High-performance liquid chromatographic assay for cytosine arabinoside, uracil arabinoside and some related nucleotides (original) (raw)
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Recent advances in analytical determination of thalidomide and its metabolites
Journal of Pharmaceutical and Biomedical Analysis, 2008
Thalidomide, a racemate, is coming into clinical use as immuno-modulating and anti-inflammatory drug. Thalidomide was approved by the FDA in July 1998 for the treatment of erythema nodusum leprosum associated with leprosy. Recently, thalidomide is proving to be a promising drug in the treatment of a number of cancers and inflammatory diseases, such as multiple myeloma, inflammatory bowel disease (Crohn's disease), HIV and cancer associated cachexia. These effects may chiefly be exerted by S-thalidomide, but the enantiomers are inter-converted in vivo. Thalidomide is given orally, although parenteral administration would be desirable in some clinical situations.
Journal of Chromatography B, 2012
A simple, robust, sensitive and selective liquid chromatography tandem mass spectrometry (LC-MS/MS) method for the quantification of thalidomide was developed and validated. The method was applied to thalidomide quantification in three different types of biological samples. Thalidomide was extracted from human serum (100 L), cells (2.5 × 10 5), or cell culture media (100 L) by LLE and separated on a Prodigy C18 (150 mm × 4.0 mm, 5 m i.d.) column with isocratic elution using water/acetonitrile (70/30, v/v) 0.1% formic acid, at a flow rate of 0.5 mL/min, with umbelliferone (600 ng/mL) as an internal standard. Thalidomide was quantified using a triple quadrupole mass spectrometer operated in multi-reaction-monitoring mode using positive electrospray ionisation. The method was validated in two separate thalidomide concentration ranges; human serum (0.05-20 g/mL) and in vitro cells (0.78-50 ng) with an inter-day precision of 1.8% and 1.9% and average accuracy of 100% and 101% in serum and cells respectively. Despite the use of small sample volume, the limit of quantification for thalidomide in serum was determined to be 3 ng/mL. The method was successfully employed to measure levels of thalidomide in cancer patient serum and cell culture model systems. Although cellular levels were quantifiable, thalidomide was shown to be unstable under in vitro conditions with a half life of approximately 2 h. In patient samples, circulating serum levels showed a broad correlation with dose and uncovered some patient compliance issues.
Clinical pharmacology of thalidomide
European Journal of Clinical Pharmacology, 2001
Background: Thalidomide has a chiral centre, and the racemate of (R)-and (S)-thalidomide was introduced as a sedative drug in the late 1950s. In 1961, it was withdrawn due to teratogenicity and neuropathy. There is now a growing clinical interest in thalidomide due to its unique anti-in¯ammatory and immunomodulatory eects. Objective: To critically review pharmacokinetic studies and brie¯y review pharmacodynamic eects and studies of thalidomide in consideration of its chemical and stereochemical properties and metabolism. Methods: Literature search and computer simulations of pharmacokinetics. Results: Rational use of thalidomide is problematic due to lack of basic knowledge of its mechanism of action, eects of the separate enantiomers and metabolites and dose-and concentration-eect relationships. Due to its inhibition of tumour necrosis factor-a and angiogenesis, racemic thalidomide has been tested with good eect in a variety of skin and mucous membrane disorders, Crohn's disease, graft-versus-host disease, complications to human immunode®ciency virus and, recently, in multiple myeloma. Adverse reactions are often related to the sedative eects. Irreversible toxic peripheral neuropathy and foetal malformations are serious complications that can be prevented. The results of several published pharmacokinetic studies can be questioned due to poor methodology and the use of non-stereospeci®c assays.
Journal of Pharmaceutical and Biomedical Analysis, 2003
Thalidomide molecule, a synthetic derivative of glutamine, can undergo hydrolysis at physiologic pH to form glutamine. Additionally, L-glutamine is one of the starting materials in the synthesis of Thalidomide drug substance. The current USP method for testing glutamine is thin-layer chromatography (TLC) with ninhydrin spray visualization. A more quantitative and automated high performance liquid chromatography (HPLC) method utilizing indirect ultraviolet (UV) detection was developed and validated for the determination of the non-UV absorbing glutamine in Thalidomide drug substance and product. The HPLC mobile phases consisted of phosphoric acid, 2-naphthalenesulfonate sodium and methanol. 2-Naphthalenesulfonate was used as a UV detection probe for glutamine. A segmented isocratic elution program was used to elute glutamine and Thalidomide, respectively. The method was found to be specific for glutamine. The linearity was 0.05 Á/1.25% glutamine with respect to a nominal concentration of 8 mg ml (1 Thalidomide sample. The limits of detection and quantitation were found to be 0.03 and 0.05% glutamine, respectively. The injection precision was 2.7% for area responses and 0.2% for the retention times. The recovery of glutamine at three concentration levels was found to be 100.89/2.8% from placebo and 99.29/5.8% from spiked Thalidomide drug substances. This newly developed HPLC method was used to determine glutamine in Thalidomide drug substances and products. The results from HPLC were in agreement with those from TLC. Therefore, the method developed is a suitable alternative to the current USP TLC procedure. Additionally, the method offers the advantage of being quantitative and automated.
Journal of Chromatography B, 2004
A high-performance liquid chromatographic assay with MS detection has been developed for the quantitative determination of the anti-angiogenic agent CC-5013 in human plasma. Sample pretreatment involved liquid-liquid extraction with acetonitrile/1-chlorobutane (4:1, v/v) solution containing the internal standard, umbelliferone. Separation of the compounds of interest was achieved on a column packed with Waters C18 Nova-Pak material (4 microm particle size; 300 mm x 3.9 mm internal diameter) using acetonitrile, de-ionized water, and glacial acetic acid in ratios of 20:80:0.1 (v/v/v) (pH 3.5) delivered at an isocratic flow rate of 1.00 ml/min. Simultaneous MS detection was performed at m/z 260.3 (CC-5013) and m/z 163.1 (umbelliferone). The calibration curve was fit to a linear response-concentration data over a range of 5-1000 ng/ml using a weighting factor of 1/x. Values for accuracy and precision, obtained from four quality controls analyzed on three different days in replicates of five, ranged from 98 to 106% and from 5.5 to 15.5%, respectively. The method was successfully applied to study the pharmacokinetics of CC-5013 in a cancer patient receiving the drug as single daily dose.
Asian Journal of Pharmaceutical Analysis, 2016
Highlights Stress testing was comprehensively carried out on posaconazole injection. Preparative isolation, characterization and determination of unknown degradants. Three novel degradants were characterized by LC-TOF/MS, LC-MS/MS, 1D and 2D NMR. Mechanisms for the formation of three degradants were proposed for the first time. A new HPLC method was developed and validated to quantify the degradants.