Objective: To study the effects of continuous epidural injection of dexamethasone on blood glucose, blood lipids, plasma cortisol, and adrenocorticotropic hormone (ACTH) in patients with neuropathic pain. Methods: Thirty patients with cervical spondylotic radiculopathy, lumbar disc herniation, herpes pain or postherpetic neuralgia were randomly divided into three groups and were treated with different doses of epidural injection of dexamethasone (Group S with a concentration of 25 μg/mL; Group M with a concentration of 50 μg/mL; Group L with a concentration of 100 μg/mL). Epidural catheterization placement was guided by computed tomography (CT), and was connected to the analgesic pump for 10 days. Visual Analog Score (VAS), fasting blood glucose (FBG), total cholesterol (CHOL), triglyceride (TG), 2 h postprandial blood glucose (2hPG) and the concentrations of cortisol, ACTH were measured before injection (T 0 ), 2, 4, 6, 8, and 10 days during injection (D 2 , D 4 , D 6 , D 8 , D 10 ), and 7, 14, 21, 28 days (W 1 , W 2 , W 3 , W 4 ) after injection. Results: During and after the treatment, VAS score was significantly decreased, and group M and L had the lowest VAS score. The concentrations of cortisol and ACTH were significantly lower during the treatment, but all of them recovered to the normal level after stopping the injection. The treatment did not affect the CHOL and TG concentrations. Discussion: Epidural injection of dexamethasone at the concentration of 50 μg/mL is recommended for patients with neuropathic pain because of its good analgesic effect and less adverse effect on blood glucose, plasma cortisol, and ACTH.

Background: Percutaneous radiofrequency thermocoagulation (PRT) is used to treat trigeminal neuralgia (TN) with a satisfactory pain relief but a high recurrence rate. Objective: To explore the efficacy and safety of repeated PRT for recurrent TN as compared to patients who received the first PRT. Methods: Between January 2013 to May 2013, 31 patients with recurrent TN who have been treated with PRT previously were recruited and underwent repeated PRT (group A), and compared with 41 TN patients received the first initial PRT (group B). Visual Analog Scale (VAS) score was assessed preoperatively and postoperatively after 2 years of follow-up, and compared in terms of initial pain relief, complications, and recurrence rate between the two groups. Results: In group A, 27 patients (87.0%) were pain free immediately, and 30 patients (96.8%) experienced pain relief at 48 h, whereas that was 37 patients (90.0%) and 40 patients (97.6%) in group B (p ≧ 0.05). Patients in group A who remained an "excellent" or "good" pain relief condition (VAS score ≦ 1) were 96.8% at 6 months, 83.9% at 1 year, 74.2% at 2 years, whereas the percentage in group B was 97.6, 85.4, and 73.2% (p ≧ 0.05). Conclusion: For patients with recurrent TN after PRT, repeated PRT might be considered as a useful treatment option when other treatments fail. In addition, the frequency and severity of adverse events for repeated PRT were similar as compared to initial PRT.

Aclidinium bromide,a novel long-acting inhaled anticholinergic bronchodilator,is developed by Almirall and Forest Laboratories for the treatment of chronic obstructive pulmonary disease.An improved synthetic process was developed in this paper.Aclidinium bromide was prepared from (3R)-1-azabicyclo [2.2.2] oct-3-yl hydroxy (di-2-thienyl) acetate (5) and 3-bromopropoxy benzene (8).The intermediate 5 was synthesized from dimethyl oxalate via Grignard reaction and transesterification.The intermediate 8 was obtained from phenol and 1,3-dibromopropane via nucleophilic reaction.The overall yield of aclidinium bromide was 33.1％ (based on dimethyl oxalate).The structure of the target compound was confirmed by MS and 1H-NMR.

目的建立GC法测定磺丁基醚-β-环糊精（betadex sulfobutyl ether sodium,SBE-β-CD）中杂质1,4-丁烷磺内酯。方法采用分散液液微萃取处理样品。50μL氯仿作为萃取剂,0.5 mL乙腈作为分散剂,通过反复抽吸并超声的方法分散于5 m L质量分数为4.0%的SBE-β-CD溶液中。色谱分离采用熔融石英毛细管色谱柱,高纯氮作载气,流速30 m L·min-（-1）,进样口温度200℃,采用程序升温,分析时间15min,氢火焰离子化检测器温度270℃。结果 1,4-丁烷磺内酯质量浓度在0.5-6 mg·L-（-1）内线性关系良好（r=0.999 3）,平均回收率在100.4%-101.5%内,精密度的RSD为4.4%,分散液液微萃取的富集因子约为12。结论该方法可用于测定SBE-β-CD样品中杂质1,4-丁烷磺内酯的限量。

A new series of 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines, with an isosteric replacement of the side chain amide moiety to a sulfur atom, were designed and synthesized as multitargeted antifolates as well as potential antitumor agents. Starting from previously synthesized 2-amino-4-oxo-pyrrolo[2,3-d]pyrimidin-6-yl-acetic acid, a reduction by lithium triethylborohydride and successive mesylation afforded the key mesylate. Nucleophilic substitution by mercaptoacetic or mercaptopropionic acid methyl esters, followed by hydrolysis and condensation with pyridinyl-methylamines provided the nonclassical compounds 1-6, whereas condensation with glutamic acid diethyl ester hydrochloride and saponification afforded the classical analogs 7-8. All target compounds exhibited inhibitory activities toward KB, SW620 and A549 tumor cell lines. The most potent compounds of this series, 7 and 8, are better inhibitors against A549 cells than methotrexate (MTX) and pemetrexed (PMX). Nucleoside protection assays establish compound 8 a dual inhibitor of thymidylate synthase (TS) and 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase (AICARFTase) targeting both de novo thymidylate and purine nucleotide biosynthesis, which is further verified by the molecular modeling studies. Analogous to PMX, target compound 8 alternates the cell cycle of SW620 cells with S-phase accumulation and induces apoptosis, leading to cell death. (C) 2016 Elsevier Masson SAS. All rights reserved.

m-Nisoldipine, as a novel 1,4-dihydropyridine calcium ion antagonist, was presented as a couple of enantiomers [(-), (+)-m-nisoldipine]. In this report, the in vitro metabolism of m-nisoldipine enantiomers was investigated in rat liver microsomes (RLM) by the combination of two liquid chromatography mass spectrometric techniques for the first time. The metabolites were separated and assayed by ultra-high performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry and further identified by comparison of their mass and chromatographic behaviors with reference substances. A total of 18 metabolites of (-)-m-nisoldipine and 16 metabolites of (+)-m-nisoldipine were detected, respectively, which demonstrated that (+)-m-nisoldipine is more metabolically stable than (-)-m-nisoldipine. In addition, the identified metabolic pathways of m-nisoldipine enantiomers were involved in dehydrogenation, oxidation and ester hydrolysis. Afterwards, based on high-performance liquid chromatography coupled to triple quadrupole linear ion trap mass spectrometry, various selective cytochrome P450 (CYP) enzyme inhibitors were employed to evaluate CYP isoforms. The results indicated that the inhibitors of CYP1A1/2, CYP2B1/2, 2D and 2C11 had no obvious inhibitory effects, yet the inhibitor of CYP 3A had a significant inhibitory effect on metabolism of m-nisoldipine enantiomers. This showed that CYP 3A might primarily metabolize m-nisoldipine in RLM.

N-[4-(4,6-Dimethyl-2-pyrimidinyloxy)-3-methylphenyl]-N′-[2-(dimethylamino)]benzoylurea (SUD) is a novel synthesized benzoylurea derivative. We selected several human cancer cell lines to investigate whether SUD can inhibit the growth of cancer cells. We selected the liver cell line L-02 to investigate the effect of SUD on the normal cells. Flow cytometric analysis was used to detect the effect of SUD on cell cycle, Hoechst 33258 staining was used to evaluate the apoptosis induced by SUD, real-time fluorescence quantitative PCR was used to investigate the expression of the cell cycle-relevant and apoptosis-relevant genes, a reactive oxygen species (ROS) assay was used to observe the production of ROS, and western blotting was used to determine the level of cell cycle-relevant and apoptosis-relevant proteins. According to the results of the MTT assay, the growth of human cancer cell lines was significantly inhibited by SUD treatment in a time-dependent and concentration-dependent manner; however, the growth of human normal cells was not significantly inhibited by SUD treatment. The results of flow cytometric analyses showed that SUD induced cell-cycle arrest at the G2-phase in MCF-7 cells and at the G1-phase in BGC-823 cells. The results of Hoechst 33258 staining showed that SUD induced apoptosis in MCF-7 and BGC-823 cells. The results of the ROS assay showed that the production of ROS was increased by SUD in MCF-7 and BGC-823 cells. Our research suggests that the growth-inhibitory effect of SUD on MCF-7 cells was related to G2-phase arrest, which was associated with the upregulated expression of p53 and Chk1 proteins, and downregulation of the cyclin B1 gene, cdc25a, and cyclin-dependent kinase 1 (CDK1) proteins; the growth-inhibitory effect of SUD on BGC-823 cells was related to G1-phase arrest, which was associated with upregulation of the p53 gene and Chk1 protein and downregulation of cdc25a protein and the CDK4 gene. SUD also induced apoptosis in MCF-7 and BGC-823 cell lines through the mitochondrial pathway in a p53-dependent manner.

A novel series of 2-amino-4-oxo-6-substituted pyrrolo[2,3-d]pyrimidines were designed and synthesized as potential nonclassical antifolates targeting both thymidylate and purine nucleotide biosynthesis. Condensation of 2,4-diamino-6-hydroxypyrimidine with ethyl-4-chloroacetoacetate and subsequent hydrolysis afforded the key intermediate, 2-amino-4-oxo-pyrrolo[2,3-d]pyrimidin-6-yl-acetic acid. Coupling with various amino acid methyl esters followed by saponification and condensation with 3(aminomethyl)pyridine provided target compounds 1-9. The new compounds exhibited micromolar to submicromolar antiproliferative potencies against a panel of tumor cell lines including KB, A549 and HepG2. Growth inhibition of compound 2 toward KB cells resulted in cytotoxicity and G1/G2-phase accumulation, and was partially protected by excess thymidine and adenosine, but was completely reversed in the combination of thymidine and adenosine, indicating both thymidylate and de novo purine nucleotide synthesis as the targeted pathway. However, 5-aminoimidazole-4-carboxamide (AICA) protection was incomplete, suggesting inhibition of both glycinamide ribonucleotide formyltransferase (GARFTase) and AICA ribonucleotide formyltransferase (AICARFTase). The results of the docking studies show that 2 could bind and inhibit both thymidylate synthase (TS) and the two folate-dependent purine biosynthetic enzymes (GARFTase and AICARFFase), which is consistent with the results of in vitro metabolic assays. Our studies establish that compound 2 is an excellent lead analog as a multitargeted antifolate for further structure optimization. (C) 2015 Elsevier Masson SAS. All rights reserved.

In this study, a liquid chromatography-tandem mass spectrometry method was developed and validated to simultaneously determine naproxcinod and naproxen concentrations in rat plasma for the first time. Plasma samples were prepared by simple one-step extraction with methanol for protein precipitation using only 50 mu L plasma. Separation was performed on a Synergi Fusion-RP C18 column with a run time of 4 min. Naproxcinod, naproxen and internal standard concentrations were detected in the positive ion mode using multiple reaction monitoring (MRM) of the transitions at m/z 348.2 -> 302.2, 231.1 -> 185.1 and 271.2 -> 203.1, respectively. The calibration curves were linear, with all correlation coefficients being >= 0.9952, in the range of 1.00-400 ng/mL for naproxcinod and 20.0-8000 ng/mL for naproxen. Their accuracy was in the range of -8.1% to 8.7%, and the intra- and inter-day variations were <= 4.53%. The mean extraction recovery of all analytes was more than 93.1% efficient. Stability testing showed that naproxcinod and naproxen remained stable during the whole analytical procedure. After validation, the method was successfully applied to a pharmacokinetic study of naproxcinod and naproxen in rats. The AUC(0-infinity) of naproxen was 74.6 times larger than that of naproxcinod, which indicated that naproxcinod was rapidly metabolized into naproxen in rats. (C) 2014 Elsevier B.V. All rights reserved.

以对羟基苯乙腈为原料,经溴苄醚化生成4-苄氧基苯乙腈,再在氢化钠作用下与环己酮缩合生成1-[1-氰基-1-(4-苄氧苯基)甲基]环己醇,在10％钯炭催化下进行常压氢化反应还原氰基,同时氢解脱苄生成1-[2-氨基-1-(4-羟基苯基)-乙基]环己醇,最后与甲醛/甲酸发生Leuckart反应进行N-甲基化得抗抑郁药去甲文拉法辛,总收率约46.5％.

以2-氨基-3,5-二溴苯甲醛为原料,经硼氢化钠还原得2-氨基-3,5-二溴苄醇,经氯化亚砜氯代所得2,4-二溴-6-氯甲基苯胺,再与N-甲基环己胺进行氨化反应及成盐酸盐即可制得祛痰药盐酸溴己新,总收率约57％.

Impaired ventricular repolarization can lead to long QT syndrome (LQT), a proarrhythmic disease with high risk of developing lethal ventricular tachyarrhythmias. The compound ICA-105574 is a recently developed hERG activator and it enhances IKr current with very high potency by removing the channel inactivation. The present study was designed to investigate antiarrhythmic properties of ICA-105574. For comparison, the effects of another compound NS1643 was in-parallel assessed, which also acts primarily to attenuate channel inactivation with moderate potency. We found that both ICA-105574 and NS1643 concentration-dependently shortened action potential duration (APD) in ventricular myocytes, and QT/QTc intervals in isolated guinea-pig hearts. ICA-105574, but not NS1643, completely prevented ventricular arrhythmias in intact guinea-pig hearts caused by IKr and IKs inhibitors, although both ICA-105574 and NS1643 could reverse the drug-induced prolongation of APD in ventricular myocytes. Reversing prolongation of QT/QTc intervals and antagonizing the increases in transmural dispersion of repolarization and instability of the QT interval induced by IKr and IKs inhibitors contributed to antiarrhythmic effect of ICA-105574. Meanwhile, ICA-105574 at higher concentrations showed a potential proarrhythmic risk in normal hearts. Our results suggest that ICA-105574 has more efficient antiarrhythmic activity than NS1643. However, its potential proarrhythmic risk implies that benefits and risks should be seriously taken into consideration for further developing this type of hERG activators.

美国的药学专业认证制度始于1932年,迄今已有80年的发展历史,达到了比较成熟的阶段.我国的药学专业认证始于2007年,目前仍处于试点阶段.通过对美国现行药学专业认证制度进行深入的分析和探讨,希望对我国正在开展的药学专业认证试点有所启示.

Stiripentol,an anti-epileptic drug,was synthesized from piperonal and 3,3-dimethylbutan-2-one by Claisen-Schmidt reaction in the presence of phase transfer catalyst benzyltributylammonium chloride to give 4,4-dimethyl-1-[(3,4-methylenedioxy)phenyl]-1-pentene-3-one,which was subjected to reduction using NaBH4 with an overall yield of about 85%.

Regorafenib is a new multi-kinase inhibitor approved for the treatment of metastatic colorectal cancer(mCRC).It was synthesized from 4-chloro-3-(trifluoromethy1)phenyl isocyanate and 4-(4-amino-3 fluorophenoxy)-2-(methylcarbamoy1)pyridine,the latter was obtained from 2-picolinic acid via chlorination,alcoholysis,amidation and nucleophilic substitution with 4-amino-3-fluorophenol.The overall yield was 38% based on 2-picolinic acid.

建立了高效毛细管电泳-间接UV法测定药用辅料磺丁基醚-B-环糊精(SBE-β-CD).采用未涂层熔融石英毛细管柱,以30 mmol/L苯甲酸-三羟甲基氨基甲烷(Tris)(pH 7.5)为运行缓冲液,分离电压30 kV,检测波长214 nm.考察了缓冲液类型与pH、检测波长、电压、温度和样品浓度对测定的影响,并评价了不同批次的SBE-β-CD.

The appointment system of pharmacy experimental teaching resources sharing on network platform is an important part of.Practice has proved,laboratory,experimental content,experimental medicine,instruments and equipment in experimental teaching resource reservation is used,can avoid the repeated purchase,resource is unused,using the conflict,resources and lack of preparation problems,improve the existing teaching resources use efficiency.The appointment system environment,application scope,and the role of functional modules are discussed.

The network-based platform construction for experiment teaching resources sharing at medical colleges and universities is an inner construction part of the National Pharmaceutical Experiment Teaching Demonstration Center.The campus network construction and integrated management of pharmaceutical resources of the experiment teaching center lays a foundation for the network-based platform construction for pharmaceutical experiment teaching resources sharing so that the limited resources of experiment teaching can provide maximal service for teaching and research.The paper discusses the design thoughts,framework,module functions,technology implementation and application effects of the platform construction.

A capillary electrophoresis method was established for the determination of dissociation constants(pKa) of darusentan and ambrisentan.An uncoated fused silica capillary column was used with DMF as the internal standard at 20 ℃,working voltage of 20 kV,pressure injection of 3 s(0.3 psi) and detection wavelength of 214 nm.The pKa values of darusentan and ambrisentan were(4.322±0.303) and(4.478±0.153),respectively.

Safinamide,an antiparkinson drug,was synthesized from 3-fluorobenzyl chloride by substitution with 4-hydroxybenzaldehyde to give 4-(3-fluorobenzyloxy)benzaldehyde,which was subjected to condensation and reduction to give(S)-2-[4-(3-fluorobenzyloxy)benzylamino]propionamide,followed by salification with methanesulfonic acid.The overall yield was about 76%.