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61.
《药学学报(英文版)》2020,10(6):1134-1142
FTY720 and IMMH002, prodrugs for sphingosine-1-phosphate receptor 1 (S1P1) agonists, show inadequate and inconsistent levels of phosphorylation in humans compared to that in rats. In this study, FTY720 or IMMH002 analogues (21–24) were designed and synthesized with modified head pieces to improve the biotransformation of the prodrugs to the active phosphorylated forms. Target compounds were synthesized via a convergent route using the key and optically pure building block 9, which was first synthesized via asymmetrically catalyzed amination. The phosphorylation rates of these analogues in rat or human blood were compared. The new methyl-substituted analogue compound 21 showed higher phosphorylation rates in both rats and humans than the parent compound, whereas compound 23 showed improvements in rats, but not in humans. In pharmacokinetics studies of rats, compounds 21 and 23 both had higher levels of phosphorylation than FTY720 and IMMH002. Thus, our study not only yielded new compounds with therapeutic potential, but also showed species differences between rats and humans in response to the structural modifications, which might be useful for predicting the biotransformation behavior and efficacy of this class of prodrugs in the clinic. 相似文献
62.
磷酸钙作为佐剂应用在乙肝核酸疫苗中的可能性研究 总被引:2,自引:0,他引:2
目的:研究使用磷酸钙作为乙DNA疫苗的佐剂,诱导机体免疫反应的可能性,方法:磷酸钙与疫苗DNA制备出磷酸钙-DNA共沉物,免疫小鼠,检测外周血抗体,观察免疫应答反应,结果:磷酸钙-DNA共沉物能激发机体免疫应答反应。结论:佐剂在核酸疫苗的应用值得进一步研究。 相似文献
63.
目的:用高效液相色谱法测定克林霉素磷酸酯片的溶出度.方法:采用转篮法测定克林霉素磷酸酯片的溶出度,以高效液相色谱法测定其浓度.色谱柱为RP-C18柱(5μm,200 mm×4.6 mm),流动相为0.1 mol/L磷酸二氢钾溶液-乙腈(775:225),流速为1.0 mL/min,检测波长为210 nm,室温下测定.结果:在0.04~1.00 mg/mL的浓度范围内,线性关系良好(r=0.999 2),平均回收率为100.0%,RSD为0.88%.结论:高效液相色谱法分析速度快,结果准确,适用于克林霉素磷酸酯片溶出度的测定. 相似文献
64.
目的探讨染不同浓度煤尘的肺泡巨噬细胞(染煤尘-AM)上清液作用成纤维细胞不同时点对肌醇-1,4-二磷酸(IP2)和肌醇-1,4,5-三磷酸(IP3)信号物质的影响.方法应用细胞培养技术,用小鼠胸腺细胞增殖法和放射免疫分析法,分别测定染煤尘-AM上清液中白细胞介素1(IL-1)、前列腺素E2(PGE2)的含量;用Dowex-1×8阴离子交换柱层析法,分析染煤尘-AM上清液作用于3H-肌醇标记成纤维细胞后IP2和IP3的液闪计数值(cpm).结果 AM培养上清液中IL-1,PGE2含量随染煤尘浓度的增加而增高,与对照组比较差异有显著性.用这种含细胞因子的染煤尘-AM上清液作用成纤维细胞,在不同的作用时点,对IP2的影响不同,在10,20 s 时点,上清液中IL-1和PGE2对IP2显示有上调作用,随着作用时间的延长,IP2出现了下调现象.对IP3的影响表现为,在不同的作用时点均随上清液中细胞因子的增加IP3呈现增加趋势.煤尘组与对照组比较,在不同的观察时点显示有不同的差异显著性.结论染煤尘-AM培养上清液中含有高于对照组的IL-1和PGE2细胞因子,用这种上清液作用于成纤维细胞后,可影响成纤维细胞中磷酸肌醇信号物质的含量,影响程度与细胞因子的浓度和作用时间有关. 相似文献
65.
Many studies have shown a special interaction between LAG3 and PD-1 in T cell inhibition, while the co-expression and effect of LAG3 and PD-1 on T cells in breast cancer patients are still not very clear. Here, with strict exclusion criteria, 88 patients with breast cancer and 18 healthy controls were enrolled. The percentages of LAG3+PD-1+ T cells in their peripheral blood (PBL) and tumor infiltrating T cells (TIL) were analyzed by flow cytometry, which showed an increase in TILs but no difference in PBLs and presented differences in TILs in different molecular subtypes (P < 0.05). In triple-negative breast cancer (TNBC), the highest percentages were observed, while in ER+/PR+ breast cancer, the lowest percentages were observed; however, these percentages were not different in different clinical stages (P > 0.05). Immunohistochemical staining showed that the expression of their ligands, PD-L1, MHC class II molecular and FGL1, was inconsistent in different molecular subtypes and clinical stages. Analysis of the functions of T cells with different phenotypes showed that the proliferation and secretion capacity of LAG3+PD-1+ T cells was obviously exhausted, with more than a two-fold of decrease compared with the groups of single positive LAG3 or PD-1 (P < 0.05). Finally, in a mouse model of TNBC, the dual blockade of LAG3 and PD-1 was indicated to achieve a better anti-tumour effect than either one alone (P < 0.05), which may provide a new strategy for the immunoregulatory treatment of patients with TNBC in the future. 相似文献
66.
目的建立双氢青蒿素哌喹片中乙醇残留检测方法。方法采用顶空气相色谱法,色谱柱:HP-Innowax(0.32 mm×30 m,0.5μm),柱温:程序升温,初始温度50℃,保持7 min,以每分钟10℃速率升温至150℃,保持2min;进样口温度180℃,FID检测器温度250℃,正丙醇为内标物,载气为氮气。顶空平衡温度:85℃,平衡时间,25min。结果乙醇、正丙醇分离度良好,乙醇在0.065 071.041 2 mg·mL-1范围内线性关系良好(r=0.999 9),平均加样回收率为102.0%,其RSD为2.20%。结论该方法操作简便快速,灵敏度高,准确度好,可作为双氢青蒿素哌喹片中乙醇残留测定。 相似文献
67.
目的探讨盐酸小檗碱联合西格列汀治疗肥胖2型糖尿病的临床疗效。方法选取2014年8月—2015年8月在武安市第一人民医院内分泌科接受治疗的肥胖2型糖尿病患者96例为研究对象,按治疗方案的差别分为对照组和治疗组,每组各48例。对照组口服磷酸西格列汀片,100 mg/次,1次/d。治疗组在对照组基础上口服盐酸小檗碱片,0.3 g/次,3次/d,餐前口服。两组患者均连续治疗12周。观察两组的临床疗效,比较两组患者的血糖指标和炎症指标。结果治疗后,对照组和治疗组的总有效率分别为83.33%、95.83%,两组比较差异有统计学意义(P0.05)。治疗后,两组患者的空腹血糖(FPG)、餐后2 h血糖及糖化血红蛋白(Hb A1c)均明显降低,同组治疗前后差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度明显优于对照组,两组比较差异具有统计学意义(P0.05)。治疗后,两组患者的C-反应蛋白(CRP)、白细胞介素-6(IL-6)、内皮素-1(ET-1)及血栓素2(TXB2)均显著下降,而前列腺素Fla(PGFla)、一氧化氮(NO)均显著上升,同组治疗前后差异有统计学意义(P0.05);且治疗组这些观察指标的改善程度明显优于对照组,两组比较差异具有统计学意义(P0.05)。结论盐酸小檗碱联合西格列汀治疗肥胖2型糖尿病具有较好的临床疗效,能明显降低患者血糖,改善炎症指标,具有一定的临床推广应用价值。 相似文献
68.
Hemendinger RA Armstrong EJ Radio N Brooks BR 《Toxicology and applied pharmacology》2012,258(2):208-215
The neuroblastoma-spinal motor neuron fusion cell line, NSC-34, in its differentiated form, NSC-34D, permits examining the effects of riluzole, a proven treatment for amyotrophic lateral sclerosis (ALS) on cell death induction by staurosporine (STS), thapsigargin (Thaps), hydrogen peroxide (H2O2) and homocysteine (HCy). These neurotoxins, applied exogenously, have mechanisms of action related to the various proposed molecular pathogenetic pathways in ALS and are differentiated from endogenous cell death that is associated with cytoplasmic aggregate formation in motor neurons. Nuclear morphology, caspase-3/7 activation and high content imaging were used to assess toxicity of these neurotoxins with and without co-treatment with riluzole, a benzothiazole compound with multiple pharmacological actions. STS was the most potent neurotoxin at killing NSC-34D cells with a toxic concentration at which 50% of maximal cell death is achieved (TC50 = 0.01 μM), followed by Thaps (TC50 = 0.9 μM) and H2O2 (TC50 = 15 μM) with HCy requiring higher concentrations to kill at the same level (TC50 = 2200 μM). Riluzole provided neurorescue with a 20% absolute reduction (47.6% relative reduction) in apoptotic cell death against Thaps-induced NSC-34D cell (p ≤ 0.05), but had no effect on STS-, H2O2- and HCy-induced NSC-34D cell death. This effect of riluzole on Thaps induction of cell death was independent of caspase-3/7 activation. Riluzole mitigated a toxin that can cause intracellular calcium dysregulation associated with endoplasmic reticulum (ER) stress but not toxins associated with other cell death mechanisms. 相似文献
69.
Case studies covering carbonaceous nanomaterials, metal oxide and metal sulphate nanomaterials, amorphous silica and organic pigments were performed to assess the Decision-making framework for the grouping and testing of nanomaterials (DF4nanoGrouping). The usefulness of the DF4nanoGrouping for nanomaterial hazard assessment was confirmed. In two tiers that rely exclusively on non-animal test methods followed by a third tier, if necessary, in which data from rat short-term inhalation studies are evaluated, nanomaterials are assigned to one of four main groups (MGs). The DF4nanoGrouping proved efficient in sorting out nanomaterials that could undergo hazard assessment without further testing. These are soluble nanomaterials (MG1) whose further hazard assessment should rely on read-across to the dissolved materials, high aspect-ratio nanomaterials (MG2) which could be assessed according to their potential fibre toxicity and passive nanomaterials (MG3) that only elicit effects under pulmonary overload conditions. Thereby, the DF4nanoGrouping allows identifying active nanomaterials (MG4) that merit in-depth investigations, and it provides a solid rationale for their sub-grouping to specify the further information needs. Finally, the evaluated case study materials may be used as source nanomaterials in future read-across applications. Overall, the DF4nanoGrouping is a hazard assessment strategy that strictly uses animals as a last resort. 相似文献
70.