地红霉素的合成研究

目的研究地红霉素的合成工艺。方法以红霉素为原料，经与水合肼缩合，硼氢化钠还原，再与2-（2-甲氧基乙氧基）乙缩醛缩合得到地红霉素。结果该合成路线不仅收率高，产品纯，而且无需过柱分离。结论该工艺路线适合工业化生产。     

新一代大环内酯类抗生素地红霉素

新一代大环内酯类抗生素地红霉素是红霉素的衍生物。其抗菌活性与红霉素类似,具有比红霉素优异的药代动力学特性,对酸稳定,临床上对各种感染性疾病均有满意的疗效。本文综述了地红霉素的合成工艺、体内外抗菌作用,药代动力学特性和临床应用。     

地红霉素的合成

以红霉素A为原料,经红霉素腙路线合成红霉素胺,与2－（2－甲氧基乙氧基）乙缩醛一步缩合得到地红霉素,总收率为38．2％。本研究对红霉素腙的合成方法及缩合反应的反应条件进行了改进。     

地红霉素多晶型对其体外抗菌活性的影响

目的研究地红霉素两种晶型的体外抗菌活性。方法采用高效液相色谱法测定含量，色谱柱为C18柱，流动相为乙腈-甲醇-pH值为7．5的0．05mol／L磷酸盐缓冲液（44：19：37），检测波长205nm，进样量10μL；用抗生素微生物检定法测定其体外抗菌活性。结果地红霉素两种晶型含量基本接近，但体外抗菌活性存在显著差异。结论试验结果为工业生产中选择高活性、低能耗的晶型，以及实现离线与在线原位监控提供了可靠的技术依据。     

地红霉素的组织分布

通常要求的抗生素体内活性,其必须在感染部位能迅速达到有效而持久浓度。由于根据血浆动力学数据不能对特定组织抗生素浓度作出精确预测,因此必须进行组织分布研究.现已对数种大环内酯抗生素进行了此类研究,其中地红霉素(dirithromycin)是一个红霉素(口恶)嗪衍生物,其抗菌谱与红霉素相似,并具有组织亲和性高及半衰期长的特点。Bergogne—Brzine综合描述了地红霉素在组织中的分布。     

地红霉素的抗菌活性,药动学特性和临床疗效

地红霉素(drithromycin)是一个14元口服大环内酯类抗生素,是红霉环胺和一个脂肪醛的缩合产物.由于其体外抗菌谱和抗菌活性与红霉素大体相似,而且在体外与体内一样容易被水解为有生物活性的代谢产物红霉环胺,因此,对该化合物活性的体外研究实际上至少可以部分地测定该化合物的活性.与红霉素相比,在软组织中地红霉素的药动学特性有所改善,其消除半衰期长,且与其它由细胞色素P450系统代谢的药物相互作用少.     

拉呋替丁鼠伤寒沙门氏菌基因回复突变试验

目的　体外观察拉呋替丁能否诱发鼠伤寒沙门氏菌组氨酸营养缺陷型突变株的回复突变。方法　Ames试验用TA97、TA98、TA10 0、TA10 2菌株并分加与不加肝微粒体酶活化系统( +/ -S9)试验。结果　拉呋替丁对四个菌株各剂量组的回复菌落数都未超过自然回复菌落数,Ames试验结果为阴性。结论　未见拉呋替丁致突变性。     

首批地红霉素国家标准品的建立

地红霉素属国家二类新药 ,为满足地红霉素质量控制之需要 ,我们参照 WHO基准品的建立指导原则 ,定义“1mg地红霉素 (C42 H78N2 O1 4 ) =10 0 0地红霉素单位 (u)”。采用正反高效液相色谱法 ,首先确定地红霉素的化学纯度 ,再根据地红霉素的效价定义 ,确定地红霉素的效价。建立了首批国家地红霉素标准品     

高效液相色谱法测定地红霉素肠溶片中地红霉素的含量

目的建立HPLC法测定地红霉素在其肠溶片中的含量。方法采用Hypersil BDS C18柱（200mm×4．6mm，5μm）；流动相为乙腈-磷酸盐缓冲液（取1．41g磷酸二氢钾与6．91g磷酸氢二钾，加水1000mL溶解后，过滤，即得）-甲醇（44：37：19）；检测波长为205nm；柱温40℃。结果地红霉素在0．8～4．7mg·mL^-1浓度与峰面积呈良好的线性关系（r=0．9999），平均回收率为99．5％，RSD为0．31％（n=9）。结论方法简便、快速、灵敏、准确。     

Monitoring the rivers Rhine and Meuse in the Netherlands for mutagenic activity using the Ames test in combination with rat or fish liver homogenates

Organic concentrates of water of the rivers Rhine and Meuse and a control lake were tested for mulagenic activity with the Ames Salmonella/microsome assay at 3-mth intervals for more than 1 yr. The river samples were concentrated by adsorption on XAD (10³-fold) followed by elution with DMSO.Using strain TA 98, all Rhine water samples except one were found to contain both direct and indirect mutagens. No significant mutagenic activity was detected in the lake samples and most of the river Meuse samples. None of the samples were shown to be mutagenic when tested with strains TA 100 or TA 1535.On examining one Rhine location more frequently, the mutagenic activity was found to be persistent and to vary about 5- to 6-fold during one year.Finally, liver homogenates of bream (Abramis brama) from these waters were compared with the standard rat liver S-9 with regard to their ability to activate the indirect mutagens present in the water concentrates. Compared with the rat liver homogenates, the liver homogenates of Rhine fish were found to be equally active and those of Meuse fish somewhat less. No metabolic activation was observed with liver homogenates of the lake fish.     

反相高效液相色谱法测定地红霉素的含量

报道反相高效液相色谱法测定地红霉素含量的方法。采用ODS柱 (15 0× 4 6mm) ,以磷酸三乙胺缓冲液 乙腈 甲醇 (35∶45∶2 0 )为流动相 ,使用紫外检测器 ,于 2 15nm波长处测定。线性范围为 1 0～ 9 0g·L-1(r =0 9999) ,RSD =0 9% (n =9)。检测限为 5 0× 10 -2 mg。本法可对地红霉素中的 (9)S 红霉胺、16 (R) 地红霉素、16 (S) 地红霉素的等组分进行分离测定 ,具有快速、简便、灵敏、准确的特点     

Mutagenicity and chemopreventive activities of Astronium species assessed by Ames test

In the neotropical savannah, Astronium species are used in popular medicine to treat allergies, inflammation, diarrhea and ulcers. Given that natural products are promising starting points for the discovery of novel potentially therapeutic agents, the aim of the present study was to investigate the mutagenic and antimutagenic activities of hydroalcoholic extracts of Astronium spp. The mutagenicity was determined by the Ames test on Salmonella typhimurium strains TA98, TA97a, TA100 and TA102. The antimutagenicity was tested against the direct-acting and indirect-acting mutagens. The results showed that none of the extracts induce any increase in the number of revertants, demonstrating the absence of mutagenic activity. On the other hand, the results on the antimutagenic potential showed a moderate inhibitory effect against NPD and a strong protective effect against B[a]P and AFB₁. This study highlights the importance of screening species of Astronium for new medicinal compounds. The promising results obtained open up new avenues for further study and provide a better understanding the mechanisms by which these species act in protecting DNA from damage. However, further pharmacological and toxicological investigations of crude extracts of Astronium spp., as well as of its secondary metabolites, are necessary to determine the mechanism(s) of action to guarantee their safer and more effective application to human health.     

遗传毒性评价Ames试验方法的比较分析

Ames试验是一项体外致突变性试验,被广泛用于药物、食品、化学品和农药的遗传毒性检测,以评价受试物致突变的可能性。药物、食品、化学品和农药的指导原则和国家标准中Ames试验方法不尽相同,就这几者Ames试验方法的主要异同点进行比较分析,以期能熟练掌握Ames试验实施要点,更加规范实施检测工作,不断提高试验质量。     

现行药物、保健食品和化妆品Ames试验方法的比较分析

Ames试验广泛应用于药物、食品、化妆品及医疗器械的遗传毒性研究,是应用最广泛的检测基因突变的体外试验.药物、保健食品和化妆品Ames试验方法有一定的差异,该文就药物、保健食品和化妆品Ames试验方法的主要异同点作一比较分析.     

白眉蝮蛇毒精氨酸酯酶Ames试验(英文)

目的　研究白眉蝮蛇 (Agkistrodonhalysussuriensis)毒中精氨酸酯酶的致突变作用。 方法　用鼠伤寒沙门细菌营养缺陷型突变株TA97,TA98,TA10 0和TA10 2 ,采用平皿掺入法进行Ames试验 ,将实验分为加和不加代谢激活系统S92组平行试验。精氨酸酯酶设 6个浓度 :10 .0× 10 -3 ,5 .0× 10 -3 ,2 .5× 10 -3 ,1.2 5× 10 -3 ,0 .6 2 5× 10 -3 和 0 .312× 10 -3 U/mL。结果　加和不加代谢激活系统S9两种条件下 ,精氨酸酯酶不诱发鼠伤寒沙门细菌营养缺陷型突株的回复突变。Ames试验结果为阴性。结论　从致突变角度考虑 ,精氨酸酯酶在高于“蝮蛇清栓酶”(主要成分为精氨酸酯酶 )临床治疗剂量约 10 0 0倍的条件下仍然较安全。     

浊度法测定地红霉素效价

目的:建立浊度法测定地红霉素效价的方法,及效价测定的最佳条件并探讨地红霉素含量测定的最佳方法。方法:浊度法以金黄色葡萄球菌为实验菌,加菌量为1.5%～3%(V/V),(37±1)℃培养4～6h 测定。同时以高效液相色谱法、管碟法对样品及对照品进行测定。结果:地红霉素浊度法抗生素线性浓度范围为1.0～10.0μg·mL~(-1),回归方程为 A=384.448C 588.816,r=0.9998;一剂量、二剂量的平均回收率分别为102.5%(n=5)、101.7%(n=6),口内 RSD 分别为1.45%,0.94%;日间 RSD 分别为1.97%,1.12%。结论:浊度法灵敏,快速,可作为地红霉素效价测定法。     

地红霉素肠溶微丸胶囊的生物等效性

目的：建立准确、灵敏的HPLC-MS测定人血浆中红霉素胺浓度的方法，研究地红霉素肠溶微丸胶囊健康志愿者生物等效性。方法：20名健康志愿者采用两制剂双周期自身对照交叉试验设计，单剂量口服地红霉素试验制剂和参比制剂各500mg，用液相色谱-质谱法测定血浆地红霉素代谢物红霉素胺的浓度，并计算两制剂的主要药动学参数及相对生物利用度。结果：红霉素胺的浓度与吸收峰面积比值在4．5-720μg·L^-1范围内线性关系良好，线性回归方程为C=0．014A-0．0214，r=0．9998（n=5），最低定量限为4．5μg·L^-1。低、中、高3种浓度的方法回收率为98．89％，99．78％，98．65％，平均提取回收率为70．55％，70．50％，71．52％，日内、日间RSD均小于10％。单剂量口服500mg的地红霉素试验制剂和参比制剂的主要药动学参数AUG0→96（梯形法）分别为（3025．6±690．9），（2862．8±672．1）μg·h·L^-1，AUG0-∞（梯形法）分别为（3679．0±888．1），（3500．9±813．2）μg·h·L^-1；Cmax（实测）分别为（390．4±81．2）ng·mL^-1和（396．0±63．2）μg·L^-1；tmax（实测）为（3．3±0．4），（3．35±0．29）h。受试制剂的相对生物利用度为（107．6±20．2）％。结论：该方法简单，准确度高，灵敏度好，可用于地红霉素人血药浓度测定。统计分析结果表明，两种制剂的主要药动学参数之间无明显差异；双单侧t检验结果表明，两种制剂具有生物等效性。     

Genotoxicity evaluation of titanium dioxide nanoparticles using the Ames test and Comet assay

Titanium dioxide nanoparticles (TiO₂‐NPs) are being used increasingly for various industrial and consumer products, including cosmetics and sunscreens because of their photoactive properties. Therefore, the toxicity of TiO₂‐NPs needs to be thoroughly understood. In the present study, the genotoxicity of 10nm uncoated sphere TiO₂‐NPs with an anatase crystalline structure, which has been well characterized in a previous study, was assessed using the Salmonella reverse mutation assay (Ames test) and the single‐cell gel electrophoresis (Comet) assay. For the Ames test, Salmonella strains TA102, TA100, TA1537, TA98 and TA1535 were preincubated with eight different concentrations of the TiO₂‐NPs for 4 h at 37 °C, ranging from 0 to 4915.2 µg per plate. No mutation induction was found. Analyses with transmission electron microscopy (TEM) and energy‐dispersive X‐ray spectroscopy (EDS) showed that the TiO₂‐NPs were not able to enter the bacterial cell. For the Comet assay, TK6 cells were treated with 0–200 µg ml^–1 TiO₂‐NPs for 24 h at 37 °C to detect DNA damage. Although the TK6 cells did take up TiO₂‐NPs, no significant induction of DNA breakage or oxidative DNA damage was observed in the treated cells using the standard alkaline Comet assay and the endonuclease III (EndoIII) and human 8‐hydroxyguanine DNA‐glycosylase (hOGG1)‐modified Comet assay, respectively. These results suggest that TiO₂‐NPs are not genotoxic under the conditions of the Ames test and Comet assay. Published 2012. This article is a US Government work and is in the public domain in the USA.