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alpha-phthalimidoglutarimide;N-Phthalimidoglutamic acid imide;N-Phthaloylglutamimide;N-Phthalylglutamic acid imide;thalidomide;Thalidomine USP26;

A piperidinyl isoindole originally introduced as a non-barbiturate hypnotic, but withdrawn from the market due to teratogenic effects. It has been reintroduced and used for a number of immunological and inflammatory disorders. Thalidomide displays immunosuppresive and anti-angiogenic activity. It inhibits release of tumor necrosis factor-alpha from monocytes, and modulates other cytokine action. [PubChem]

• Celgene corp

• Celgene
• IDT Australia Ltd.
• Penn Pharmaceutical Services Ltd.

Synthesis Reference	Not Available
General Reference	Not Available

Type	small molecule

Classes

Delta Lactams Piperidines Indoles and Indole Derivatives Benzoyl Derivatives Benzamides

Substructures

Delta Lactams Carboxylic Acids and Derivatives Amino Ketones Benzene and Derivatives Piperidines Indoles and Indole Derivatives Heterocyclic compounds Aromatic compounds Carboxamides and Derivatives Benzoyl Derivatives Benzamides Pyrrolines

IMMUNOSUPPRESSIVE 免疫抑制;

Indication	For the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). Also for use as maintenance therapy for prevention and suppression of the cutaneous manifestations of ENL recurrence.
Pharmacodynamics	Thalidomide is an immunomodulatory agent with a spectrum of activity that is not fully characterized. Thalidomide is racemic — it contains both left and right handed isomers in equal amounts: one enantiomer is effective against morning sickness, and the other is teratogenic. The enantiomers are converted to each other in vivo. That is, if a human is given D-thalidomide or L-thalidomide, both isomers can be found in the serum. Hence, administering only one enantiomer will not prevent the teratogenic effect in humans.
Mechanism of action	In patients with erythema nodosum leprosum (ENL) the mechanism of action is not fully understood. Available data from in vitro studies and preliminary clinical trials suggest that the immunologic effects of this compound can vary substantially under different conditions, but may be related to suppression of excessive tumor necrosis factor-alpha (TNF-a) production and down-modulation of selected cell surface adhesion molecules involved in leukocyte migration. For example, administration of thalidomide has been reported to decrease circulating levels of TNF-a in patients with ENL, however, it has also been shown to increase plasma TNF-a levels in HIV-seropositive patients. As a cancer treatment, the drug may act as a VEGF inhibitor.
Absorption	The absolute bioavailability has not yet been characterized in human subjects due to its poor aqueous solubility. In studies of both healthy volunteers and subjects with Hansen’s disease, the mean time to peak plasma concentrations (Tmax) ranged from 2.9 to 5.7 hours indicating that thalidomide is slowly absorbed from the gastrointestinal tract.
Volume of distribution	Not Available
Protein binding	55% and 66% for the (+)R and (−)S enantiomers, respectively.
Metabolism	Thalidomide itself does not appear to be hepatically metabolized to any large extent, but appears to undergo non-enzymatic hydrolysis in plasma to multiple metabolites. Thalidomide may be metabolized hepatically by enzymes of the cytochrome P450 enzyme system. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate. Important The metabolism module of DrugBank is currently in beta. Questions or suggestions? Please contact us. Substrate Enzymes Product Thalidomide Cytochrome P450 2C19 cis, trans-5'-Hydroxythalidomide Details Thalidomide Cytochrome P450 2C19 5-Hydroxythalidomide Details Thalidomide Cytochrome P450 1A1 Cytochrome P450 1A2 Cytochrome P450 2C19 Cytochrome P450 2E1 Arene oxide Details
Route of elimination	Thalidomide itself has less than 0.7% of the dose excreted in the urine as unchanged drug.
Half life	The mean half-life of elimination ranges from approximately 5 to 7 hours following a single dose and is not altered upon multiple dosing.
Clearance	Not Available
Toxicity	The R-configuration and the S-configuration are more toxic individually than the racemic mixture. The LD50 could not be established in mice for racemic thalidomide, whereas LD50 values for the R and S configurations are reported to be 0.4 to 0.7 g/kg and 0.5 to 1.5 g/kg, respectively.
Affected organisms	Humans and other mammals
Pathways	Not Available

Properties
State	solid
Experimental Properties	Property Value Source melting point 270 °C PhysProp water solubility 545 mg/L (at 25 °C) BUDAVARI,S ET AL. (1996) logP 0.33 HANSCH,C ET AL. (1995)
Predicted Properties	Property Value Source water solubility 2.55e+00 g/l ALOGPS logP 0.42 ALOGPS logP 0.016 ChemAxon logS -2 ALOGPS pKa (strongest acidic) 11.59 ChemAxon pKa (strongest basic) -6.4 ChemAxon physiological charge 0 ChemAxon hydrogen acceptor count 4 ChemAxon hydrogen donor count 1 ChemAxon polar surface area 83.55 ChemAxon rotatable bond count 1 ChemAxon refractivity 64.32 ChemAxon polarizability 24.42 ChemAxon

Drug	Interaction
Abatacept	Thalidomide may increase the adverse effects of Abatacept. Increased risk of serious infection. Concomitant therapy should be avoided.
Amikacin	Thalidomide increases the renal toxicity of the aminoglycoside
Anakinra	Thalidomide may increase the adverse effects of Anakinra. Increased risk of serious infection. Concomitant therapy should be avoided.
Dexamethasone	Increased risk of dermatologic adverse effects and venous thromboembolic events (VTE). Consider VTE prophylaxis during concomitant therapy and monitor for adverse dematologic effects.
Gentamicin	Thalidomide increases the renal toxicity of the aminoglycoside
Natalizumab	Thalidomide may increase the adverse effects of Natalizumab. Concurrent administration should be avoided due to increased risk of infection.
Netilmicin	Thalidomide increases the renal toxicity of the aminoglycoside
Rilonacept	Thalidomide may increase the adverse effects of Rilonacept. Increased risk of serious infection. Concomitant therapy should be avoided.
Tobramycin	Thalidomide increases the renal toxicity of the aminoglycoside
Trastuzumab	Trastuzumab may increase the risk of neutropenia and anemia. Monitor closely for signs and symptoms of adverse events.
Triprolidine	The CNS depressants, Triprolidine and Thalidomide, may increase adverse/toxic effects due to additivity. Monitor for increased CNS depressant effects during concomitant therapy.

Not Available