Investigation of the Properties of Polyphenylene Sulfone Blends

Polyphenylene sulfones (PPSU) blends with different viscosities have been studied. It is shown that the blends have a single-phase structure, regardless of the viscosities of the mixed polymers. It was found that blends having close values of the melt flow index (MFR) are also characterized by a similar melt viscosity in a wide range of shear rates, regardless of the viscosities of its constituent components. It has been found that PPSU blends with smaller MFR differences exhibit higher heat resistance and stability of mechanical properties, while blends with similar viscosity containing oligomers exhibit a broader molecular weight distribution (MWD) and have lower thermal and mechanical properties.     

In vivo metabolism of 2,5-dimethoxy-4-propylthiophenethylamine in rat

The in vivo metabolism of 2,5-dimethoxy-4-propylthiophenethylamine (2C-T-7), a ring-substituted psychoactive phenethylamine, was studied in rat. Male Wistar rats were administered 10?mg/kg 2C-T-7 hydrochloride orally, and 24-h urine fractions were collected. After enzymatic hydrolysis of the urine sample, the metabolites were extracted by liquid–liquid extraction and analyzed by liquid chromatography/mass spectrometry. 2C-T-7-sulfoxide, N-acetyl-2C-T-7-sulfoxide, N-acetyl-2,5-dimethoxy-4-methylthiophenethylamine-sulfoxide, N-acetyl-2,5-dimethoxy-4-(2-hydroxypropylthio)phenethylamine-sulfoxide, and N-acetyl-2,5-dimethoxy-4-(2-hydroxypropylthio)phenethylamine-sulfone were detected as the primary metabolites of 2C-T-7. These findings suggest that sulfoxidation, sulfone formation, hydroxylation of the propyl side chain at the β-position, and S-depropylation followed by methylation of thiol were the major metabolic pathways of 2C-T-7 in rat.     

An improved LC-MS/MS method for quantitative determination of ilaprazole and its metabolites in human plasma and its application to a pharmacokinetic study

Aim： To improve and validate an analytical method based on liquid chromatography and electrospray ionization tandem mass spectrometry （LC-ESI-MS/MS） for the quantitative measurement of ilaprazole and its two metablites in human plasma. Methods： Separation of analytes and the internal standard （IS）, omeprazole, was performed on a Thermo HyPURITY C18 column （150×2.1 mm, 5 um） with a mobile phase consisting of 10 mmol/L ammonium formate water-acetonitrile solution （50：50, v/v） at a flow rate of 0.25 mL/min. The API4000 triple quadruple mass spectrometer was operated in multiple reactions monitoring mode via positive electrospray ionization interface using the transition m/z 367.2 → m/z 184.0 for ilaprazole, m/z 383.3 → m/z 184.1 for ilaprazole sulfone, m/z 351.2 → m/z 168.1 for ilaprazole thiol ether and m/z 346.2 → m/z 198.0 for omeprazole. Results： The method was linear over the concentration range of 0.23-2400.00 ng/mL for ilaprazole, 0.05-105.00 ng/mL for ilaprazole thiol ether and 0.06-45.00 ng/mL for ilaprazole sulfone. The intra- and inter-day precisions were all less than 15% in terms of relative standard deviation （RSD）, and the accuracy was within 15% in terms of relative error （RE） for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether. The lower limit of quantification （LLOQ） was identifiable and reproducible at 0.23, 0.05 and 0.06 ng/mL with acceptable precision and accuracy for ilaprazole, ilaprazole sulfone and ilaprazole thiol ether, respectively. Conclusion： The validated method offered sensitivity and a wide linear concentration range. This method was successfully applied for the evaluation of the pharmacokinetics of ilaprazole and its two metabolites after single oral doses of 5 mg ilaprazole to 12 healthy Chinese volunteers.     

Vinyl sulfones: synthetic preparations and medicinal chemistry applications

Vinyl sulfones have long been known for their synthetic utility in organic chemistry, easily participating in 1,4-addition reactions and cycloaddition reactions. This functional group has also recently been shown to potently inhibit a variety of enzymatic processes providing unique properties for drug design and medicinal chemistry. This review includes traditional methods used for the synthesis of vinyl sulfones, but focuses mainly on newer reactions applied to vinyl sulfones, including olefin metathesis, conjugate reduction, asymmetric dihydroxylation (AD), and the use of vinyl sulfones to arrive at highly functionalized targets, all illustrating the rich and versatile chemistry this group can efficiently perform. In addition, geminal disulfones are discussed with respect to their formation, reactions, and medicinal applications of this underutilized functional group.     

呋喃唑酮对兰索拉唑及其代谢产物在大鼠体内药动学的影响

 目的 研究呋喃唑酮对兰索拉唑及其代谢产物在大鼠体内药动学参数的影响。方法 采用HPLC-MS/MS测定与呋喃唑酮联用前后兰索拉唑、5-羟基兰索拉唑及其兰索拉唑砜的血药浓度,以DAS2.0程序拟合药动学参数。结果 单次联用呋喃唑酮后,兰索拉唑的AUC值显著增加,从(487.33±122.40) 增至 (779.82±126.67) μg·L^-1·h (P<0.05),兰索拉唑砜与兰索拉唑AUC_{0-4 h}的比值显著降低,从(0.70±0.34) 降至 (0.33±0.09) (P<0.05)。结论 呋喃唑酮与兰索拉唑合用后,可显著增加兰索拉唑的生物利用度。
     

Simultaneous determination of albendazole metabolites, praziquantel and its metabolite in plasma by high-performance liquid chromatography-electrospray mass spectrometry

The analysis of albendazole sulfoxide, albendazole sulfone, praziquantel and trans-4-hydroxypraziquantel in plasma was carried out by high-performance liquid chromatography-mass spectrometry ((LC-MS-MS). The plasma samples were prepared by liquid-liquid extraction using dichloromethane as extracting solvent. The partial HPLC resolution of drug and metabolites was obtained using a cyanopropyl column and a mobile phase consisting of methanol:water (3:7, v/v) plus 0.5% of acetic acid, at a flow rate of 1.0 mL/min. Multi reaction monitoring detection was performed by electrospray ionization in the positive ion mode, conferring additional selectivity to the method. Method validation showed relative standard deviation (precision) and relative errors (accuracy) lower than 15% for all analytes evaluated. The quantification limit was 5 ng/mL and the linear range was 5-2500 ng/mL for all analytes. The method was used for the determination of drug and metabolites in swine plasma samples and proved to be suitable for pharmacokinetic studies.     

Toxicology and carcinogenesis studies of p,p'-dichlorodiphenyl sulfone in rats and mice.

p,p'-Dichlorodiphenyl sulfone (DDS) is used as a starting material in the production of polysulfones and polyethersufones, a family of thermoplastics. DDS was studied because of its high production volume and use. In toxicology studies, 10 Fischer 344 rats and 10 B6C3F1 mice/sex/group were fed diets containing 0, 30, 100, 300, 1,000 or 3,000 ppm DDS for 14 weeks. All animals survived until the end of the studies. Mean body weights of groups exposed to 300 ppm or greater were significantly decreased. Liver and kidney in rats and liver in mice were the major target organs of DDS toxicity. Dose-related increases in liver weights and incidences of centrilobular hepatocyte hypertrophy were observed in DDS-exposed groups. Nephropathy was seen in male and female rats only at and above 300 ppm. Neurotoxicity evaluations were negative in DDS-treated animals. Clinical chemistry and hematology parameters were minimally affected. In the 2-year toxicity and carcinogenicity studies, 50 rats and 50 mice/sex/group were fed diets containing 0, 10 (male rats), 30, 100, or 300 ppm DDS for 104 to 105 weeks. Survival of exposed groups was not affected. There were no clinical signs of toxicity related to DDS exposure. Final mean body weights were 2-17% lower in DDS-treated groups. Liver was the only target organ of DDS-induced toxicity. The incidence of centrilobular hepatocyte hypertrophy in mice and rats, and the incidence of bile duct hyperplasia and centrilobular degeneration in female rats was significantly greater than in controls. A no-observed-adverse-effect level (NOAEL) of 30 ppm DDS in the diet (1.5 mg/kg body weight) was established for rats. DDS was not carcinogenic in these studies.     

Synthesis and 11C-labelling of the ACTH fragment analogue H-Met(O2)-Glu-His-Phe-d-Lys-Phe-OH (Org 2766) via its homocystine-containing precursor

The hexapeptide dimer (H-Hcy-Glu-His-Phe-d -Lys-Phe-OH)₂ was synthesized using solution methods and characterized. Its conversion into H-Met(O₂)-Glu-His-Phe-d -Lys-Phe-OH, Org 2766, was studied on a small scale in as short a time as possible; reduction of the disulfide bond using Na/NH₃, reaction with CH₃I, oxidation with H₂O₂ and catalyst and purification by HPLC were carried out starting with 2 mg of the dimer in a total preparation time of approximately 22min, starting with the addition of CH₃I. The preparation of the ¹¹C-labelled analogue was carried out by methylation with ¹¹CH₃I. Restrictions imposed by working with carbon-11 will be discussed.     

兰索拉唑肠溶胶囊在健康人体的生物等效性

目的评价2种国产兰索拉唑肠溶胶囊制剂(抗溃疡药)的生物等效性。方法 24例健康成年男性受试者随机分组,按照自身对照的方法单次口服兰索拉唑肠溶胶囊30 mg,用LC-MS/MS测定兰索拉唑和其代谢物5-羟基兰索拉唑、兰索拉唑砜的浓度,用非房室模型方法计算主要药代动力学参数。结果参比制剂和试验制剂的主要药代动力学参数如下。兰索拉唑:t1/2分别为(2.10±1.58),(2.18±1.85)h;tmax分别为(2.20±1.10),(2.00±1.01)h;Cmax分别为(1160.8±550.3),(1232.3±628.1)ng.mL-1;AUC0-t分别为(4963.7±4233.4),(4947.0±4669.3)ng.mL-1.h;AUC0-∞分别为(5027.4±4256.9),(5036.0±4751.2)ng.mL-1.h。5-羟基兰索拉唑:t1/2分别为(1.95±1.20),(1.75±1.00)h,tmax分别为(2.10±1.20),(1.80±1.00)h,Cmax分别为(106.2±61.2),(114.5±61.0)ng.mL-1,AUC0-t分别为(279.1±124.2),(27...