Thalidomide

Absorption

The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. The mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours following a single dose from 50 to 400 mg. Patients with Hansen’s disease may have an increased bioavailability of thalidomide, although the clinical significance of this is unknown.
Due to its low aqueous solubility and thus low dissolution is the gastrointestinal tract, thalidomide's absorption is slow, with a tlag of 20-40 min. Therefore, thalidomide exhibits absorption rate-limited pharmacokinetics or "flip-flop" phenomenon. Following a single dose of 200 mg in healthy male subjects, cmax and AUC∞ were calculated to be 2.00 ± 0.55 mg/L and 19.80 ± 3.61 mg*h/mL respectively.

Toxicity

The oral LD50 in rats is 113 mg/kg and 2 g/kg in mouse.
Two-year carcinogenicity studies were conducted in male and female rats and mice. No compound-related tumorigenic effects were observed at the highest dose levels of 3,000 mg/kg/day to male and female mice (38-fold greater than the highest recommended daily human dose of 400 mg based upon body surface area [BSA]), 3,000 mg/kg/day to female rats (75-fold the maximum human dose based upon BSA), and 300 mg/kg/day to male rats (7.5-fold the maximum human dose based upon BSA).
Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (S. typhimurium and E. coli) reverse mutation assay, a Chinese hamster ovary cell (AS52/XPRT) forward mutation assay, and an in vivo mouse micronucleus test.
Fertility studies were conducted in male and female rabbits; no compound-related effects in mating and fertility indices were observed at any oral thalidomide dose level including the highest of 100 mg/kg/day to female rabbits and 500 mg/kg/day to male rabbits (approximately 5- and 25- fold the maximum human dose, respectively, based upon BSA). Testicular pathological and histopathological effects (classified as slight) were seen in male rabbits at dose levels ≥30 mg/kg/day (approximately 1.5-fold the maximum human dose based upon BSA).
There is no specific antidote for a thalidomide overdose. In the event of an overdose, the patient’s vital signs should be monitored and appropriate supportive care given to maintain blood pressure and respiratory status.

Description

Thalidomide is a glutamic acid derivative first synthesized in 1953 by Swiss Pharmaceuticals; however, due to lack of pharmacological effects, the development was discontinued. In 1954, Chemie Grünenthal, a German company, undertook the development of thalidomide and, in 1957, thalidomide was marketed as an anticonvulsant for the treatment of epilepsy. Since the drug caused drowsiness, it was also marketed as a sedative. Thalidomide was considered a safe and effective drug that caused deep sleep with no hangover, and by the end of the 1950s, 14 pharmaceutical firms were marketing the drug in countries of Europe, Asia, Australia, the Americas, and Africa. However, the drug was never approved for use in the United States due to concerns about the safety of the drug raised by Frances Kelsey, MD, a drug reviewer at Food and Drug Administration (FDA). The approval process was delayed due to her repeated requests for additional safety information from William S. Merrell Company, the licensee of Chemie Grünenthal that applied to market thalidomide in the United States. Dr Kelsey’s concerns were mostly related to thalidomideinduced neuropathy. Previous research had shown that drugs that irritated nerves in adult rabbits could have adverse effects on growth and cause deformities in fetal rabbits. During this time, the use of the drug became widespread and, because it was effective in alleviating morning sickness, it became popular among pregnant women. In 1961, two physicians, William G. McBride, MD of Australia and Widulind Lenz, MD of Germany, associated the increase in malformation of the limbs (phocomelia) and other congenital abnormalities with the use of thalidomide by pregnant women. By late 1961, birth defects in more than 12 000 children were associated with thalidomide use, which forced companies to withdraw the drug worldwide.
The birth defects were due to thalidomide teratogenecity: mainly phocomelia and malformation of ears, often accompanied by malformation of the internal organ. In 1965, an experimental use of thalidomide in patients with lepromatous leprosy proved to be effective in treating painful skin lesions that resulted from the inflammatory complications of leprosy. In fact, experimental use of thalidomide had been extended to a variety of diseases with various degrees of success, including refractory rheumatoid arthritis, Crohn’s disease, human immunodeficiency virus (HIV)-1 associated Kaposi’s sarcoma, cutaneous lupus, prostate cancer, and colorectal cancer. In 1998, the FDA approved Thalomid as a therapy for erythema nodosum leprosum (ENL), or leprosy. Subsequently in 2006, Thalomid in combination with dexamethasone was approved for treatment of multiple myeloma.

Description

Thalidomide has a tragic history: It was introduced in Germany in 1957 as a sedative and hypnotic and was marketed over the counter largely as a drug for treating morning sickness in pregnant women. In the following few years, about 10,000 infants worldwide were born with phocomelia, or limb malformation. Only half of the infants survived, and some of those who did had other defects in addition to limb deficiencies. The thalidomide disaster caused many countries to tighten drug approval regulations.
Thalidomide exists in two mirror-image forms: it is a racemic mixture of (R)- and (S)-enantiomers. The (R)-enantiomer, shown in the figure, has sedative effects, whereas the (S)-isomer is teratogenic. Under biological conditions, the isomers interconvert, so separating the isomers before use is ineffective.
More recently, thalidomide has proven useful for treating cancer and leprosy and is approved for these uses. But although more than 2000 papers have been written about its mechanism of teratogenic action, it was not until the past few years that this mechanism was established. In 2010, H. Handa and colleagues at the Tokyo Institute of Technology showed that its biological target is cereblon, a component of an E3 ubiquitin ligase complex. Earlier this year, N. H.?Thom?? and co-workers at the Friedrich Miescher Institute for Biomedical Research (Basel, Switzerland) determined the crystal structure of thalidomide bound to cereblon, which allowed them to characterize the mechanism.
Thalidomide was also the Molecule of the Week for May 17, 2010.
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The Uses of Thalidomide

Inhibits FGF-induced angiogenesis. Inhibits replication of human immunodeficiency virus type 1. Teratogenic sedative. There is now a growing clinical interest in Thalidomide, and it is introduced as an immunomodulatory agent used primarily in combination with dexamethasone to treat multiple myeloma.

What are the applications of Application

Thalidomide is a selective inhibitor of TNF alpha biosynthesis shown to have immunomodulatory and antiangeogenic activity

Background

A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, thalidomide was withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of inflammatory disorders and cancers. Thalidomide displays immunosuppressive and anti-angiogenic activity through modulating the release of inflammatory mediators like tumor necrosis factor-alpha (TNF-a) and other cytokine action. Due to severe teratogenicity, pregnancy must be excluded before the start of treatment and patients must enrol in the THALIDOMID Risk Evaluation and Mitigation Strategy (REMS) program to ensure contraception adherence.

Indications

Thalidomide is primarily used for the acute treatment and maintenance therapy to prevent and suppress the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL).

Pharmacokinetics

Thalidomide, originally developed as a sedative, is an immunomodulatory and anti-inflammatory agent with a spectrum of activity that is not fully characterized. However, thalidomide is believed to exert its effect through inhibiting and modulating the level of various inflammatory mediators, particularly tumor necrosis factor-alpha (TNF-a) and IL-6. Additionally, thalidomide is also shown to inhibit basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), suggesting a potential anti-angiogenic application of thalidomide in cancer patients.
Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: the (+)R enantiomer is effective against morning sickness, and the (?)S enantiomer is teratogenic. The enantiomers are interconverted to each other in vivo; hence, administering only one enantiomer will not prevent the teratogenic effect in humans .

Metabolism

Thalidomide appears to undergo primarily non-enzymatic hydrolysis in plasma to multiple metabolites, as the four amide bonds in thalidomide allow for rapid hydrolysis under physiological pH.
Evidences for enzymatic metabolism of thalidomide is mixed, as in vitro studies using rat liver microsome have detected 5-hydroxythalidomide (5-OH), a monohydroxylated metabolite of thalidomide catalyzed by the CYP2C19 enzyme, and the addition of omeprazole, a CYP2C19 inhibitor, inhibits the metabolism of thalidomide. 5-hydroxythalidomide (5-OH) has also been detected in the plasma of 32% of androgen-independent prostate cancer patients undergoing oral thalidomide treatment. However, significant interspecies difference in thalidomide metabolism has been noted, potentially signifying that animals like rats and rabbits rely on enzymatic metabolism of thalidomide more than human.