E3 Ligase

There is significantly less (R)-thalidomide transfer from R-imprinted MIP-1 from the donor phase to the receiver phase as a result of the increased thalidomide retention in the organic phase. The affinity of (R)-thalidomide for surface trapping caused by MIP is higher than that of other forms. We discovered that (R)-thalidomide binds to MIP-selective sites more firmly than other medications, which is consistent with the fact that the two medicines are distinct biological entities [1]. In comparison to (R)-thalidomide-imprinted MIP, (S)-thalidomide-imprinted MIP nanoparticles exhibit a higher cytotoxic effect on caco-2 cells [1].

Adult female F344 rats were implanted with 9L gliosarcoma tumors intracranially, subcutaneously (flank), or both. The efficacy of oral thalidomide alone and intraperitoneal BCNU or cisplatin with chemotherapy will be examined after several weeks of treatment. Both serum and tissue concentrations of (R)-thalidomide are 40-50% greater than (S)-thalidomide. Coadministration of BCNU or cisplatin with thalidomide does not modify concentration enantioselectivity [1].

Thalidomide is currently under evaluation as an anti-angiogenic agent in cancer treatment, alone and in combination with cytotoxic agents. Thalidomide is a racemate with known pharmacologic and pharmacokinetic enantioselectivity. In a previous study with thalidomide combination chemotherapy, we found evidence of anti-tumour synergy. In this study, we examined whether the synergy involved altered pharmacokinetics of thalidomide enantiomers. Adult female F344 rats were implanted with 9L gliosarcoma tumours intracranially, subcutaneously (flank), or both. Effectiveness of oral thalidomide alone, and with intraperitoneal BCNU or cisplatin combination chemotherapy, was assessed after several weeks treatment. Presumed pseudo steady-state serum, tumour and other tissues, collected after treatment, were assayed for R- and S-thalidomide by chiral HPLC. Both serum and tissue concentrations of R-thalidomide were 40-50% greater than those of S-thalidomide. Co-administration of BCNU or cisplatin with thalidomide did not alter the concentration enantioselectivity. Poor correlation of concentration with subcutaneous anti-tumour effect was found for individual treatments, and with all treatments for intracranial tumours. The consistency of the enantiomer concentration ratios across treatments strongly suggests that the favourable antitumour outcomes from interactions between thalidomide and the cytotoxic agents BCNU and cisplatin did not have altered enantioselectivity of thalidomide pharmacokinetics as their basis.[1]

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Thalidomide, a racemate, is coming into clinical use as an immunomodulating and antiinflammatory drug. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are interconverted in-vivo. Thalidomide is given orally, although parenteral administration would be desirable in some clinical situations. The aim of this study was to prepare solutions of the enantiomers of thalidomide for intravenous administration and to investigate their pharmacokinetics and sedative effects following infusion in man. Solubility and stability of the enantiomers in 5% glucose solution was investigated. After a dose-determination experiment in one subject, six healthy male volunteers received R- and S-thalidomide separately by 1-h infusions in a randomized double-blind cross-over study. Blood was sampled over 22h and sedative effects were recorded. Blood concentrations of the enantiomers were determined by stereospecific HPLC. A four-compartment model consisting of a two-compartment model for each enantiomer, with elimination from both compartments, connected by rate constants for chiral inversion was fitted to the concentration data, while the sedative effects were correlated with the blood concentrations of R- and S-thalidomide by means of logistic regression. The enantiomers of thalidomide were chemically stable in solution for at least a week at room temperature. The infusions were well tolerated. Sedation, which was the only observed effect, was related to the blood concentration of R-thalidomide. Inter-individual variation in the disposition of the enantiomers was modest (e.g. terminal half-lives ranged between 3.9 and 5.3h). Pharmacokinetic modelling predicted that varying the infusion time of a fixed dose of S-thalidomide between 10 min and 6h would have little influence on the maximal blood concentration of formed R-thalidomide. To our knowledge this is the first time that thalidomide has been administered intravenously.[2]

mouse LD50 oral 400 mg/kg BEHAVIORAL: SOMNOLENCE (GENERAL DEPRESSED ACTIVITY) Nature., 215(296), 1967 [PMID:6059519]

[1]. Enantioselectivity of thalidomide serum and tissue concentrations in a rat glioma model and effects of combination treatment with cisplatin and BCNU. J Pharm Pharmacol. 2007 Jan;59(1):105-14.

[2]. Intravenous formulations of the enantiomers of thalidomide: pharmacokinetic and initial pharmacodynamic characterization in man. J Pharm Pharmacol. 2000 Jul;52(7):807-17.

(R)-thalidomide is a 2-(2,6-dioxopiperidin-3-yl)-1H-isoindole-1,3(2H)-dione that has R-configuration at the chiral centre. It has a role as a sedative. It is an enantiomer of a (S)-thalidomide.
See also: Thalidomide (annotation moved to).

C13H10N2O4

258.2295

258.064

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

2614-06-4

Thalidomide;50-35-1;(S)-Thalidomide;841-67-8;Thalidomide-d4;1219177-18-0

75792

White to off-white solid powder

1.503g/cm3

509.7ºC at 760 mmHg

269-271ºC

262.1ºC

1.65E-10mmHg at 25°C

1.646

0.354

1

4

1

19

449

1

C1CC(=O)NC(=O)[C@@H]1N2C(=O)C3=CC=CC=C3C2=O

UEJJHQNACJXSKW-SECBINFHSA-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)/t9-/m1/s1

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

(R)-Thalidomide; (R)-(+)-thalidomide; (+)-Thalidomide; D-Thalidomide; 2614-06-4; R-(+)-Thalidomide; Thalidomide, (R)-; QN61H68KLK;

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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

Note: Listed below are some common formulations that may be used to formulate products with low water solubility (e.g. < 1 mg/mL), you may test these formulations using a minute amount of products to avoid loss of samples.

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Injection Formulation 1: DMSO : Tween 80： Saline = 10 : 5 : 85 (i.e. 100 μL DMSO stock solution → 50 μL Tween 80 → 850 μL Saline)
*Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH ₂ O to obtain a clear solution.
Injection Formulation 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL DMSO → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)
Injection Formulation 3: DMSO : Corn oil = 10 : 90 (i.e. 100 μL DMSO → 900 μL Corn oil)
Example: Take the Injection Formulation 3 (DMSO : Corn oil = 10 : 90) as an example, if 1 mL of 2.5 mg/mL working solution is to be prepared, you can take 100 μL 25 mg/mL DMSO stock solution and add to 900 μL corn oil, mix well to obtain a clear or suspension solution (2.5 mg/mL, ready for use in animals).

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Injection Formulation 4: DMSO : 20% SBE-β-CD in saline = 10 : 90 [i.e. 100 μL DMSO → 900 μL (20% SBE-β-CD in saline)]
*Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution.
Injection Formulation 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (i.e. 500 μL 2-Hydroxypropyl-β-cyclodextrin → 500 μL Saline)
Injection Formulation 6: DMSO : PEG300 : castor oil : Saline = 5 : 10 : 20 : 65 (i.e. 50 μL DMSO → 100 μLPEG300 → 200 μL castor oil → 650 μL Saline)
Injection Formulation 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (i.e. 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
Injection Formulation 8: Dissolve in Cremophor/Ethanol (50 : 50), then diluted by Saline
Injection Formulation 9: EtOH : Corn oil = 10 : 90 (i.e. 100 μL EtOH → 900 μL Corn oil)
Injection Formulation 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (i.e. 100 μL EtOH → 400 μLPEG300 → 50 μL Tween 80 → 450 μL Saline)

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Oral Formulation 1: Suspend in 0.5% CMC Na (carboxymethylcellulose sodium)
Oral Formulation 2: Suspend in 0.5% Carboxymethyl cellulose
Example: Take the Oral Formulation 1 (Suspend in 0.5% CMC Na) as an example, if 100 mL of 2.5 mg/mL working solution is to be prepared, you can first prepare 0.5% CMC Na solution by measuring 0.5 g CMC Na and dissolve it in 100 mL ddH2O to obtain a clear solution; then add 250 mg of the product to 100 mL 0.5% CMC Na solution, to make the suspension solution (2.5 mg/mL, ready for use in animals).

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Oral Formulation 3: Dissolved in PEG400
Oral Formulation 4: Suspend in 0.2% Carboxymethyl cellulose
Oral Formulation 5: Dissolve in 0.25% Tween 80 and 0.5% Carboxymethyl cellulose
Oral Formulation 6: Mixing with food powders

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Note: Please be aware that the above formulations are for reference only. InvivoChem strongly recommends customers to read literature methods/protocols carefully before determining which formulation you should use for in vivo studies, as different compounds have different solubility properties and have to be formulated differently.

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