E3 Ligase; TNF-alpha

沙利度胺必须由肝脏代谢形成环氧化物，环氧化物可能是活性致畸代谢物。 [1]在培养物中用脂多糖和其他激动剂激活的人单核细胞会产生肿瘤坏死因子 α (TNF-α)，沙利度胺可特异性抑制该因子。 [2]沙利度胺增加 mRNA 降解，抑制肿瘤坏死因子 α 的产生。[3]沙利度胺通过诱导细胞凋亡或 G1 期生长停滞，直接影响对美法仑、阿霉素和地塞米松 (Dex) 耐药的 MM 细胞系和患者 MM 细胞。沙利度胺可增加 Dex 的抗 MM 活性，该活性可被白细胞介素 6 抑制。[4]沙利度胺是体外原代人类 T 细胞的有效共刺激剂。当与 T 细胞受体复合物的刺激相结合时，它通过白细胞介素 2 促进 T 细胞增殖并产生干扰素 γ。在缺乏 CD4+ T 细胞的情况下，沙利度胺还可以增强同种异体树突状细胞引起的初级 CD8+ 细胞毒性 T 细胞反应。 [5]

沙利度胺是一种强效致畸原，可导致人类肢体发育不良。研究人员在兔角膜微袋试验中证明，口服沙利度胺是碱性成纤维细胞生长因子诱导的血管生成抑制剂。包括沙利度胺类似物分析在内的实验表明，抗血管生成活性与沙利度酰胺的致畸性相关，但与镇静剂或轻度免疫抑制特性无关。沙利度胺处理的兔角膜新生血管的电子显微镜检查显示，与沙利度酰胺处理的胚胎畸形肢芽脉管系统相似的特定超微结构变化。这些实验揭示了沙利度胺致畸的机制，并有望将沙利度米作为口服药物用于治疗许多依赖血管生成的疾病。[1]

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在三项实验中，沙利度胺（200 mg/kg）使家兔角膜血管数量减少了 30% 至 51%，中位减少量为 36%。 [1]

在20世纪50年代，沙利度胺作为孕妇的镇静剂，导致数千名患有多种缺陷的儿童出生。尽管沙利度胺及其衍生物来那度胺和泊马度胺具有致畸性，但这些免疫调节药物（IMiDs）最近成为多发性骨髓瘤和5q缺失相关发育不良的有效治疗方法。IMiDs靶向E3泛素连接酶CUL4-RBX1-DDB1-CBN（称为CRL4（CRBN）），并促进IKAROS家族转录因子IKZF1和IKZF3被CRL4泛素化。在这里，我们介绍了与沙利度胺、来那度胺和泊马度胺结合的DDB1-CRBN复合物的晶体结构。该结构确定CRBN是CRL4（CRBN）内的底物受体，并对映选择性结合IMiDs。通过无偏筛选，我们确定同源框转录因子MEIS2是CRL4（CRBN）的内源性底物。我们的研究表明，IMiDs阻断内源性底物（MEIS2）与CRL4（CRBN）的结合，而连接酶复合物正在招募IKZF1或IKZF3进行降解。这种双重活性意味着小分子可以调节E3泛素连接酶，从而上调或下调蛋白质的泛素化。[6]

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研究人员研究了沙利度胺抑制脂多糖（LPS）诱导的肿瘤坏死因子α（TNF-α）产生的机制，发现该药物增强了TNF-αmRNA的降解。因此，在50微克/毫升沙利度米的存在下，该分子的半衰期从约30分钟缩短到约17分钟。抑制TNF-α的产生是有选择性的，因为其他LPS诱导的单核细胞因子不受影响。己酮可可碱和地塞米松是TNFα产生的另外两种抑制剂，已知它们通过不同的机制发挥作用，这表明这三种药物在细胞因子生物合成途径的不同点抑制TNFα的合成。这些观察结果为这些药物的协同作用提供了解释。选择性抑制TNF-α的产生使沙利度胺成为治疗炎症性疾病的理想候选者，在这些疾病中观察到TNF-α诱导的毒性，并且免疫必须保持完整[3]。

THP-1 细胞、A549 细胞和 KYSE30 细胞在添加有 10% 胎牛血清的 RPMI-1640 培养基中培养，并在 5% CO2 和 95% 室内空气环境中于 37°C 保存。使用单剂量4 Gy 6-MV X射线照射THP-1细胞，然后用或不用含有沙利度胺0.2μmol/mL的培养基处理细胞48小时。根据初步结果[2]，选择沙利度胺的浓度。

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沙利度胺选择性抑制人单核细胞肿瘤坏死因子-α（TNF-α）的产生，当这些细胞在培养物中被脂多糖和其他激动剂触发时。在临床上可实现的药物剂量为1微克/毫升时，抑制率为40%。相比之下，用[35S]甲硫氨酸标记并在SDS-PAGE上表达的总蛋白和单个蛋白的量不受影响。单核细胞产生的白细胞介素1β（IL-1β）、IL-6和粒细胞/巨噬细胞集落刺激因子的量保持不变。这种药物的选择性可能有助于确定TNF-α在体内的作用，并在临床环境中调节其毒性作用。[2]

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尽管沙利度胺（Thal）最初因其已知的抗血管生成作用而用于治疗多发性骨髓瘤（MM），但其抗MM活性的机制尚不清楚。这些研究证明了Thal对传统治疗无效的MM的临床活性，并描述了Thal及其强效类似物（免疫调节药物[IMiDs]）的抗肿瘤活性机制。重要的是，这些药物通过诱导细胞凋亡或G1期生长停滞，直接作用于对美法仑、阿霉素和地塞米松（Dex）耐药的MM细胞系和患者MM细胞。此外，Thal和IMiDs增强了Dex的抗MM活性，相反，它们被白细胞介素6抑制。对于Dex，由Thal和IMiDs触发的凋亡信号与相关粘附局灶性酪氨酸激酶的激活有关。这些研究为在新的治疗范式中开发和测试Thal和IMiDs建立了框架，以靶向肿瘤细胞和微环境，克服传统的耐药性，并在这种目前无法治愈的疾病中取得更好的疗效。[4]

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沙利度胺（α-邻苯二甲酰亚胺戊二酰亚胺）治疗麻风结节性红斑患者的疗效被认为是由于抑制了肿瘤坏死因子α。在其他据报道对沙利度胺有反应的疾病中，该药物的作用机制尚不清楚。我们表明，沙利度胺是体外原代人类T细胞的强效共刺激物，通过T细胞受体复合物与刺激协同作用，增加白细胞介素2介导的T细胞增殖和干扰素γ的产生。共刺激作用对CD8+的影响大于CD4+T细胞亚群。该药物还增加了在没有CD4+T细胞的情况下由同种异体树突状细胞诱导的原发性CD8+细胞毒性T细胞反应。因此，沙利度胺可以在药理学上实现人类T细胞共刺激，并且优先在CD8+T细胞亚群中实现[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

83.55

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)

配方 1 中的溶解度: ≥ 2.5 mg/mL (9.68 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (9.68 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液添加到 900 μL 玉米油中并混合均匀。

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配方 3 中的溶解度: 30% PEG400+0.5% Tween80+5% Propylene glycol : 5 mg/mL

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配方 4 中的溶解度: 20 mg/mL (77.45 mM) in 0.5% CMC-Na/saline water (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 5 中的溶解度: 20 mg/mL (77.45 mM) in 10% Tween80 in PBS (这些助溶剂从左到右依次添加，逐一添加), 悬浊液; 超声助溶。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。