2-(咪唑并[1,2-a]吡啶-3-基)乙酸的合成工艺改进

目的改进骨质疏松治疗药米诺膦酸的关键中间体2-(咪唑并[1,2-a]吡啶-3-基)乙酸的合成工艺。方法以反式-4-氧基-2-丁烯酸乙酯和2-氨基吡啶为起始原料,经环合、水解得到2-(咪唑并[1,2-a]吡啶-3-基)乙酸。结果与结论该合成方法首次以纯水替代有机溶剂作为反应溶剂,采用"一锅法"合成目标化合物,降低了该中间体的制备成本,而且环境友好,更适合于工业化生产。     

2-甲基-4-(2,6,6-三甲基-1-环己烯-1-基)-2-丁烯醛的合成

2,6,6-三甲基-1-环己烯-1-甲醛与(3-甲氧基-2-甲基烯丙基)膦酸二乙酯经Wittig-Homer缩合制得1-甲氧基-2-甲基-4-(2,6,6-三甲基-1-环己烯-1-基)-1,3-丁二烯,然后经酸催化水解得到维生素A的关键中间体2-甲基-4-(2,6,6-三甲基-1-环己烯-1-基)-2-丁烯醛,总收率约47%.     

2-(咪唑并[1, 2-a]吡啶-3-基)乙酸的合成工艺改进

目的 改进抗骨质疏松药米诺膦酸的关键中间体2-(咪唑并[1, 2-a]吡啶-3-基)乙酸的制备方法。方法 以2-氧代戊二酸二乙酯为起始原料,经溴代、环合、水解和脱羧4步反应制得目标产物。结果 目标化合物的熔点与¹H-NMR 谱数据与文献报道相符,总收率为40.5%(以2-氧代戊二酸二乙酯计)。结论 与文献报道的方法相比,改进后的工艺路线后处理简单,更有利于工业化生产。     

唑来膦酸的临床应用研究进展

唑来膦酸(zoledronic acid)是继帕米膦酸二钠(pam-idronate)之后的第3代双膦酸盐类(Bisphosphonates,Bps)药物,4 mg·支-1,由瑞士Novartis公司开发,2000年在加拿大首次上市,目前已在80多个国家广泛使用。唑来膦酸的咪唑侧链上含有2个氮原子,其主要药理作用是通过抑制破骨细胞的活性和诱导破骨细胞凋亡来抑制骨吸收[1]。还可以降低血清钙和磷的水平,增加尿钙和磷的排泄,使肿瘤相关高钙血症患者的血钙水平恢复正常。也可以通过诱导细胞凋亡或抑制血管生长,直接影响肿瘤细胞生长[2]。据文献报道,唑来膦酸抑制骨转移和抗骨吸收的作用是前几代…     

咪唑乙酸盐酸盐的制备

咪唑乙酸盐酸盐(1)是合成治疗恶性高钙血症药物唑来膦酸(zoledronic acid)的中间体[1].其合成可先以氨基乙缩醛为原料合成中间体SCNCH2CH(OEt)2,然后与乙基甘氨酸反应,产物经酸性水解及氧化反应即可制得咪唑乙酸,总收率42%[2],最后通入氯化氢气体,即得终产物1.此法步骤较多,操作繁琐.     

浙江省11家医院2010-2015年双膦酸盐类药物治疗乳腺癌骨转移相关骨损害及疼痛的利用研究

目的:了解双膦酸盐类药物在浙江省乳腺癌骨转移患者中的应用现状及趋势,为进一步促进该类药物的临床合理使用提供参考。方法:采用金额排序分析和用药频度分析方法,对抽取的浙江省11家医院2010-2015年接受双膦酸盐类药物治疗的乳腺癌骨转移患者样本处方中所使用的该类药物相关品种的使用金额、用药频度(DDDs)和日均费用(DDC)等进行统计、计算、排序及分析。结果:6年间双膦酸盐类药物的使用金额总体稳中有升(其中2011年增幅较大),2015年比2010年增加了96.26%。使用金额排前3位的品种分别是注射用唑来膦酸(进口)、注射用唑来膦酸(国产)和注射用帕米膦酸二钠,其中注射用唑来膦酸(进口)的使用金额总体基本呈上升趋势,而注射用帕米膦酸二钠的使用金额总体基本呈下降趋势。DDDs排前3位的品种分别是注射用唑来膦酸(国产)、注射用唑来膦酸(进口)和注射用帕米膦酸二钠,其中注射用唑来膦酸(国产)和注射用唑来膦酸(进口)的DDDs总体基本呈上升趋势,而注射用帕米膦酸二钠的DDDs总体基本呈下降趋势。双膦酸盐类药物各品种的B/A值介于0.33~2.00之间,其中2012-2015年注射用唑来膦酸(国产)的B/A值均为2.00,注射用唑来膦酸(进口)的B/A值均为0.50。DDC排第1、2位的品种均为注射用氯屈膦酸二钠、注射用唑来膦酸(进口)。结论:浙江省11家医院2010-2015年乳腺癌骨转移患者双膦酸盐类药物的使用金额总体稳中有升,其中疗效确切、安全性较好、价格适中的第二和第三代双膦酸盐类药物的部分品种(如注射用帕米膦酸二钠、注射用唑来膦酸等,尤其是后者)在临床使用中占优势。双膦酸盐类药物的选择与使用基本合理,但价格仍然是限制部分品种进一步广泛应用的首要因素。     

唑来膦酸对骨质疏松患者骨痛、骨密度和血清骨代谢标志物的影响

目的 探讨唑来膦酸对骨质疏松症(0P)患者骨痛、骨密度(BMD)和血清骨代谢标志物的影响.方法 将2013年6月-2014年7月收治的OP 84例根据治疗方式分为唑来膦酸组与阿仑膦酸钠组,每组42例.记录并比较2组治疗前后骨痛程度、BMD和血清骨代谢标志物水平变化.结果 唑来膦酸组显效率和总有效率高于阿仑膦酸钠组(P＜0.05);2组腰椎正位(L2-4)与右股骨颈BMD在治疗后6、12个月均高于治疗前,且治疗12个月唑来膦酸组高于阿仑膦酸钠组(P＜0.05).唑来膦酸组特异性碱性磷酸酶、β-胶原片段水平低于阿仑膦酸钠组和治疗前,降钙素高于阿仑膦酸钠组和治疗前(P＜0.05).2组不良反应发生率比较差异无统计学意义(P＞0.05).结论 唑来膦酸可有效减轻OP患者骨痛症状,改善患者血清骨代谢相关指标并提高BMD水平.     

1,2,2-三甲基丙氧基-苯氧基-甲膦酰-对-氨基-和-偶氮基-中国鲎血蓝蛋白的制备

报道了1,2,2-三甲基丙氧基-苯氧基-甲膦酰-对-氨基和偶氮基中国鲎血蓝蛋白的合成。它们的合成是由甲膦酰二氯(1)与对-硝基苯酚作用,制得对-硝基苯氧基甲膦酰氯(2),化合物(2)再与1,2,2-三甲基丙醇反应,生成甲磷酸(1,2,2-三甲基丙基-O′-对-硝基苯基)酯(3),化合物(3)中的硝基经10％Pd-C催化氢化,转化成氨基化合物(4)。化合物(4)与中国鲎血蓝蛋白(TTH)用缩合法和重氮化法制备了缩合物(Ⅰ)和偶联物(Ⅱ)它们是均未见报道的新化合物,生物试验表明,化合物(Ⅰ)和(Ⅱ)可诱导产生一定的抗体。     

唑来膦酸含量及有关物质质控分析方法的建立

目的　测定唑来膦酸的含量及有关物质。方法　高效液相色谱法。色谱条件 :Hypersil SAX色谱柱 ,流动相为磷酸溶液(1.0mL→ 10 0 0mL ,pH4 .3± 0 .2 ) ,流速为 0 .8mL·min-1,检测波长 2 10nm。结果　唑来膦酸在 0 .2～ 2 .0mg·mL-1范围内线性关系良好 ,r =0 .9995 ,线性方程为C =2 2 5 4 36A - 3930。重现性RSD =0 .5 % (n =5 )。结论　该方法能简单、快捷、准确地同时测定唑来膦酸的含量及有关物质     

（1R，2S）-（-）-cis-1，2-环氧丙基膦酸（R）-（＋）-α-苯乙胺盐的合成

炔丙醇和三氯化磷经取代、重排、水解反应"一锅法"制得丙二烯膦酸,用Lindlar催化选择性加氢制cis-丙烯膦酸,与(+)-α-苯乙胺成盐后再经双氧水氧化成环、重结晶拆分得到磷霉素中间体(1R,2,S)-cis-1,2-环氧丙基膦酸(R)-(+)-α-苯乙胺盐,总收率约24%.     

Comparison of the choleretic properties of bile acids

The choleretic properties of cholic, chenodeoxycholic, and deoxycholic acid and their taurine and glycine conjugates were compared to their ability to form micelles. It has previously been concluded that deoxycholate has the lowest critical micellar concentration; chenodeoxycholate is slightly higher and cholic is much higher. Conjugation with glycine and taurine has little or no effect on the critical micelle concentration. Since the choleretic properties of bile salts are thought to be directly proportional to their osmotic activities, one might suspect that deoxycholic acid would be the least choleretic, chenodeoxycholic slightly more choleretic and cholic much more choleretic, with little difference between the conjugated and unconjugated forms. However, in the present study, cholic, chenodeoxycholic and taurocholic acid produced similar increases in bile flow (450–700 μl/kg) after an equimolar dose (55 μM/kg). Except for the conjugation of deoxycholic acid with taurine, conjugation of these bile acids with glycine or taurine always decreased the choleretic properties of the bile acids. Therefore, it has been concluded that there is not a good correlation between the in vitro osmotic properties of bile acids and their ability to increase bile flow.     

HPLC测定L-天门冬氨酸中的有关物质

目的建立L-天门冬氨酸中羟基丁二酸、丁二酸和富马酸等有关物质的检查方法。方法采用HPLC法,使用AQ C18色谱柱,0.01 mol.L-1的磷酸二氢钾水溶液(磷酸调pH3)为流动相,检测波长200 nm。结果主成分和杂质可完全分离。结论建立的方法灵敏、专属,可用于L-天门冬氨酸中有关物质的测定。     

儿童抽动障碍血浆兴奋性氨基酸水平与行为心理的相关性研究

目的 了解抽动障碍患儿血兴奋性氨基酸中谷氨酸(GLU)、天门冬氨酸(ASP)水平现状及其与行为心理的相关性。方法 采用高效液相色谱法检测了48例抽动障碍患儿血浆GLU、ASP水平，其中暂时性抽动13例，慢性运动性抽动20例，抽动-秽语综合征15例；并对其家庭状况和相关行为进行了问卷调查。结果 (1)48例抽动患儿血浆GLU水平明显高于对照组(P＜0．01)；(2)慢性运动性抽动组和抽动-秽语综合征组患儿血浆GLU、ASP分别与对照组和暂时性抽动组比较，结果发现前两组血浆GLU水平明显高于后两组(P＜0．05、P＜0．01)；各组血浆ASP水平无显差异(P＞0．05)。(3)抽动障碍患儿注意缺陷多动障碍、精神紧张、脾气暴躁等行为心理问题较对照组明显增高(P＜0．01，P＜0．05)。(4)抽动组血浆兴奋性氨基酸(EAAs)与多动注意缺陷障碍发生率呈正相关。结论 (1)儿童抽动障碍存在EAA水平变化，GLU可能参与抽动障碍的病理生理过程。(2)EAA与抽动障碍所致的部分行为心理问题有一定关系。     

Sensitivity of fetus and pups to excess levels of maternal intakes of alpha linolenic acid at marginal protein levels in Wistar rats

There is growing interest in the role omega 3 fatty acids (n3), in promoting fetal growth. Present study examined whether alpha linolenic acid, primary vegetarian dietary omega 3 fatty acid source and precursor to cellular membrane phospholipid eicosapentaenoic acid and docosahexaenoic acid, can improve birth outcome. Pregnant dams from three groups (seven in each) were fed: control diet (18% protein with 7% soybean oil, normal alpha linolenic acid), or two treatment diets at marginal protein level of 12%; one with 7% soybean oil (Treatment I, normal alpha linolenic acid), and other with 3% flax oil and 4% soybean oil (Treatment II, four times normal alpha linolenic acid) during gestation. There was a reduction in litter size and litter weight (p < 0.05) at birth in the Treatment II group as compared to the Control group. Alpha linolenic acid (p < 0.05), eicosapentaenoic acid (p < 0.05) levels increased while arachidonic acid levels (p < 0.05) reduced in gastric milk at birth and blood at end of lactation in Treatment II as compared to Treatment I group. Brain fatty acid levels showed reduction (p < 0.05) only in docosahexaenoic acid levels in dams from Treatment I and Treatment II, at the end of lactation. Results suggest sensitivity of fetus and pups for excess levels of alpha linolenic acid ’in a diet at marginal protein level’.     

甘露醇-旋光法测定鞣柳硼三酸散中硼酸的含量

目的建立旋光法测定鞣柳硼三酸散中硼酸的含量。方法以低浓度明胶溶液提取制剂中硼酸,利用甘露醇结合硼酸形成具有旋光性复合物,并建立鞣柳硼三酸散中硼酸的含量测定方法。结果硼酸浓度在5～20 g.L-1的浓度范围内与旋光度线性关系良好(r=0.999 2),方法的平均回收率为99.98%,RSD为1.3%。结论旋光法测定鞣柳硼三酸散中硼酸的含量,操作简便、快速,结果准确,重现性好。     

The pharmacokinetics of anthocyanins and their metabolites in humans

BACKGROUND AND PURPOSE

Anthocyanins are phytochemicals with reported vasoactive bioactivity. However, given their instability at neutral pH, they are presumed to undergo significant degradation and subsequent biotransformation. The aim of the present study was to establish the pharmacokinetics of the metabolites of cyanidin-3-glucoside (C3G), a widely consumed dietary phytochemical with potential cardioprotective properties.

EXPERIMENTAL APPROACH

A 500 mg oral bolus dose of 6,8,10,3′,5′-¹³C₅-C3G was fed to eight healthy male participants, followed by a 48 h collection (0, 0.5, 1, 2, 4, 6, 24, 48 h) of blood, urine and faecal samples. Samples were analysed by HPLC-ESI-MS/MS with elimination kinetics established using non-compartmental pharmacokinetic modelling.

KEY RESULTS

Seventeen ¹³C-labelled compounds were identified in the serum, including ¹³C₅-C3G, its degradation products, protocatechuic acid (PCA) and phloroglucinaldehyde (PGA), 13 metabolites of PCA and 1 metabolite derived from PGA. The maximal concentrations of the phenolic metabolites (C_max) ranged from 10 to 2000 nM, between 2 and 30 h (t_max) post-consumption, with half-lives of elimination observed between 0.5 and 96 h. The major phenolic metabolites identified were hippuric acid and ferulic acid, which peaked in the serum at approximately 16 and 8 h respectively.

CONCLUSIONS AND IMPLICATIONS

Anthocyanins are metabolized to a structurally diverse range of metabolites that exhibit dynamic kinetic profiles. Understanding the elimination kinetics of these metabolites is key to the design of future studies examining their utility in dietary interventions or as therapeutics for disease risk reduction.     

绿原酸、新绿原酸、隐绿原酸与溶菌酶相互作用的荧光光谱法研究

用荧光光谱法研究了绿原酸、新绿原酸、隐绿原酸与溶菌酶之间的相互作用。绿原酸（cA）、新绿原酸（NcA）、隐绿原酸（CCA）均能显著焊灭溶菌酶的内源荧光并以静态焯灭为主;随着温度的升高其结合常数和结合位点均呈现降低的趋势。根据热力学参数判断确定CA与LYSO之间以疏水作用力为主,NCA与LYSO之间以氢键和范德华力为主,CCA与LYSO之间以静电作用力为主。     

齐墩果酸磷酸酯单钠的合成

本文首次报道了齐墩果酸磷酸酯单钠的合成。首先齐墩果酸与三氯氧磷作用生成其磷酸酯,然后转化成单钠盐。     

Induction of differentiation of the cultured rat mammary epithelial cells by triterpene acids

We investigated the effects of triterpene acids (TAs), ursolic acid (UA) and oleanolic acid (OA), on the induction of proliferation and differentiation of normal rat mammary epithelial cells (RMEC) or organoids cultured in Matrigel or primary culture system. To elucidate the effects, we tested their differentiation inducing activities with intercellular communication ability, cell cycle patterns, induction of apoptosis, and morphological differentiation in the three dimensional extracellular culture system. To study the changes of RMEC subpopulation in culture, the cultured cells were isolated, immunostained with peanut lectin (PNA) and anti-Thy-1.1 antibody and then analyzed with flow cytometry. Four different subpopulations, such as PNA and Thy-1.1 negative cells (B-), PNA positive cells (PNA+), Thy-1.1 positive cells (Thy-1.1+), PNA and Thy-1.1 positive cells (B+), were obtained and the size of each subpopulation was changed in culture with time in the presence of TAs. Intercellular communication was observed in culture for 7 days in TAs-treated cells, but not in culture for 4 days with scrape-loading dye transfer technique. G₂/M phase cells and the number of apoptotic population were increased in TAs-treated groups in cell cycle analyses. S phase fractions were reduced and the change of G₁ phase cells was not observed. The colonies with distinct multicellular structures, such as stellate, ductal, webbed, squamous, lobulo-ductal colonies, were observed in Matrigel culture and the frequencies of each colony were changed in the presence of TAs. These results suggest that UA and OA have differentiation inducing effects on rat mammary epithelial cells in primary or in Matrigel culture.     

复方苯甲酸凝胶的研制

目的研制外用抗真菌药复方苯甲酸凝胶,并对制剂稳定性进行观察。方法以卡波姆-940为基质,用常规方法制备凝胶。结果制剂稳定性较好,对黏膜无刺激作用。结论该制剂的制备工艺简单、检测方便、制剂稳定、安全。