Thalidomide, sold under the brand names Contergan and Thalomid among others, is a
medication
A medication (also called medicament, medicine, pharmaceutical drug, medicinal drug or simply drug) is a drug used to diagnose, cure, treat, or prevent disease. Drug therapy (pharmacotherapy) is an important part of the medical field and re ...
used to treat a number of cancers (including
multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
),
graft-versus-host disease, and a number of skin conditions including complications of
leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
.
While it has been used in a number of
HIV
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immune ...
-associated conditions, such use is associated with increased levels of the virus.
[ It is taken ]by mouth
Oral administration is a route of administration where a substance is taken through the mouth. Per os abbreviated to P.O. is sometimes used as a direction for medication to be taken orally. Many medications are taken orally because they are i ...
.[
Common side effects include sleepiness, rash, and ]dizziness
Dizziness is an imprecise term that can refer to a sense of disorientation in space, vertigo, or lightheadedness. It can also refer to disequilibrium or a non-specific feeling, such as giddiness or foolishness.
Dizziness is a common medical c ...
.[ Severe side effects include ]tumor lysis syndrome
Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off ( lysed) from the treatment, releasing their contents into the blood ...
, blood clots
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
, and peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
. Use in pregnancy
Pregnancy is the time during which one or more offspring develops ( gestates) inside a woman's uterus (womb). A multiple pregnancy involves more than one offspring, such as with twins.
Pregnancy usually occurs by sexual intercourse, but ca ...
may harm the fetus, including resulting in malformation of the limbs.[ In males who are taking the medication, contraception is essential if a partner could become pregnant.][ It is an immunomodulatory medication and works by a number of mechanisms, including stimulating ]T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
and decreasing TNF-α
Tumor necrosis factor (TNF, cachexin, or cachectin; formerly known as tumor necrosis factor alpha or TNF-α) is an adipokine and a cytokine. TNF is a member of the TNF superfamily, which consists of various transmembrane proteins with a homolog ...
production.[
Thalidomide was first marketed in 1957 in West Germany, where it was available ]over the counter
Over-the-counter (OTC) drugs are medicines sold directly to a consumer without a requirement for a prescription from a healthcare professional, as opposed to prescription drugs, which may be supplied only to consumers possessing a valid prescr ...
.[ When first released, thalidomide was promoted for ]anxiety
Anxiety is an emotion which is characterized by an unpleasant state of inner turmoil and includes feelings of dread over anticipated events. Anxiety is different than fear in that the former is defined as the anticipation of a future threat wh ...
, trouble sleeping
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
, "tension", and morning sickness. While it was initially thought to be safe in pregnancy, concerns regarding birth defects arose until the medication was removed from the market in Europe in 1961.[ The total number of infants affected by use during pregnancy is estimated at 10,000, of whom about 40% died around the time of birth.][ Those who survived had limb, eye, urinary tract, and heart problems.][ Its initial entry into the US market was prevented by ]Frances Kelsey
Frances Kathleen Kelsey ( Oldham; July 24, 1914 – August 7, 2015) was a Canadian-American pharmacologist and physician. As a reviewer for the U.S. Food and Drug Administration (FDA), she refused to authorize thalidomide for market because sh ...
, a reviewer at the FDA.[ The birth defects caused by thalidomide led to the development of greater ]drug regulation
The regulation of therapeutic goods, defined as drugs and therapeutic devices, varies by jurisdiction. In some countries, such as the United States, they are regulated at the national level by a single agency. In other jurisdictions they are reg ...
and monitoring in many countries.[
It was approved in the United States in 1998 for use as a treatment for cancer.][ It is on the ]World Health Organization's List of Essential Medicines
The WHO Model List of Essential Medicines (aka Essential Medicines List or EML), published by the World Health Organization (WHO), contains the medications considered to be most effective and safe to meet the most important needs in a health ...
. It is available as a generic medication
A generic drug is a pharmaceutical drug that contains the same chemical substance as a drug that was originally protected by chemical patents. Generic drugs are allowed for sale after the patents on the original drugs expire. Because the active ch ...
.[
]
Medical uses
Thalidomide is used as a first-line treatment in multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
in combination with dexamethasone
Dexamethasone is a glucocorticoid medication used to treat rheumatic problems, a number of skin diseases, severe allergies, asthma, chronic obstructive lung disease, croup, brain swelling, eye pain following eye surgery, superior vena cav ...
or with melphalan
Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma, ovarian cancer, melanoma, and AL amyloidosis. It is taken by mouth or by injection into a vein.
Common side effects incl ...
and prednisone
Prednisone is a glucocorticoid medication mostly used to immunosuppressive drug, suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium ...
to treat acute episodes of erythema nodosum leprosum
Erythema nodosum (EN) is an inflammatory condition characterized by inflammation of the fat cells under the skin, resulting in tender red nodules or lumps that are usually seen on both shins. It can be caused by a variety of conditions, and typi ...
and for maintenance therapy.[ For label updates see ]
The bacterium that causes tuberculosis
Tuberculosis (TB) is an infectious disease usually caused by '' Mycobacterium tuberculosis'' (MTB) bacteria. Tuberculosis generally affects the lungs, but it can also affect other parts of the body. Most infections show no symptoms, in ...
(TB) is related to leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
. Thalidomide may be helpful in some cases where standard TB drugs and corticosteroid
Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex of vertebrates, as well as the synthetic analogues of these hormones. Two main classes of corticosteroids, glucocorticoids and mineralocorticoids, are involv ...
s are not sufficient to resolve severe inflammation in the brain.
It is used as a second-line treatment to manage graft versus host disease
Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.
White blood cells of the donor's immune system which remain wit ...
and aphthous stomatitis
Aphthous stomatitis, or recurrent aphthous stomatitis (RAS), is a common condition characterized by the repeated formation of benign and non-contagious mouth ulcers (aphthae) in otherwise healthy individuals. The informal term ''canker sore'' i ...
in children and has been prescribed for other conditions in children, including actinic prurigo and epidermolysis bullosa
Epidermolysis bullosa (EB) is a group of rare medical conditions that result in easy blistering of the skin and mucous membranes. Blisters occur with minor trauma or friction and are painful. Its severity can range from mild to fatal. Inherited E ...
; the evidence for these uses is weak. It is recommended only as a third line treatment in graft-versus-host-disease in adults because of lack of efficacy and side effects observed in clinical trials.
Contraindications
Thalidomide should not be used by men or women who are trying to father or conceive a child, or who cannot or will not follow the risk management program to prevent pregnancies, or by women who are breastfeeding or pregnant. The prescribing doctor is required to ensure that contraception
Birth control, also known as contraception, anticonception, and fertility control, is the use of methods or devices to prevent unwanted pregnancy. Birth control has been used since ancient times, but effective and safe methods of birth contr ...
is being used, and regular pregnancy tests are taken. Those allergic to thalidomide should not take it. It should be used with caution in people with chronic infections like HIV or hepatitis B.[
]
Adverse effects
Thalidomide causes birth defects. The U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) and other regulatory agencies have approved marketing of the drug only with an auditable risk evaluation and mitigation strategy Risk Evaluation and Mitigation Strategies (REMS) is a program of the US Food and Drug Administration for the monitoring of medications with a high potential for serious adverse effects. REMS applies only to specific prescription drugs, but can apply ...
that ensures that people using the drug are aware of the risks and avoid pregnancy; this applies to both men and women, as the drug can be transmitted in semen
Semen, also known as seminal fluid, is an organic bodily fluid created to contain spermatozoa. It is secreted by the gonads (sexual glands) and other sexual organs of male or hermaphroditic animals and can fertilize the female ovum. Semen i ...
.[
There is a high risk that thalidomide can cause excessive ]blood clots
A thrombus (plural thrombi), colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cr ...
. 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
Neutropenia is an abnormally low concentration of neutrophils (a type of white blood cell) in the blood. Neutrophils make up the majority of circulating white blood cells and serve as the primary defense against infections by destroying bacteria ...
, leukopenia
Leukopenia () is a decrease in the number of leukocytes (WBC). Found in the blood, they are the white blood cells, and are the body's primary defense against an infection. Thus the condition of leukopenia places individuals at increased risk of inf ...
, and lymphopenia
Lymphocytopenia is the condition of having an abnormally low level of lymphocytes in the blood. Lymphocytes are a white blood cell with important functions in the immune system. It is also called lymphopenia. The opposite is lymphocytosis, which ...
, and risks that blood will not clot via thrombocytopenia
Thrombocytopenia is a condition characterized by abnormally low levels of platelets, also known as thrombocytes, in the blood. It is the most common coagulation disorder among intensive care patients and is seen in a fifth of medical patients an ...
. There is also a risk of anemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, th ...
via lack of red blood cells. The drug can also damage nerves, causing potentially irreversible peripheral neuropathy
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or or ...
.[
Thalidomide has several adverse cardiovascular effects, including risk of ]heart attack
A myocardial infarction (MI), commonly known as a heart attack, occurs when blood flow decreases or stops to the coronary artery of the heart, causing damage to the heart muscle. The most common symptom is chest pain or discomfort which may tr ...
s, pulmonary hypertension, and changes in heart rhythm, such as syncope, bradycardia
Bradycardia (also sinus bradycardia) is a slow resting heart rate, commonly under 60 beats per minute (BPM) as determined by an electrocardiogram. It is considered to be a normal heart rate during sleep, in young and healthy or elderly adults, a ...
, and atrioventricular block
Atrioventricular block (AV block) is a type of heart block that occurs when the electrical signal traveling from the atria, or the upper chambers of the heart, to ventricles, or the lower chambers of the heart, is impaired. Normally, the sinoatr ...
.[
Thalidomide can cause ]liver damage
Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common.
Signs and symptoms
Some of the si ...
and severe skin reactions like Stevens–Johnson syndrome
Stevens–Johnson syndrome (SJS) is a type of severe skin reaction. Together with toxic epidermal necrolysis (TEN) and Stevens–Johnson/toxic epidermal necrolysis (SJS/TEN), it forms a spectrum of disease, with SJS being less severe. Erythema ...
. It tends to make people sleepy, which creates risk when driving and operating other machinery. As it kills cancer cells, it can cause tumor lysis syndrome
Tumor lysis syndrome (TLS) is a group of metabolic abnormalities that can occur as a complication from the treatment of cancer, where large amounts of tumor cells are killed off ( lysed) from the treatment, releasing their contents into the blood ...
. Thalidomide can prevent menstruation.[
In addition, very common (reported in more than 10% of people) adverse effects include tremor, dizziness, tingling, numbness, constipation, and ]peripheral edema
Peripheral edema is edema (accumulation of fluid causing swelling) in tissues perfused by the peripheral vascular system, usually in the lower limbs. In the most dependent parts of the body (those hanging distally), it may be called dependent ede ...
.[
Common adverse effects (reported by 1–10% of people) 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.][
]
Interactions
There are no expected pharmacokinetic
Pharmacokinetics (from Ancient Greek ''pharmakon'' "drug" and ''kinetikos'' "moving, putting in motion"; see chemical kinetics), sometimes abbreviated as PK, is a branch of pharmacology dedicated to determining the fate of substances administered ...
interactions between thalidomide and other medicines due to its neutral effects on P-glycoprotein
P-glycoprotein 1 (permeability glycoprotein, abbreviated as P-gp or Pgp) also known as multidrug resistance protein 1 (MDR1) or ATP-binding cassette sub-family B member 1 (ABCB1) or cluster of differentiation 243 (CD243) is an important protein ...
and the cytochrome P450
Cytochromes P450 (CYPs) are a Protein superfamily, superfamily of enzymes containing heme as a cofactor (biochemistry), cofactor that functions as monooxygenases. In mammals, these proteins oxidize steroids, fatty acids, and xenobiotics, and are ...
family. It may interact with sedatives due to its sedative action and bradycardic agents, like beta-blockers, 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 thromboembolism
Venous thrombosis is blockage of a vein caused by a thrombus (blood clot). A common form of venous thrombosis is deep vein thrombosis (DVT), when a blood clot forms in the deep veins. If a thrombus breaks off (embolizes) and flows to the lungs to ...
s with thalidomide seems to be increased when patients are treated with oral contraceptives Oral contraceptives, abbreviated OCPs, also known as birth control pills, are medications taken by mouth for the purpose of birth control.
Female
Two types of female oral contraceptive pill, taken once per day, are widely available:
* The combin ...
or other cytotoxic agents (including doxorubicin
Doxorubicin, sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer. This includes breast cancer, bladder cancer, Kaposi's sarcoma, lymphoma, and acute lymphocytic leukemia. It is often used toge ...
and melphalan
Melphalan, sold under the brand name Alkeran among others, is a chemotherapy medication used to treat multiple myeloma, ovarian cancer, melanoma, and AL amyloidosis. It is taken by mouth or by injection into a vein.
Common side effects incl ...
) 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 taking thalidomide.[
]
Overdose
As of 2013, eighteen cases of overdoses had been reported with doses of up to 14.4 grams, none of them fatal.[ No specific antidote for overdose exists and treatment is purely supportive.][
]
Pharmacology
The precise mechanism of action for thalidomide is not known, although efforts to identify thalidomide's teratogenic
Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...
action generated 2,000 research papers and the proposal of 15 or 16 plausible mechanisms by 2000. , the main theories were inhibition of the process of angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
, its inhibition of cereblon
Cereblon is a protein that in humans is encoded by the ''CRBN'' gene. The gene that encodes the cereblon protein is found on the human chromosome 3, on the short arm at position p26.3 from base pair 3,190,676 to base pair 3,221,394. CRBN ortholog ...
, a ubiquitin ligase
A ubiquitin ligase (also called an E3 ubiquitin ligase) is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin ...
, and its ability to generate reactive oxygen species
In chemistry, reactive oxygen species (ROS) are highly reactive chemicals formed from diatomic oxygen (). Examples of ROS include peroxides, superoxide, hydroxyl radical, singlet oxygen, and alpha-oxygen.
The reduction of molecular oxygen () p ...
which in turn kills cells. In 2018, results were first published which suggested that thalidomide's teratogenic effects are mediated through degradation of the transcription factor, SALL4
Sal-like protein 4 (SALL4) is a transcription factor encoded by a member of the ''Spalt-like'' (''SALL'') gene family, ''SALL4''. The ''SALL'' genes were identified based on their sequence homology to ''Spalt,'' which is a homeotic gene originally ...
, an as yet unverified finding.
Thalidomide also binds to and acts as an antagonist
An antagonist is a character in a story who is presented as the chief foe of the protagonist.
Etymology
The English word antagonist comes from the Greek ἀνταγωνιστής – ''antagonistēs'', "opponent, competitor, villain, enemy, riv ...
of the androgen receptor
The androgen receptor (AR), also known as NR3C4 (nuclear receptor subfamily 3, group C, member 4), is a type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone in th ...
(AR) and hence is a nonsteroidal antiandrogen
A nonsteroidal antiandrogen (NSAA) is an antiandrogen with a nonsteroidal chemical structure. They are typically selective and full or silent antagonists of the androgen receptor (AR) and act by directly blocking the effects of androgens like ...
(NSAA) of some capacity. In accordance, it can produce gynecomastia
Gynecomastia (also spelled gynaecomastia) is the abnormal non-cancerous enlargement of one or both breasts in males due to the growth of breast tissue as a result of a hormone imbalance between estrogens and androgens. Updated by Brent Wisse ( ...
and sexual dysfunction
Sexual dysfunction is difficulty experienced by an individual or partners during any stage of normal sexual activity, including physical pleasure, desire, preference, arousal, or orgasm. The World Health Organization defines sexual dysfunction as ...
as side effects in men.
Chirality and biological activity
Thalidomide is provided as a racemic mixture
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
of two enantiomer
In chemistry, an enantiomer ( /ɪˈnænti.əmər, ɛ-, -oʊ-/ ''ih-NAN-tee-ə-mər''; from Ancient Greek ἐνάντιος ''(enántios)'' 'opposite', and μέρος ''(méros)'' 'part') – also called optical isomer, antipode, or optical ant ...
s; 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.[ The (R)-enantiomer has the desired sedative effect while the (S)-enantiomer harbors embryo-toxic and teratogenic effect. The hypothesis that the tragedy could be avoided in this case by using a single enantiomer is misleading and pointless, because it was later demonstrated that the “safe” ''R''-thalidomide undergoes an ''in vivo'' ]chiral inversion Chiral inversion is the process of conversion of one enantiomer of a chiral molecule to its mirror-image version with no other change in the molecule.
Chiral inversion happens depending on various factors (viz. biological-, solvent-, light-, temper ...
to the “teratogenic” ''S''-thalidomide. Under biological conditions, the enantiomers interconvert 'bidirectional chiral inversion'' - (R)- to (S)- and vice versa
Chemistry
Thalidomide is racemic
In chemistry, a racemic mixture, or racemate (), is one that has equal amounts of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as racemates. ...
; while ''S''-thalidomide is the bioactive form of the molecule, the individual enantiomers can racemize In chemistry, racemization is a conversion, by heat or by chemical reaction, of an optically active compound into a racemic (optically inactive) form. This creates a 1:1 molar ratio of enantiomers and is referred too as a racemic mixture (i.e. conta ...
to each other due to the acidic hydrogen at the chiral centre
In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...
, which is the carbon of the glutarimide
Glutarimide is the organic compound with the formula (CH2)3(CO)2NH. It is a white solid. The compound forms upon dehydration of the amide of glutaric acid.
Glutarimide is sometimes called 2,6-piperidinedione. It is the core of a variety of dru ...
ring bonded to the phthalimide
Phthalimide is the organic compound with the formula C6H4(CO)2NH. It is the imide derivative of phthalic anhydride. It is a sublimable white solid that is slightly soluble in water but more so upon addition of base. It is used as a precursor ...
substituent
A substituent is one or a group of atoms that replaces (one or more) atoms, thereby becoming a moiety in the resultant (new) molecule. (In organic chemistry and biochemistry, the terms ''substituent'' and ''functional group'', as well as ''side ...
. The racemization process can occur ''in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
''. The process of conversion of one enantiomer to its mirror-image version with no other change in the molecule is called chiral inversion.
Celgene Corporation
Celgene Corporation is a pharmaceutical company that makes cancer and immunology drugs. Its major product is Revlimid (lenalidomide), which is used in the treatment of multiple myeloma, and also in certain anemias. The company is incorporated in ...
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''-carbethoxyphthalimide (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.
History
In 1952, thalidomide was synthesised by Chemical Industry Basel
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loca ...
(CIBA), but was found "to have no effect on animals and was discarded" on that basis. In 1957, it was acquired by Chemie Grünenthal in Germany.[ The German company had been established as a soap maker after World War II ended, to address the urgent market need for antibiotics. ]Heinrich Mückter
Heinrich Mückter (14 June 1914 – 22 May 1987) was a German medical doctor, pharmacologist and chemist.
World War II
During the Nazi occupation of Poland, Mückter was deputy director of the Kraków Institute for Typhus and Virus Research. M ...
was appointed to head the discovery program based on his experience working with the German army's antiviral research. While preparing reagents
In chemistry, a reagent ( ) or analytical reagent is a substance or compound added to a system to cause a chemical reaction, or test if one occurs. The terms ''reactant'' and ''reagent'' are often used interchangeably, but reactant specifies a ...
for the work, Mueckter's assistant Wilhelm Kunz isolated a by-product that was recognized by pharmacologist Herbert Keller as an analog of glutethimide, a sedative
A sedative or tranquilliser is a substance that induces sedation by reducing irritability or excitement. They are CNS depressants and interact with brain activity causing its deceleration. Various kinds of sedatives can be distinguished, but t ...
. 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, but it was never tested on pregnant women.
Researchers at Chemie Grünenthal found that thalidomide was a particularly effective antiemetic
An antiemetic is a drug that is effective against vomiting and nausea. Antiemetics are typically used to treat motion sickness and the side effects of opioid analgesics, general anaesthetics, and chemotherapy directed against cancer. They may ...
that had an inhibitory effect on morning sickness. On 1 October 1957, the company launched thalidomide and began marketing it under the trade name Contergan. It was proclaimed a "wonder drug" for insomnia
Insomnia, also known as sleeplessness, is a sleep disorder in which people have trouble sleeping. They may have difficulty falling asleep, or staying asleep as long as desired. Insomnia is typically followed by daytime sleepiness, low energy, ...
, coughs, colds and headaches.
During that period, the use of medications during pregnancy was not strictly controlled, and drugs were not thoroughly tested for potential harm to the fetus
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
.[ 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
The placenta is a temporary embryonic and later fetal organ that begins developing from the blastocyst shortly after implantation. It plays critical roles in facilitating nutrient, gas and waste exchange between the physically separate materna ...
and harm the developing fetus. There soon appeared reports of abnormalities in children being born to mothers using thalidomide. In late 1959, it was noticed that peripheral neuritis
Peripheral neuropathy, often shortened to neuropathy, is a general term describing disease affecting the peripheral nerves, meaning nerves beyond the brain and spinal cord. Damage to peripheral nerves may impair sensation, movement, gland, or o ...
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.
While initially considered safe, the drug was responsible for teratogenic
Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...
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 thalidomide led to the death of approximately 2,000 children and serious birth defects in more than 10,000 children, with over half of them in West Germany. The regulatory authorities in East Germany
East Germany, officially the German Democratic Republic (GDR; german: Deutsche Demokratische Republik, , DDR, ), was a country that existed from its creation on 7 October 1949 until its dissolution on 3 October 1990. In these years the state ...
never approved 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 were tested for toxicity on rodents only, as was usual at the time.
In the UK, the British pharmaceutical company The Distillers Company
The Distillers Company Limited was a leading Scottish drinks and pharmaceutical company and, at one time, a constituent of the FTSE 100 Index. It was taken over by Guinness & Co. (now part of Diageo) in 1986 in a transaction which was later fou ...
(Biochemicals) Ltd, a subsidiary of Distillers Co. Ltd (now part of Diageo plc
Diageo plc () is a multinational alcoholic beverage company, with its headquarters in London, England. It operates from 132 sites around the world. It was the world's largest distiller before being overtaken by Kweichow Moutai of China in 201 ...
), marketed thalidomide throughout the UK, Australia and New Zealand, under the brand name Distaval, as a remedy for morning sickness. 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." Globally, 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 US, representatives from Chemie Grünenthal approached Smith, Kline & French
Smith, Kline & French (SKF) was an American pharmaceutical company.
History
In 1830, John K. Smith opened a drugstore in Philadelphia, and his younger brother, George, joined him in 1841 to form John K Smith & Co. In 1865, Mahlon Kline joined ...
(SKF), now GlaxoSmithKline
GSK plc, formerly GlaxoSmithKline plc, is a British multinational pharmaceutical and biotechnology company with global headquarters in London, England. Established in 2000 by a merger of Glaxo Wellcome and SmithKline Beecham. GSK is the ten ...
(GSK), with a request to market and distribute the drug in North America. A memorandum, rediscovered in 2010 in the archives of the FDA, shows that in 1956–57, as part of its in-licensing approach, Smith, Kline and French conducted animal tests and ran a clinical trial of the drug in the US involving 875 people, including pregnant women. In 1956, researchers involved in clinical trials at SKF 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. In 1958, Chemie Grünenthal reached an agreement with William S Merrell Company in Cincinnati, Ohio ( later Richardson-Merrell, now part of Sanofi
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
), to market and distribute thalidomide throughout the US.
The US 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-Merrell
Marion Merrell Dow and its predecessor Marion Laboratories was a U.S. pharmaceutical company based in Kansas City, Missouri from 1950 until 1996.
The company specialized in bringing to market drugs that had been discovered but unmarketed by other ...
had applied for its approval in September 1960. The official in charge of the FDA review, Frances Oldham Kelsey
Frances Kathleen Kelsey ( Oldham; July 24, 1914 – August 7, 2015) was a Canadian-American pharmacologist and physician. As a reviewer for the U.S. Food and Drug Administration (FDA), she refused to authorize thalidomide for market because sh ...
, 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 US. 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 U.S.
In Canada, the history of thalidomide dates back to April 1961. There were many different forms sold, with the most common variant being called 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 1962, that both drugs were banned from the Canadian market by the FDD and, soon afterward, physicians were warned to destroy their supplies.][
]
Leprosy treatment
In 1964, Israeli physician Jacob Sheskin administered thalidomide to a patient critically ill with leprosy
Leprosy, also known as Hansen's disease (HD), is a long-term infection by the bacteria ''Mycobacterium leprae'' or ''Mycobacterium lepromatosis''. Infection can lead to damage of the nerves, respiratory tract, skin, and eyes. This nerve damag ...
. The patient exhibited erythema nodosum leprosum
Erythema nodosum (EN) is an inflammatory condition characterized by inflammation of the fat cells under the skin, resulting in tender red nodules or lumps that are usually seen on both shins. It can be caused by a variety of conditions, and typi ...
(ENL), a painful skin condition, one of the complications of leprosy. The treatment was attempted despite the ban on thalidomide's use, and 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. 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
Celgene Corporation is a pharmaceutical company that makes cancer and immunology drugs. Its major product is Revlimid (lenalidomide), which is used in the treatment of multiple myeloma, and also in certain anemias. The company is incorporated in ...
, 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
The World Health Organization (WHO) is a specialized agency of the United Nations responsible for international public health. The WHO Constitution states its main objective as "the attainment by all peoples of the highest possible level of h ...
(WHO) stated that it did not recommend thalidomide for leprosy due to the difficulty of adequately controlling its use, and due to the availability of clofazimine
Clofazimine, sold under the brand name Lamprene, is a medication used together with rifampicin and dapsone to treat leprosy. It is specifically used for multibacillary (MB) leprosy and erythema nodosum leprosum. Evidence is insufficient to sup ...
.
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
Moses Judah Folkman (February 24, 1933 – January 14, 2008) was an American medical scientist best known for his research on tumor angiogenesis, the process by which a tumor attracts blood vessels to nourish itself and sustain its existence. He ...
pioneered studies into the role of angiogenesis
Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature by processes of sprouting and splitting ...
(the proliferation and growth of blood vessels) in the development of cancer, and in the early 1970s had shown that solid tumors
A neoplasm () is a type of abnormal and excessive growth of tissue. The process that occurs to form or produce a neoplasm is called neoplasia. The growth of a neoplasm is uncoordinated with that of the normal surrounding tissue, and persists ...
could not expand without it. In 1993 he surprised the scientific world by hypothesizing the same was true of blood cancers
Tumors of the hematopoietic and lymphoid tissues (American English) or tumours of the haematopoietic and lymphoid tissues (British English) are tumors that affect the blood, bone marrow, lymph, and lymphatic system. Because these tissues are all ...
, and the next year he published work showing that a biomarker
In biomedical contexts, a biomarker, or biological marker, is a measurable indicator of some biological state or condition. Biomarkers are often measured and evaluated using blood, urine, or soft tissues to examine normal biological processes, p ...
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 An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels ( angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical d ...
, 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
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
patients.[
It was also evaluated whether thalidomide can be combined with melphalan and prednisone for patients with multiple myeloma. This combination of drugs probably results in an increase of the overall survival.
]
Society and culture
Birth defect crisis
In the late 1950s and early 1960s, more than 10,000 children in 46 countries were born with deformities, such as phocomelia
Phocomelia is a condition that involves malformations of human arms and legs. Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide scandal, thalidomide and from genes, genetic inheritance.
Occu ...
, 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. Despite the side effects, thalidomide was sold in pharmacies in Canada until 1962.[
]
Notable cases
*Lorraine Mercer
Lorraine Mercer is a British thalidomide survivor, painter, lace maker, and carriage driver with the RDA.
Mercer was a representative of the global thalidomide community as a bearer of the Olympic Torch in 2012 for her country. Her chariot ...
MBE Mbe may refer to:
* Mbé, a town in the Republic of the Congo
* Mbe Mountains Community Forest, in Nigeria
* Mbe language, a language of Nigeria
* Mbe' language, language of Cameroon
* ''mbe'', ISO 639 code for the extinct Molala language
Molal ...
of the United Kingdom, born with phocomelia
Phocomelia is a condition that involves malformations of human arms and legs. Although many factors can cause phocomelia, the prominent roots come from the use of the drug thalidomide scandal, thalidomide and from genes, genetic inheritance.
Occu ...
of both arms and legs, is the only thalidomide survivor to carry the Olympic Torch.
*Thomas Quasthoff
Thomas Quasthoff (born 9 November 1959) is a German bass-baritone. Quasthoff has a range of musical interest from Bach cantatas, to lieder, and solo jazz improvisations. Born with severe birth defects caused by thalidomide, Quasthoff is , and has ...
, 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
Niko von Glasow (''né'' Brücher; born 1960) is a German film director and producer.
The founder and Artistic Director of Palladio Film, von Glasow began his training with Rainer Werner Fassbinder and then worked for many film directors includ ...
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.
* Mat Fraser, born with phocomelia of both arms, is an English rock musician, actor, writer and performance artist. He produced a 2002 television documentary "Born Freak", which looked at this historical tradition and its relevance to modern disabled performers. This work has become the subject of academic analysis in the field of disability studies.
*Sue Kent, born in 1963 with phocomelia of both arms, eight inches long, no thumbs, and seven fingers – three on one hand, four on the other - has appeared as a presenter on the BBC TV show "Gardener's World" since 2020, demonstrating her ability to garden using her feet and toes where others would use their hands.
Change in drug regulations
The disaster prompted many countries to introduce tougher rules for the testing and licensing of drugs, such as the 1962 Kefauver Harris Amendment
Carey Estes Kefauver (;
July 26, 1903 – August 10, 1963) was an American politician from Tennessee. A member of the Democratic Party, he served in the U.S. House of Representatives from 1939 to 1949 and in the Senate from 1949 until his d ...
(U.S.), 1965 Directive 65/65/EEC1 (E.U.), and the Medicines Act 1968
The Medicines Act 1968 is an Act of Parliament of the United Kingdom, more properly: An Act to make new provision with respect to medicinal products and related matters, and for purposes connected therewith. It governs the control of medicines for ...
(UK). 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.
Quality of life
In the 1960s, thalidomide was successfully marketed as a safer alternative to barbiturate
Barbiturates are a class of depressant drugs that are chemically derived from barbituric acid. They are effective when used medically as anxiolytics, hypnotics, and anticonvulsants, but have physical and psychological addiction potential as we ...
s. Due to a successful marketing campaign, thalidomide was widely used by pregnant women during the first trimester of pregnancy. However, thalidomide is a teratogenic
Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The related t ...
substance, and a proportion of children born during the 1960s had thalidomide embryopathy (TE). Of these babies born with TE, "about 40% of them died before their first birthday". The surviving individuals are now middle-aged and they report experiencing challenges (physical, psychological, and socioeconomic) related to TE.
Individuals born with TE frequently experience a wide variety of health problems secondary to their TE. These health conditions include both physical and psychological conditions. When compared to individuals of similar demographic profiles, those born with TE report less satisfaction with their quality of life and their overall health. Access to health care services can also be a challenge for these people, and women in particular have experienced difficulty in locating healthcare professionals who can understand and embrace their needs.
Brand names
Brand names include Contergan, Thalomid, Talidex, Talizer, Neurosedyn, Distaval and many others.
Research
Research efforts have been focused on determining how thalidomide causes birth defects and its other activities in the human body, efforts to develop safer analogs, and efforts to find further uses for thalidomide.
Thalidomide analogs
The exploration of the antiangiogenic An angiogenesis inhibitor is a substance that inhibits the growth of new blood vessels ( angiogenesis). Some angiogenesis inhibitors are endogenous and a normal part of the body's control and others are obtained exogenously through pharmaceutical d ...
and immunomodulatory activities of thalidomide has led to the study and creation of thalidomide analog
Analog or analogue may refer to:
Computing and electronics
* Analog signal, in which information is encoded in a continuous variable
** Analog device, an apparatus that operates on analog signals
*** Analog electronics, circuits which use analog ...
s. Celgene has sponsored numerous clinical trials with analogues to thalidomide, such as lenalidomide, that are substantially more powerful and have fewer side effects — except for greater myelosuppression
Bone marrow suppression also known as myelotoxicity or myelosuppression, is the decrease in production of cells responsible for providing immunity (leukocytes), carrying oxygen (erythrocytes), and/or those responsible for normal blood clotting (t ...
. In 2005, Celgene received FDA approval for lenalidomide (Revlimid) as the first commercially useful derivative. Revlimid is available only in a restricted distribution setting to avoid its use during pregnancy. Further studies are being conducted to find safer compounds with useful qualities. Another more potent analog, pomalidomide
Pomalidomide ( INN; marketed as Pomalyst in the US and Imnovid in the European Union and Russia) is a derivative of thalidomide marketed by Celgene. It is anti-angiogenic and also acts as an immunomodulator.
Pomalidomide was approved in Februa ...
, is now FDA approved. Additionally, apremilast
Apremilast, sold under the brand name Otezla among others, is a medication for the treatment of certain types of psoriasis and psoriatic arthritis. It may also be useful for other immune system-related inflammatory diseases. The drug acts as a se ...
was approved by the FDA in March 2014. These thalidomide analogs can be used to treat different diseases, or used in a regimen to fight two conditions.
Interest turned to pomalidomide
Pomalidomide ( INN; marketed as Pomalyst in the US and Imnovid in the European Union and Russia) is a derivative of thalidomide marketed by Celgene. It is anti-angiogenic and also acts as an immunomodulator.
Pomalidomide was approved in Februa ...
, a derivative
In mathematics, the derivative of a function of a real variable measures the sensitivity to change of the function value (output value) with respect to a change in its argument (input value). Derivatives are a fundamental tool of calculus. F ...
of thalidomide marketed by Celgene
Celgene Corporation is a pharmaceutical company that makes cancer and immunology drugs. Its major product is Revlimid ( lenalidomide), which is used in the treatment of multiple myeloma, and also in certain anemias. The company is incorporated i ...
. It is a very active anti-angiogenic agent [ and also acts as an ]immunomodulator
Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
. Pomalidomide was approved in February 2013 by the U.S. Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA) as a treatment for relapsed and refractory multiple myeloma
Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. Often, no symptoms are noticed initially. As it progresses, bone pain, an ...
. It received a similar approval from the European Commission
The European Commission (EC) is the executive of the European Union (EU). It operates as a cabinet government, with 27 members of the Commission (informally known as "Commissioners") headed by a President. It includes an administrative body o ...
in August 2013, and is expected to be marketed in Europe under the brand name Imnovid.
Clinical research
There is no conclusive evidence that thalidomide or lenalidomide is useful to bring about or maintain remission in Crohn's disease.
Thalidomide was studied in a Phase II trial for Kaposi's sarcoma
Kaposi's sarcoma (KS) is a type of cancer that can form masses in the skin, in lymph nodes, in the mouth, or in other organs. The skin lesions are usually painless, purple and may be flat or raised. Lesions can occur singly, multiply in a limit ...
, a rare soft-tissue cancer most commonly seen in the immunocompromised, that is caused by the Kaposi's sarcoma-associated herpesvirus
Kaposi's sarcoma-associated herpesvirus (KSHV) is the ninth known human herpesvirus; its formal name according to the International Committee on Taxonomy of Viruses (ICTV) is ''Human gammaherpesvirus 8'', or HHV-8 in short. Like other herpesvir ...
(KSHV).
* AIDS wasting syndrome, associated diarrhea
* Renal cell carcinoma
Renal cell carcinoma (RCC) is a kidney cancer that originates in the lining of the Proximal tubule, proximal convoluted tubule, a part of the very small tubes in the kidney that transport primary urine. RCC is the most common type of kidney cance ...
(RCC)
* Glioblastoma multiforme
Glioblastoma, previously known as glioblastoma multiforme (GBM), is one of the most aggressive types of cancer that begin within the brain. Initially, signs and symptoms of glioblastoma are nonspecific. They may include headaches, personality cha ...
* Prostate cancer
Prostate cancer is cancer of the prostate. Prostate cancer is the second most common cancerous tumor worldwide and is the fifth leading cause of cancer-related mortality among men. The prostate is a gland in the male reproductive system that sur ...
* Melanoma
Melanoma, also redundantly known as malignant melanoma, is a type of skin cancer that develops from the pigment-producing cells known as melanocytes. Melanomas typically occur in the skin, but may rarely occur in the mouth, intestines, or eye ( ...
* Colorectal cancer
Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel m ...
* Crohn's disease
Crohn's disease is a type of inflammatory bowel disease (IBD) that may affect any segment of the gastrointestinal tract. Symptoms often include abdominal pain, diarrhea (which may be bloody if inflammation is severe), fever, abdominal distension ...
* Rheumatoid arthritis
Rheumatoid arthritis (RA) is a long-term autoimmune disorder that primarily affects joints. It typically results in warm, swollen, and painful joints. Pain and stiffness often worsen following rest. Most commonly, the wrist and hands are involv ...
* Behcet's syndrome
* Breast cancer
Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a re ...
* Head and neck cancer
Head and neck cancer develops from tissues in the lip and oral cavity (mouth), larynx (throat), salivary glands, nose, sinuses or the skin of the face. The most common types of head and neck cancers occur in the lip, mouth, and larynx. Symptoms ...
* Ovarian cancer
Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different c ...
* Chronic heart failure
* Graft-versus-host disease
* Tuberculous meningitis
Tuberculous meningitis, also known as TB meningitis or tubercular meningitis, is a specific type of bacterial meningitis caused by the '' Mycobacterium tuberculosis'' infection of the meninges—the system of membranes which envelop the central ...
References
Further reading
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External links
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