E3 Ligase; TNF-alpha

Thalidomide is a potent teratogen causing dysmelia (stunted limb growth) in humans. Researchers have demonstrated that orally administered thalidomide is an inhibitor of angiogenesis induced by basic fibroblast growth factor in a rabbit cornea micropocket assay. Experiments including the analysis of thalidomide analogs revealed that the antiangiogenic activity correlated with the teratogenicity but not with the sedative or the mild immunosuppressive properties of thalidomide. Electron microscopic examination of the corneal neovascularization of thalidomide-treated rabbits revealed specific ultrastructural changes similar to those seen in the deformed limb bud vasculature of thalidomide-treated embryos. These experiments shed light on the mechanism of thalidomide's teratogenicity and hold promise for the potential use of thalidomide as an orally administered drug for the treatment of many diverse diseases dependent on angiogenesis.[1]

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In three experiments, thalidomide (200 mg/kg) reduced the amount of vascularized cornea in rabbits by a range of 30% to 51%, with a median reduction of 36%. [1]

In the 1950s, the drug thalidomide, administered as a sedative to pregnant women, led to the birth of thousands of children with multiple defects. Despite the teratogenicity of thalidomide and its derivatives lenalidomide and pomalidomide, these immunomodulatory drugs (IMiDs) recently emerged as effective treatments for multiple myeloma and 5q-deletion-associated dysplasia. IMiDs target the E3 ubiquitin ligase CUL4-RBX1-DDB1-CRBN (known as CRL4(CRBN)) and promote the ubiquitination of the IKAROS family transcription factors IKZF1 and IKZF3 by CRL4(CRBN). Here we present crystal structures of the DDB1-CRBN complex bound to thalidomide, lenalidomide and pomalidomide. The structure establishes that CRBN is a substrate receptor within CRL4(CRBN) and enantioselectively binds IMiDs. Using an unbiased screen, we identified the homeobox transcription factor MEIS2 as an endogenous substrate of CRL4(CRBN). Our studies suggest that IMiDs block endogenous substrates (MEIS2) from binding to CRL4(CRBN) while the ligase complex is recruiting IKZF1 or IKZF3 for degradation. This dual activity implies that small molecules can modulate an E3 ubiquitin ligase and thereby upregulate or downregulate the ubiquitination of proteins. [6]

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Researchers have examined the mechanism of thalidomide inhibition of lipopolysaccharide (LPS)-induced tumor necrosis factor alpha (TNF-alpha) production and found that the drug enhances the degradation of TNF-alpha mRNA. Thus, the half-life of the molecule was reduced from approximately 30 to approximately 17 min in the presence of 50 micrograms/ml of thalidomide. Inhibition of TNF-alpha production was selective, as other LPS-induced monocyte cytokines were unaffected. Pentoxifylline and dexamethasone, two other inhibitors of TNF-alpha production, are known to exert their effects by means of different mechanisms, suggesting that the three agents inhibit TNF-alpha synthesis at distinct points of the cytokine biosynthetic pathway. These observations provide an explanation for the synergistic effects of these drugs. The selective inhibition of TNF-alpha production makes thalidomide an ideal candidate for the treatment of inflammatory conditions where TNF-alpha-induced toxicities are observed and where immunity must remain intact[3].

THP-1 cells, A549 cells, and KYSE30 cells are cultured in RPMI-1640 Medium with 10% fetal bovine serum supplement and kept at 37 °C in a 5% CO2 and 95% room air environment. A single dose of 4 Gy 6-MV X-rays is used to irradiate THP-1 cells, and the cells are then treated for 48 hours with or without medium containing thalidomide 0.2 μmol/mL). Based on the preliminary results[2,] the concentration of Thalidomide is chosen.

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Thalidomide selectively inhibits the production of human monocyte tumor necrosis factor alpha (TNF-alpha) when these cells are triggered with lipopolysaccharide and other agonists in culture. 40% inhibition occurs at the clinically achievable dose of the drug of 1 micrograms/ml. In contrast, the amount of total protein and individual proteins labeled with [35S]methionine and expressed on SDS-PAGE are not influenced. The amounts of interleukin 1 beta (IL-1 beta), IL-6, and granulocyte/macrophage colony-stimulating factor produced by monocytes remain unaltered. The selectivity of this drug may be useful in determining the role of TNF-alpha in vivo and modulating its toxic effects in a clinical setting.[2]

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Although thalidomide (Thal) was initially used to treat multiple myeloma (MM) because of its known antiangiogenic effects, the mechanism of its anti-MM activity is unclear. These studies demonstrate clinical activity of Thal against MM that is refractory to conventional therapy and delineate mechanisms of anti-tumor activity of Thal and its potent analogs (immunomodulatory drugs [IMiDs]). Importantly, these agents act directly, by inducing apoptosis or G1 growth arrest, in MM cell lines and in patient MM cells that are resistant to melphalan, doxorubicin, and dexamethasone (Dex). Moreover, Thal and the IMiDs enhance the anti-MM activity of Dex and, conversely, are inhibited by interleukin 6. As for Dex, apoptotic signaling triggered by Thal and the IMiDs is associated with activation of related adhesion focal tyrosine kinase. These studies establish the framework for the development and testing of Thal and the IMiDs in a new treatment paradigm to target both the tumor cell and the microenvironment, overcome classical drug resistance, and achieve improved outcome in this presently incurable disease.[4]

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The efficacy of thalidomide (alpha-phthalimido-glutarimide) therapy in leprosy patients with erythema nodosum leprosum is thought to be due to inhibition of tumor necrosis factor alpha. In other diseases reported to respond to thalidomide, the mechanism of action of the drug is unclear. We show that thalidomide is a potent costimulator of primary human T cells in vitro, synergizing with stimulation via the T cell receptor complex to increase interleukin 2-mediated T cell proliferation and interferon gamma production. The costimulatory effect is greater on the CD8+ than the CD4+ T cell subset. The drug also increases the primary CD8+ cytotoxic T cell response induced by allogeneic dendritic cells in the absence of CD4+ T cells. Therefore, human T cell costimulation can be achieved pharmacologically with thalidomide, and preferentially in the CD8+ T cell subset [5].

Mice: For the experiments, a total of 24 WT C57BL/6 mice are divided into 4 groups (n = 6 in each group): a control group, an irradiated group, an irradiated group plus Thalidomide, and a Thalidomide only group. The experiment uses 100 mg/kg of Thalidomide based on the preliminary findings. In a DMSO vehicle, thalidomide is dissolved. Every other day starting on day 1 for six treatments, the treatment group is gavaged with the recommended dose of thalidomide in 200 μL. 200 μL of 0.1% DMSO-containing saline is all that is given to the control mice. For the analysis, the lungs are removed 12 weeks after the radiation treatment. For the experiments, a total of 20 Nrf2-/- mice are divided into 4 groups at random (n = 5 per group). The same as with WT C57BL/6 mice, Nrf2-/- mice undergo the same experimental procedures. For the following experiments, 30 WT C57BL/6 mice are additionally randomly assigned to 5 groups (n = 6 in each group): a control group, an irradiated group, a group irradiated along with CDDO-Me and Thalidomide, a group irradiated along with CDDO-Me, and a group irradiated along with Thalidomide. The experimental CDDO-Me and Thalidomide doses are chosen to be 600 ng and 100 mg/kg, respectively. Every other day starting on day 1, for a total of six times, the treatment group is gavaged with the recommended dose of CDDO-Me or thalidomide in 200 μL. For the combined group receiving CDDO-Me and thalidomide, 200 L of CDDO-Me is administered by gavage every other day starting on day 1 for six treatments. Every other day starting on day 2 for six treatments, thalidomide is administered by gavage in 200 μL .

Absorption, Distribution and Excretion
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.
Thalidomide is primarily excreted in urine as hydrolytic metabolites since less than 1% of the parent form is detected in the urine. Fecal excretion of thalidomide is minimal.
The volume of distribution of thalidomide is difficult to determine due to spontaneous hydrolysis and chiral inversion, but it is estimated to be 70-120 L.
The oral clearance of thalidomide is 10.50 ± 2.10 L/h.
... Thalidomide given orally to rats was poorly absorbed.
In animal studies, high concentrations of thalidomide were found in the gastrointestinal tract, liver, and kidney; and lower concentrations were found in the muscle, brain, and adipose tissue. Thalidomide crosses the placenta. It is not known whether thalidomide is present in the ejaculate of males.
Thalidomide has a renal clearance of 1.15 mL per minute; less than 0.7% of the total dose is excreted unchanged.
... The present study determined the bioequivalence and pharmacokinetics of ... commercial and clinical trial thalidomide formulations and the Brazillian Tortuga formulation in an open label, single dose, three-way crossover design. ... The terminal rate constant for the Tortuga formulation was significantly less, giving rise to a terminal half-life of 15 hr compared to about 5-6 hr in the /Commercial/ formulations. ... Extent of absorption, as measured by AUC0-infinity was approx equal for all three formulations. Terminal half-life for Tortuga was two to three times longer than compared to the /commercial/ formulations and is clear evidence for absorption rate limitations. The two ... /commercial/ formulations showed similar pharmacokinetic parameters with profiles that were best described by one compartment model with first order absorption and elimination. ...
For more Absorption, Distribution and Excretion (Complete) data for THALIDOMIDE (20 total), please visit the HSDB record page.

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Metabolism / Metabolites
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.
Studies on thalidomide metabolism in humans have not been done. In animals, nonenzymatic hydrolytic cleavage appears to be the main pathway of degradation, producing seven major and at least five minor hydrolysis products. Thalidomide may be metabolized hepatically by the enzymes of the cytochrome p450 enzyme system. Thalidomide does not appear to induce or inhibit its own metabolism. However, it may interfere with enzyme induction caused by other compounds. The end product of metabolism, phthalic acid, is excreted as a glycine conjugate.
The chiral inversion and hydrolysis of thalidomide and the catalysis by bases and human serum albumin were investigated by /utilizing/ a stereoselective HPLC assay. Chiral inversion was catalyzed by albumin, hydroxyl ions, phosphate and amino acids. Basic amino acids (arginine and lysine) had a superior potency in catalyzing chiral inversion compared to acid and neutral ones. The chiral inversion of thalidomide is thus subject to specific and general base catalysis and it is suggested that the ability of HSA to catalyze the reaction is due to basic groups of the amino acids arginine and lysine and not to a single catalytic site on the macromolecule. The hydrolysis of thalidomide was also base catalyzed. ... Albumin had no effect on hydrolysis and there was no difference between the catalytic potencies of acidic, neutral and base amino acids. ... Chiral inversion is deduced to occur by electrophilic substitution involving specific and general base catalysis, whereas hydrolysis is thought to occur by nucleophilic substitution involving specific and general base as well as nucleophilic catalysis. As nucleophilic attack is sensitive to steric properties of the catalyst, steric hindrance might be the reason albumin is not able to catalyze hydrolysis. (1)H NMR experiments revealed that the three teratogenic metabolites of thalidomide, in sharp contrast to the drug itself had complete chiral stability. This leads to the speculation that, were some enantioselectivity to exist in the teratogenicity of thalidomide, it could result from fast hydrolysis to chirally stable teratogenic metabolites.
Thalidomide has been shown to be an inhibitor of angiogenesis in a rabbit cornea micropocket model; however, it has failed to demonstrate this activity in other models. These results suggest that the anti-angiogenic effects of thalidomide may only be observed following metabolic activation of the compound. This activation process may be species specific, similar to the teratogenic properties associated with thalidomide. Using a rat aorta model and human aortic endothelial cells, we co-incubated thalidomide in the presence of either human, rabbit, or rat liver microsomes. These experiments demonstrated that thalidomide inhibited microvessel formation from rat aortas and slowed human aortic endothelial cell proliferation in the presence of human or rabbit microsomes, but not in the presence of rat microsomes. In the absence of microsomes, thalidomide had no effect on either microvessel formation or cell proliferation, thus demonstrating that a metabolite of thalidomide is responsible for its anti-angiogenic effects and that this metabolite can be formed in both humans and rabbits, but not in rodents. /There are five primary metabolites of thalidomide [4-OH-thalidomide, 3-OH-thalidomide, 39-OH-thalidomide, 49-OH-thalidomide, and 59-OH-thalidomide], and the antiangiogenic property could be the result of either of these compounds, or of an intermediate. Also, thalidomide undergoes rapid spontaneous hydrolysis in aqueous solutions at a pH of 6.0 or greater to form three primary products [4-phthalimidoglutaramic acid, 2-phthalimidoglutaramic acid, and a-(o-carboxybenzamido) glutarimide] and eight minor products. Furthermore, each of the five metabolites of the parent compound undergoes similar hydrolysis./
Three CD-1 mice were dosed orally with 3000 mg/kg thalidomide in 1% carboxymethylcellulose daily for three days and plasma samples were obtained 2, 4 and 6 hours postdose on the third day. Extracts of mouse plasma from thalidomide treated mice contained at least four components that absorbed at 230 nm, not observed in control plasma extracts. The first two components did not match any standards and may represent other metabolites, possibly hydrolysis products of thalidomide. The second pair of components closely matched standards for 4-hydroxythhalidomide and thalidomide respectively.
For more Metabolism/Metabolites (Complete) data for THALIDOMIDE (7 total), please visit the HSDB record page.
At the present time, the exact metabolic route and fate of thalidomide is not known in humans. 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. In a repeat dose study in which THALOMID™ (thalidomide) 200 mg was administered to 10 healthy females for 18 days, thalidomide displayed similar pharmacokinetic profiles on the first and last day of dosing. This suggests that thalidomide does not induce or inhibit its own metabolism.
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.

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Biological Half-Life
The half-life of thalidomide in healthy male subjects after a single dose of 200 mg is 6.17 ± 2.56 h.
... The pharmacokinetics and hemodynamic effects of two oral doses of thalidomide (100 and 200 mg) were investigated, using a randomized two period crossover design, in a group of asymptomatic male HIV seropositive subjects. Thalidomide pharmacokinetics were linear at the doses studied, and were best described by a one compartment model with first order absorption and elimination processes. The drug was rapidly absorbed with a mean absorption half life of 0.95 hr (range 0.16-2.49 hr) and 1.19 hr (0.33-3.53 hr) after 100 and 200 mg doses, respectively. The corresponding Cmax values were 1.15 +/-0.24 ug/mL (100 mg) and 1.92 +/- 0.47- ug/mL (200 mg; p<0.001) which were achieved (Tmax) at 2.5 +/-1.5 hr and 3.3 +/-1.4 hr, respectively. Plasma concn of thalidomide declined thereafter, in a log linear manner, with elimination half lives of 4.6+/-1.2 hr (100 mg) and 5.3+/-2.2 hr -(200 mg). The apparent volumes of distribution (Vdss/F) were 69.9+/-1.56 L (100 mg) and 82.7+/-34.9 L (200 mg) while total body clearances (C1F) were 10.4+/-2.1 and 10.8+/- 1.7 L/hr, respectively. ...
The mean elimination half-life of thalidomide following a single 200-mg oral dose ranges from 3-6.7 hours and the elimination half-life appears to be similar following multiple doses of the drug. In a study in healthy adults who received a single 50-, 200-, or 400-mg oral dose of the drug, the mean elimination half-life of thalidomide was 5.5, 5.5, or 7.3 hours, respectively. The mean elimination half-life of thalidomide was 6.9 hours in adults with leprosy who received a single 400-mg oral dose and 4.6-6.5 hours in HIV-infected adults who received a single 100- to 300-mg dose.

Toxicity Summary
IDENTIFICATION AND USE: Thalidomide is a white to off-white crystalline powder. Thalidomide is an immunomodulatory agent with anti-inflammatory, antiangiogenic, and sedative and hypnotic activity. It is used for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). It is also used as maintenance therapy for prevention and suppression of the cutaneous manifestations of erythema nodosum leprosum recurrence. It is used in combination with dexamethasone for the treatment of patients with newly diagnosed multiple myeloma. HUMAN EXPOSURE AND TOXICITY: Overdosage of thalidomide may cause prolonged sleep as a result of the drug's sedative and hypnotic effects, but fatalities are unlikely since the drug does not cause respiratory depression. In 3 reported suicide attempts involving deliberate ingestion of up to 14.4 g of thalidomide, all individuals recovered without reported sequelae. Thalidomide is a known human teratogen. The severe malformation induced by thalidomide may involve defects of the limbs, axial skeleton, head and face, eyes, ears, tongue, teeth, central nervous, respiratory, cardiovascular, and genitourinary systems, and the gastrointestinal tract. The neurological complications may include severe mental retardation secondary to sensory deprivation. Thus, thalidomide is contraindicated during pregnancy. Thalidomide is also known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (> or =10%) and potentially severe adverse reaction of treatment with thalidomide that may be irreversible. Seizures have been reported, including tonic-clonic (grand mal) seizures. Serious dermatologic reactions including Stevens-Johnson syndrome and toxic epidermal necrolysis, which may be fatal, have also been reported. The use of thalidomide in multiple myeloma patients causes an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. ANIMAL STUDIES: In an acute toxicity study, guinea pigs administered a 650 mg/kg oral dose became quiet and sedated. Two-year carcinogenicity studies were conducted in male and female mice, male and female rats. No compound-related tumorigenic effects were observed at the highest dose levels in male and female mice (9 to 14-fold human exposure), and male rats (12-fold human exposure). In female rats, a tumorigenic effect was not observed at 300 mg/kg/day (16-fold human exposure). In another carcinogenicity study, 56 adult beagle dogs were orally administered thalidomide for 53 weeks. There were no deaths during the study. There was no gross and histopathologic evidence of any tumors. A large number of reproductive studies have shown that thalidomide is a potent teratogen. Cynomolgus monkeys were orally administered thalidomide at 15 or 20 mg/kg-d on days 26-28 of gestation, and fetuses were examined on day 100-102 of gestation. Limb defects such as micromelia/amelia, paw/foot hyperflexion, polydactyly, syndactyly, and brachydactyly were observed in seven of eight fetuses. The teratogenicity of thalidomide in rats was investigated after a single maternal intravenous injection during the organogenesis period. Thalidomide induced skeletal deformities of thoracic ribs and of the spinal column in fetuses upon maternal administration of the drug. Deformities of the eyeball in fetuses were induced by the maternal administration of the drug on day 10 and 12. A single dose (500 mg/kg) of thalidomide was administered orally to pregnant rabbits in various stages of organogenesis. Head anomalies in fetuses were induced at a high frequency by the maternal administration of thalidomide on day 7. Microphthalmia in fetuses was observed with a single administration from day 7 to 12 of gestation. Contracture of forearms and club foot in fetuses resulted from the maternal administration of thalidomide on day 8 or 9 of gestation, respectively. With a single administration on day 8 or 9 of gestation, kinky tail in fetuses resulted, and brachyury was observed with a high frequency from day 8 to 11 of gestation. Skeletal anomalies such as fusion or displacement of coccygeal vertebral bodies were observed at a high frequency with a single treatment from day 8 to 10 of gestation. Among the internal anomalies observed was abnormal lobation of the lung, and abnormal lobation of the liver, cardiovascular anomalies. 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. Thalidomide was neither mutagenic nor genotoxic in the following assays: the Ames bacterial (Salmonella typhimurium and Escherichia coli) reverse mutation assay, a Chinese hamster ovary cell forward mutation assay, and an in vivo mouse micronucleus test.
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.

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Toxicity Data
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.

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Interactions
Thalidomide has been reported to enhance the sedative effects of some drugs, including barbiturates, chlorpromazine, and reserpine, and may potentiate the somnolence caused by alcohol.
Because of the potential for additive effects, drugs known to be associated with peripheral neuropathy (e.g., certain antiretroviral agents (e.g., didanosine), certain antineoplastic agents (e.g., paclitaxel; platinum-containing drugs such as cisplatin; vinca alkaloids such as vincristine)) should be used with caution in patients receiving thalidomide.
Use of these medications /carbamazepine or griseofulvin or human immunodeficiency virus (HIV)-protease inhibitors or rifabutin or rifampin/ with hormonal contraceptive agents may reduce the effectiveness of the contraception; women requiring treatment with one or more of these medications must abstain from heterosexual intercourse or use two other effective or highly effective methods of contraception.
Erythropoietic agents, or other agents that may increase the risk of thromboembolism, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving thalidomide with dexamethasone.
For more Interactions (Complete) data for THALIDOMIDE (17 total), please visit the HSDB record page.

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Non-Human Toxicity Values
LD50 Rat oral 113 mg/kg
LD50 Rat dermal 1550 mg/kg
LD50 Mouse oral 2000 mg/kg

[1]. Proc Natl Acad Sci U S A. 1994 Apr 26;91(9):4082-5.

[2]. J Exp Med . 1991 Mar 1;173(3):699-703.

[3]. J Exp Med . 1993 Jun 1;177(6):1675-80.

[4]. Blood . 2000 Nov 1;96(9):2943-50.

[5]. J Exp Med . 1998 Jun 1;187(11):1885-92.

[6]. Nature . 2014 Aug 7;512(7512):49-53.

Therapeutic Uses
Angiogenesis Inhibitors; Immunosuppressive Agents; Leprostatic Agents; Teratogens
Thalomid in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma (MM). /Included in US product label/
Thalomid is indicated for the acute treatment of the cutaneous manifestations of moderate to severe erythema nodosum leprosum (ENL). /Included in US product label/
Thalomid is also indicated as maintenance therapy for prevention and suppression of the cutaneous manifestations of erythema nodosum leprosum (ENL) recurrence. /Included in US product label/
For more Therapeutic Uses (Complete) data for THALIDOMIDE (17 total), please visit the HSDB record page.

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Drug Warnings
/BOXED WARNING/ WARNING: EMBRYO-FETAL TOXICITY. If thalidomide is taken during pregnancy, it can cause severe birth defects or embryo-fetal death. Thalidomide should never be used by females who are pregnant or who could become pregnant while taking the drug. Even a single dose (1 capsule (regardless of strength)) taken by a pregnant woman during her pregnancy can cause severe birth defects. Because of this toxicity and in an effort to make the chance of embryo-fetal exposure to Thalomid (thalidomide) as negligible as possible, Thalomid (thalidomide) is approved for marketing only through a special restricted distribution program: Thalomid REMS program, approved by the Food and Drug Administration. This program was formerly known as the "System for Thalidomide Education and Prescribing Safety (S.T.E.P.S. program)".
/BOXED WARNING/ WARNING: VENOUS THROMBOEMBOLISM. The use of Thalomid (thalidomide) in multiple myeloma results in an increased risk of venous thromboembolism, such as deep venous thrombosis and pulmonary embolism. This risk increases significantly when thalidomide is used in combination with standard chemotherapeutic agents including dexamethasone. In one controlled trial, the rate of venous thromboembolism was 22.5% in patients receiving thalidomide in combination with dexamethasone compared to 4.9% in patients receiving dexamethasone alone (p = 0.002). Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Instruct patients to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. Consider thromboprophylaxis based on an assessment of individual patients' underlying risk factors.
Use of thalidomide in patients with multiple myeloma is associated with increased risk of venous thromboembolic events (e.g., deep venous thrombosis, pulmonary embolus). Such risk increases substantially when thalidomide is used in combination with standard chemotherapy, including dexamethasone. In a controlled clinical trial, an increased incidence of venous thromboembolic events was observed in patients receiving thalidomide in combination with dexamethasone compared with those receiving dexamethasone alone (22.5 versus 4.9%). Patients and clinicians are advised to watch for signs and symptoms of thromboembolism. Patients should be instructed to notify a clinician if they develop shortness of breath, chest pain, and/or arm or leg swelling.
Thalidomide is known to cause nerve damage that may be permanent. Peripheral neuropathy is a common (> or =10%) and potentially severe adverse reaction of treatment with thalidomide that may be irreversible. Peripheral neuropathy generally occurs following chronic use over a period of months; however, peripheral neuropathy following relatively short-term use has been reported. The correlation with cumulative dose is unclear. Symptoms may occur some time after thalidomide treatment has been stopped and may resolve slowly or not at all.
For more Drug Warnings (Complete) data for THALIDOMIDE (36 total), please visit the HSDB record page.

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Pharmacodynamics
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.

C13H10N2O4

258.23

258.064

C, 60.47; H, 3.90; N, 10.85; O, 24.78

50-35-1

(S)-Thalidomide;841-67-8;Thalidomide-d4;1219177-18-0;(R)-Thalidomide;2614-06-4

5426

White to off-white powder or needles

1.5±0.1 g/cm3

509.7±43.0 °C at 760 mmHg

269-271°C

262.1±28.2 °C

0.0±1.3 mmHg at 25°C

1.646

0.54

1

4

1

19

449

0

O=C1C([H])(C([H])([H])C([H])([H])C(N1[H])=O)N1C(C2=C([H])C([H])=C([H])C([H])=C2C1=O)=O

UEJJHQNACJXSKW-UHFFFAOYSA-N

InChI=1S/C13H10N2O4/c16-10-6-5-9(11(17)14-10)15-12(18)7-3-1-2-4-8(7)13(15)19/h1-4,9H,5-6H2,(H,14,16,17)

2-(2,6-dioxopiperidin-3-yl)isoindole-1,3-dione

Nphthaloylglutamimide; alphaphthalimidoglutarimide; Nphthalylglutamic acid imide; US brand names: Synovir; Thalomid; Foreign brand names: Distaval; Contergan; Kevadon; Neurosedyn; Pantosediv; Softenon Talimol; Sedoval K17; Abbreviation: THAL; Thalomid; 2-(2,6-dioxopiperidin-3-yl)isoindoline-1,3-dione; Contergan;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

Solubility in Formulation 1: ≥ 2.5 mg/mL (9.68 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 2: ≥ 2.5 mg/mL (9.68 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly.

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Solubility in Formulation 3: 30% PEG400+0.5% Tween80+5% Propylene glycol : 5 mg/mL

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Solubility in Formulation 4: 20 mg/mL (77.45 mM) in 0.5% CMC-Na/saline water (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.
Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution.

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Solubility in Formulation 5: 20 mg/mL (77.45 mM) in 10% Tween80 in PBS (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication.

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 (Please use freshly prepared in vivo formulations for optimal results.)