period of time, and it was only after this point that
thalidomide ceased to be provided over the counter.
Hence, while initially considered safe, the drug was responsible
for teratogenic deformities in children born after their mothers
used it during pregnancies, prior to the third trimester. In
November 1961, thalidomide was taken off the market due to
massive pressure from the press and public. Experts estimate
that the drug thalidomide led to the death of approximately 2,000
children and serious birth defects in more than 10,000 children,
about 5,000 of them in West Germany. The regulatory authorities
in East Germany did not approve thalidomide. One reason for the
initially unobserved side effects of the drug and the subsequent
approval in West Germany was that at that time drugs did not
have to be tested for teratogenic effects. They had been tested on
rodents only, as was usual at the time.
In the UK, the British pharmaceutical company The Distillers
Company (Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd
(now part of Diageo plc), marketed thalidomide under the brand
name Distaval as a remedy for morning sickness throughout the
United Kingdom, Australia and New Zealand. Their advertisement
claimed that "Distaval can be given with complete safety to
pregnant women and nursing mothers without adverse effect on
mother or child...Outstandingly safe Distaval has been prescribed
for nearly three years in this country."[4] Around the world, more
and more pharmaceutical companies started to produce and
market the drug under license from Chemie Grünenthal. By the
mid-1950s, 14 pharmaceutical companies were marketing
thalidomide in 46 countries under at least 37 different trade
names.
In the U.S., representatives from Chemie
Grünenthal approached Smith, Kline & French (SKF),
now GlaxoSmithKline (GSK) with a request to market and
distribute the drug in North America. A memorandum
rediscovered in 2010 in the archives of the U.S. Food and Drug
Administration (FDA) shows that, as part of its in-licensing
approach, Smith, Kline and French conducted animal tests and
ran a clinical trial of the drug in the United States involving 875
people, including pregnant women, in 1956–57. In 1956,
researchers at SKF involved in clinical trials noted that even when
used in very high doses, thalidomide could not induce sleep in
mice. And when administered at doses 50 to 650 times larger
than that claimed by Chemie Grünenthal to be "sleep inducing",
the researchers could still not achieve the hypnotic effect in
animals that it had on humans. After completion of the trial, and
based on reasons kept hidden for decades, SKF declined to
commercialize the drug. Later, Chemie Grünenthal, in 1958,
reached an agreement with William S Merrell Company in
Cincinnati, Ohio, (later Richardson-Merrell, now part of Sanofi), to
market and distribute thalidomide throughout the United States.
The U.S. FDA refused to approve thalidomide for marketing and
distribution. However, the drug was distributed in large quantities
for testing purposes, after the American distributor and
manufacturer Richardson-Merrellhad applied for its approval in
September 1960. The official in charge of the FDA
review, Frances Oldham Kelsey, did not rely on information from
the company, which did not include any test results. Richardson-
Merrell was called on to perform tests and report the results. The
company demanded approval six times, and was refused each
time. Nevertheless, a total of 17 children with thalidomide-induced
malformations were born in the U.S. Oldham Kelsey was given a
Presidential award for distinguished service from the federal
government for not allowing Thalidomide to be approved for sale
in the USA.
In Canada, the history of the drug thalidomide dates back to April
1, 1961. There were many different forms sold, with the most
common variant being Talimol.  Two months after Talimol went on
sale, pharmaceutical companies sent physicians letters warning
about the risk of birth defects. It was not until March 2, 1962, that
both drugs were banned from the Canadian market by the FDD,
and soon afterward physicians were warned to destroy their
supplies.

7.1 Leprosy treatment

In 1964, Israeli physician Jacob Sheskin administered thalidomide
to a patient critically ill with leprosy. The patient
exhibited erythema nodosum leprosum (ENL), a painful skin
condition, one of the complications of leprosy. This was attempted
despite the ban on thalidomide's use, but results were favourable:
the patient slept for hours and was able to get out of bed without
aid upon awakening. A clinical trial studying the use of
thalidomide in leprosy soon followed.
Thalidomide has been used by Brazilian physicians as the drug of
choice for the treatment of severe ENL since 1965, and by 1996,
at least 33 cases of thalidomide embryopathy were recorded in
people born in Brazil after 1965. Since 1994, the production,
dispensing, and prescription of thalidomide have been strictly
controlled, requiring women to use two forms of birth control and
submit to regular pregnancy tests. Despite this, cases of
thalidomide embryopathy continue, with at least 100 cases
identified in Brazil between 2005 and 2010. 5.8 million
thalidomide pills were distributed throughout Brazil in this time
period, largely to poor Brazilians in areas with poor access to
healthcare, and these cases have occurred despite the controls.
In 1998 the FDA approved the drug's use in the treatment of ENL.
[41]
 Because of thalidomide's potential for causing birth defects, the
drug may be distributed only under tightly controlled conditions.
The FDA required that Celgene Corporation, which planned to
market thalidomide under the brand name Thalomid, establish a
system for thalidomide education and prescribing safety (STEPS)
oversight program. The conditions required under the program
include limiting prescription and dispensing rights to authorized
prescribers and pharmacies only, keeping a registry of all patients
prescribed thalidomide, providing extensive patient education
about the risks associated with the drug, and providing periodic
pregnancy tests for women who take the drug.
In 2010, the World Health Organization (WHO) stated that it did
not recommend thalidomide due the difficulty of adequately
controlling its use, and due to the availability of clofazimine.

7.2 Cancer treatment

Shortly after the teratogenic properties of thalidomide were
recognized in the mid-1960s, its anti-cancer potential was
explored and two clinical trials were conducted in people with
advanced cancer, including some people with multiple myeloma;
the trials were inconclusive.
Little further work was done with thalidomide in cancer until the
1990s.
Judah Folkman pioneered studies into the role
of angiogenesis (the proliferation and growth of blood vessels) in
the development of cancer, and in the early 1970s had shown
that solid tumors could not expand without it. In 1993 he surprised
the scientific world by hypothesizing the same was true of blood
cancers,  and the next year he published work showing that
a biomarker of angiogenesis was higher in all people with cancer,
but especially high in people with blood cancers, and other
evidence emerged as well. Meanwhile, a member of his lab,
Robert D'Amato, who was looking for angiogenesis inhibitors,
discovered in 1994 that thalidomide inhibited angiogenesis and
was effective in suppressing tumor growth in rabbits. Around that
time, the wife of a man who was dying of multiple myeloma and
whom standard treatments had failed, called Folkman asking him
about his anti-angiogenesis ideas. Folkman persuaded the
patient's doctor to try thalidomide, and that doctor conducted a
clinical trial of thalidomide for people with multiple myeloma in
which about a third of the subjects responded to the
treatment. The results of that trial were published in the New
England Journal of Medicine in 1999.
After further work was done by Celgene and others, in 2006 the
U.S. Food and Drug Administration granted accelerated approval
for thalidomide in combination with dexamethasone for the
treatment of newly diagnosed multiple myeloma patients.

8 Society and culture

Shortly after the teratogenic properties of thalidomide were
recognized in the mid-1960s, its anti-cancer potential was
explored and two clinical trials were conducted in people with
advanced cancer, including some people with multiple myeloma;
the trials were inconclusive.

Little further work was done with thalidomide in cancer until the
1990s. Judah Folkman pioneered studies into the role
of angiogenesis (the proliferation and growth of blood vessels) in
the development of cancer, and in the early 1970s had shown
that solid tumors could not expand without it. In 1993 he surprised
the scientific world by hypothesizing the same was true of blood
cancers, and the next year he published work showing that
a biomarker of angiogenesis was higher in all people with cancer,
but especially high in people with blood cancers, and other
evidence emerged as well. Meanwhile, a member of his lab,
Robert D'Amato, who was looking for angiogenesis inhibitors,
discovered in 1994 that thalidomide inhibited angiogenesis and
was effective in suppressing tumor growth in rabbits.  Around that
time, the wife of a man who was dying of multiple myeloma and
whom standard treatments had failed, called Folkman asking him
about his anti-angiogenesis ideas. Folkman persuaded the
patient's doctor to try thalidomide, and that doctor conducted a
clinical trial of thalidomide for people with multiple myeloma in
which about a third of the subjects responded to the
treatment. The results of that trial were published in the New
England Journal of Medicine in 1999.
After further work was done by Celgene and others, in 2006 the
U.S. Food and Drug Administration granted accelerated approval
for thalidomide in combination with dexamethasone for the
treatment of newly diagnosed multiple myeloma patients.

8. Society and culture

o 8.1Birth defect crisis

In the late 1950s and early 1960s, more than 10,000 children in
46 countries were born with deformities such as phocomelia as a
consequence of thalidomide use. The severity and location of the
deformities depended on how many days into the pregnancy the
mother was before beginning treatment; thalidomide taken on the
20th day of pregnancy caused central brain damage, day 21
would damage the eyes, day 22 the ears and face, day 24 the
arms, and leg damage would occur if taken up to day 28.
Thalidomide did not damage the fetus if taken after 42 days
gestation.
It is not known exactly how many worldwide victims of the drug
there have been, although estimates range from 10,000 to
20,000 to 100,000. Despite the side effects, thalidomide was sold
in pharmacies in Canada until 1962
In the United Kingdom, the drug was licensed in 1958 and
withdrawn in 1961. Of the approximately 2,000 babies born with
defects, around half died within a few months and 466 survived to
at least 2010.
In Spain, thalidomide was widely available throughout the 1970s,
perhaps even into the 1980s. There were two reasons for this.
First, state controls and safeguarding were poor; indeed, it was
not until 2008 that the government even admitted the country had
ever imported thalidomide. Second, Grünenthal failed to insist that
its sister company in Madrid warn Spanish doctors, and permitted
it to not warn them. The Spanish advocacy group for victims of
thalidomide estimates that in 2015, there were 250–300 living
victims of thalidomide in Spain.
Although the Australian obstetrician William McBride took credit
for raising the alarm about thalidomide it was a midwife who first
suspected the drug was causing birth defects in the babies of
patients under his care at Crown Street Women's Hospital in
Sydney.  German paediatrician; Widukind Lenz, who also
suspected the link, is credited with conducting the scientific
research that proved thalidomide was causing birth defects in
1961. McBride was later awarded a number of honors, including a
medal and prize money by L'Institut de la Vie in Paris, but he was
eventually struck off the Australian medical register in 1993 for
scientific fraud. Further animal tests were conducted by Dr
George Somers, Chief Pharmacologist of Distillers Company in
Britain, which showed foetal abnormalities in rabbits. Similar
results were also published showing these effects in rats and
other species.

o 8.2Aftermath of scandal

The numerous reports of malformations in babies brought about

the awareness of the side effects of the drug on pregnant women.
The birth defects caused by the drug thalidomide can range from
moderate malformation to more severe forms. Possible birth
defects include phocomelia, dysmelia, amelia, bone
hypoplasticity, and other congenital defects affecting the ear,
heart, or internal organs.  Franks et al. looked at how the drug
affected newborn babies, the severity of their deformities, and
reviewed the drug in its early years. Webb in 1963 also reviewed
the history of the drug and the different forms of birth defects it
had caused. "The most common form of birth defects from
thalidomide is shortened limbs, with the arms being more
frequently affected. This syndrome is the presence of deformities
of the long bones of the limbs resulting in shortening and other
abnormalities

o 8.3Notable cases

Lorraine Mercer MBE of the United Kingdom, born with

phocomelia of both arms and legs, is the only thalidomide survivor
to carry the Olympic Torch.

Thomas Quasthoff, an internationally acclaimed bass-baritone,

who describes himself: "1.34 meters tall, short arms, seven
fingers — four right, three left — large, relatively well-formed
head, brown eyes, distinctive lips; profession: singer".

Niko von Glasow produced a documentary called NoBody's

Perfect, based on the lives of 12 people affected by the drug,
which was released in 2008.

Mercédes Benegbi, born with phocomelia of both arms, drove the

successful campaign for compensation from her government for
Canadians who were affected by thalidomide.
o 8.4Change in drug regulations

The disaster prompted many countries to introduce tougher rules

for the testing and licensing of drugs, such as the Kefauver Harris
Amendment (U.S.), Directive 65/65/EEC1 (E.U.), and
the Medicines Act 1968. In the United States, the new regulations
strengthened the FDA, among other ways, by requiring applicants
to prove efficacy and to disclose all side effects encountered in
testing. The FDA subsequently initiated the Drug Efficacy Study
Implementation to reclassify drugs already on the market.