近年来国外前列腺素全合成的进展

(一) 前列腺素(Prostaglandin,简称PG)是一类活性很广泛的人体内部化学物质。于五十年代末从羊精囊中分离得到纯品。其基本结构是一个具五碳环和二个侧链(简称C_7和C_8侧链)的二十碳脂肪酸,称为前列酸。现已发现的天然PG至少有14种,按其五碳环上的取代情     

碳青霉烯类抗生素国内外开发现状与前景分析

碳青霉烯类抗生素是迄今为止抗感染药物中抗菌谱最广、抗菌活性最强的“非典型性”B内酰胺类抗生素。碳青霉烯的化学结构不同于青霉素／头孢菌素类抗生素之处在于其母环的2位上多了一个双键,4位上的硫原子被碳原子所取代。     

[1,2,4]三嗪并[3,4-h][1,8]萘啶-8-酮-7-羧酸衍生物的设计合成及抗菌和抗细胞增殖活性

为发现新结构氟喹诺酮先导物,基于药效团拼合药物设计原理,用[1,2,4]三嗪核为稠合环,设计合成了新三环氟喹诺酮衍生物[1,2,4]三嗪并[3,4-h][1,8]萘啶-8-酮-7-羧酸目标化合物(5a~5p),结构经光谱数据和元素分析确证,并对其体外抗菌和抗细胞增殖活性进行了评价。结果表明,目标化合物对耐药菌株和SMMC-7721肝癌细胞株有较强的抑制活性。构-效关系显示,供电子基取代的苯基化合物有利于提高抗菌活性,而吸电子基取代的苯基化合物显示出较强的抗肿瘤活性,其中部分化合物的IC50值与对照药阿霉素相当。因此,三嗪稠合的三环氟喹诺酮羧酸作为新的抗菌抗肿瘤新先导物值得关注和进一步的研究。     

二氢吲哚类化合物的合成及其抑酶活性

本文报道了一系列二氢吲哚衍生物的合成,并测定其抑制胆碱酯酶活性,发现二氢吲哚环被二氢吲哚酮结构所取代,3位季碳被仲碳原子所取代,5位以可能有抑制酶活性的环磷酰基或磺酰基代替二甲氨甲酰基,均使抑酶活性几乎完全消失。在合成过程中,使1位N-烃化或5位O-酰化选择性地进行。     

头孢菌素类的现行使用法

头孢菌素是一类广谱半合成β-内酰胺抗生素。它们的7-氨基头孢霉烷酸,或头孢烯母核由β-内酰胺环与二氢噻嗪环稠合组成。在3位上的侧链取代基常常影响动力学的性质及个别药物的代谢稳定性,而在7位或7α位上的侧链取代基则影响其抗菌谱和对β-内酰胺酶的稳定性。具有7α-甲氧基取代基的头霉素类[如:头孢西丁(Cefoxitin)]和     

新碳头孢烯KT3777

KT3777系日本协和发酵工业公司采用全合成法创制的口服碳头孢烯抗生素.结构与头孢克罗最近似,所不同的是β-内酰胺邻接的六元环上的硫原子被碳原子所取代.     

meropenem

meropenem(SM-7338,MEPM)是注射用极广谱的碳青霉烯类抗生素.由于它与亚胺培南(IPM)碳青霉烯环的取代基结构不同,因而对人肾脱氢肽酶(DHP-1)的灭活作用极其稳定,就不必像用IPM那样必须同时用DHP-1抑制剂西司他丁(CS).     

药物设计中一种实验性的Hansch方法

药物设汁中一个常见的问题是寻找苯环或稠环系统中苯核上的适当取代基,以获得最大的作用强度。根据Hansch方法的基本原理,应用图解方式,不必进行多元回归分析就可迅速选择合成最有效的化合物。本文通过合成一组代表苯环上不同取代基类型的化合物来进行取代基的选择,因而可作为实     

前列地尔的剂型及研究进展

前列地尔，又名前列腺素E1，是天然前列腺素（Prostaglandinum，PG）类物质中的一种。前列腺素存在于大多数哺乳动物组织内，基本结构为含有1个环戊烷及2个脂肪侧链的20碳脂肪酸。根据环戊烷上双键位置和取代基的不同可以分为几种类型，其中主要有E、F、A、B等4类。每一类有不同的亚型，具有广泛的生物学效应。     

鬼臼脂素C—环不同结构类型对抗肿瘤活性的影响

合成了鬼臼脂素C环4－位羟基不同取向．C环芳构化．C环反式和非反式稠合．C环2,3－不饱和．C环3－位引入溴原子等不同结构类型的化合物,并测试了其体外抑制KB细胞和L1210白血病细胞活性。C环结构类型不同,对细胞毒活性影响也不同。     

Zinc: a multipurpose trace element

Zinc (Zn) is one of the most important trace elements in the body and it is essential as a catalytic, structural and regulatory ion. It is involved in homeostasis, in immune responses, in oxidative stress, in apoptosis and in ageing. Zinc-binding proteins (metallothioneins, MTs), are protective in situations of stress and in situations of exposure to toxic metals, infections and low Zn nutrition. Metallothioneins play a key role in Zn-related cell homeostasis due to their high affinity for Zn, which is in turn relevant against oxidative stress and immune responses, including natural killer (NK) cell activity and ageing, since NK activity and Zn ion bioavailability decrease in ageing. Physiological supplementation of Zn in ageing and in age-related degenerative diseases corrects immune defects, reduces infection relapse and prevents ageing. Zinc is not stored in the body and excess intakes result in reduced absorption and increased excretion. Nevertheless, there are cases of acute and chronic Zn poisoning.     

耐药鲍曼不动杆菌不同年份分离株耐药元件基因比较研究

目的 调查两组相隔7年的鲍曼不动杆菌菌株可能存在的耐药基因状况及菌株间的亲缘关系。方法 分别收集南京医科大学附属淮安第一医院2008年20株鲍曼不动杆菌，2016年20株鲍曼不动杆菌。菌种鉴定为鲍曼不动杆菌种特异mdfA基因与blaOXA-51基因PCR双重检测为阳性方确认为鲍曼不动杆菌。再用PCR方法检测32种β-内酰胺类药物获得性耐药基因、15种氨基糖苷类药物获得性耐药基因、10种可移动遗传元件遗传标记，最后对检测结果作样本聚类分析(UPGMA法)。 结果 2016年分离株对第三代头孢类药物、碳青霉烯类药物、氨基糖苷类药物、喹诺酮药物均为耐药。2008年分离株仅对第三代头孢类药物均为耐药，而对碳青霉烯类药物均为敏感，对喹诺酮药物、氨基糖苷类药物分别有50.00%和60.00%的敏感性。2008和2016年分离株均检出blaADC和blaOXA-51，但blaOXA-2群、blaOXA-23群只有2016年分离株均被检出。2008年分离株对第三代头孢类药物耐药主要与blaADC相关，2016年分离株对第三代头孢类药物、碳青霉烯类药物耐药主要与blaADC、blaOXA-2群和blaOXA-23群相关。2016年分离株均测出aac(2)-Ⅰb、aph(3)-Ⅰ、armA等3种氨基糖苷类药物耐药相关基因，而2008年分离株均无检出。可移动遗传元件遗传标记tnpU、tnp513、IS26和ISaba1等4种也只有2016年分离株被全部检出。菌株亲缘关系分析可见2008和2016年不同年份分离株分成两个独立的簇群(A簇群和B簇群)，2016年分离株聚集性更强相差系数更小。A和B簇群均可分为两个亚簇群。A-1亚簇群有两个克隆播散，A-2、B-1和B2亚簇群各有一个克隆播散。其中2016年分离株B-簇群一个有14株菌构成的大克隆播散。分离株耐药元件检测阳性模式显示，2008年分离株仅携带2~7种耐药元件基因；2016年分离株则携带14种~16种耐药元件基因。结论 多种β-内酰胺类药物耐药基因、氨基糖苷类药物耐药基因和可移动遗传元件是导致鲍曼不动杆菌对抗菌药物耐药的重要原因。在同一家医院的对相隔7年的鲍曼不动杆菌临床分离株进行耐药元件基因检测与分析是国内首次报道。不同年份分离株的耐药性和耐药元件基因携带状况差异明显：2016年分离株比2008年分离株耐药性更强，携带的耐药元件基因更多。2008年和2016年分离株均有克隆播散，提示有医院感染的存在。     

糖尿病性偏侧舞蹈症的临床分析

目的探讨糖尿病性偏侧舞蹈症的临床特点、发病机制、影像学改变及预后,防止误诊及漏诊。方法回顾性分析10例糖尿病性偏侧舞蹈症的临床症状、影像学变化、实验室检查结果和治疗经过,并复习相关文献。结果①10例均为未经治疗的糖尿病患者,其中6例为糖尿病非酮症高血糖症,4例为酮症高血糖症。②临床表现;7例为突发起病并以一侧肢体为主的持续性舞蹈样运动,3例为发作性口角抽动伴单肢不自主舞动起病。症状均清醒时出现,睡眠时消失。肌力均为5级,肌张力均正常。③影像学表现:早期CT表现为舞蹈症状对侧的尾状核、壳核和(或)苍白球,丘脑的高密度影像,内囊未受累,并在1个月左右减弱或消失;磁共振(MRI) T_1像为病灶部位的片状高信号,在持续数月后信号减低,T_2则表现为稍低信号或病灶部位区域中心混杂信号而周边高信号,边界清晰,无明显水肿征象。④本组患者均给予氟哌啶醇及氯硝安定等药物治疗并控制血糖,症状均在短期内迅速改善。结论糖尿病性偏侧舞蹈症多见于血糖控制不佳的糖尿病患者,结合特定部位的变化性磁共振成像及肢体舞蹈样动作可以做出诊断。在控制血糖的基础上,应用氟哌啶醇和氯硝安定治疗效果较好。     

Species differences in bile acids I. Plasma and urine bile acid composition

Maintenance of bile acid (BA) homeostasis is essential to achieve their physiologic functions and avoid their toxic effects. The marked differences in BA composition between preclinical safety models and humans may play a major role in the poor prediction of drug‐induced liver injury using preclinical models. We compared the composition of plasma and urinary BAs and their metabolites between humans and several animal species. Total BA pools and their composition varied widely among different species. Highest sulfation of BAs was observed in human and chimpanzee. Glycine amidation was predominant in human, minipig, hamster and rabbit, while taurine amidation was predominant in mice, rat and dogs. BA profiles consisted primarily of tri‐OH BAs in hamster, rat, dog and mice, di‐OH BAs in human, rabbit and minipig, and mono‐OH BA in chimpanzee. BA profiles comprised primarily hydrophilic and less toxic BAs in mice, rat, pig and hamster, while it primarily comprised hydrophobic and more toxic BAs in human, rabbit and chimpanzee. Therefore, the hydrophobicity index was lowest in minipig and mice, while it was highest in rabbit, monkey and human. Glucuronidation and glutathione conjugation were low in all species across all BAs. Total concentration of BAs in urine was up to 10× higher and more hydrophilic than plasma in most species. This was due to the presence of more tri‐OH, amidated, sulfated and primary BAs, in urine compared to plasma. In general, BA profiles of chimpanzee and monkeys were most similar to human, while minipig, rat and mice were most dissimilar to human.     

Methylmercury exposure associated with reduced productivity in common loons

Methylmercury can impair the reproduction of fish-eating wildlife. We measured lake pH, mercury (Hg) concentrations in small fish, blood Hg levels in adult male, female and juvenile common loons, and loon productivity from 120 lakes in Wisconsin, USA and New Brunswick and Nova Scotia, Canada (Maritimes). Mean lake pH was higher in Wisconsin than in the Maritimes. Body masses of adult loons and Hg concentrations in the blood of loons and in small fish were greater in the Maritimes. Hg levels in fish increased with lake acidity. Abundance of small fish increased in acidic lakes in the Maritimes. Blood Hg concentrations in adult and juvenile loons decreased with lake pH and increased with Hg levels in fish prey. Hg levels in male, female and juvenile loons were 22, 16 and 2.3 times greater than those in small fish. Loon Hg exposure, measured either as Hg levels in female loon blood or in fish prey, appeared to impose an upper limit on loon productivity. Loon productivity decreased as Hg exposure increased. Quantile regression analysis indicated that maximum observed loon productivity dropped 50% when fish Hg levels were 0.21 ug/g (wet wt), and failed completely when fish Hg concentrations were 0.41 ug/g.     

Differential anxiogenic,aversive, and locomotor effects of THC in adolescent and adult rats

Rationale Unpleasant side effects of drugs of abuse often limit their repeated use; however, such effects may be attenuated in adolescents compared to adults. Objectives We investigated whether the anxiogenic, aversive, or locomotor effects of delta-9-tetrahydrocannabinol (THC) differ between adolescent and adult rats. Methods We used the elevated plus maze (EPM) and light-dark tests of anxiety, the conditioned taste aversion and conditioned place aversion (CPA) tests of generalized aversion, and measures of stress hormone levels in serum to examine effects of THC in adolescent and adult rats. Locomotor activity was also recorded in the EPM, light-dark task, and CPA association sessions. Results In the EPM and light-dark tasks, THC was anxiogenic in both age groups, but the drug was more anxiogenic in adults than in adolescents. In the place and taste aversion tasks, THC was aversive in both ages, and at 1.25 and 5 mg/kg, was more aversive in adults than in adolescents. The locomotor response to THC, as measured in the anxiety tasks and CPA, affected adults more than adolescents. Multiple measures revealed a locomotor-decreasing effect in adults, whereas some measures suggested a small locomotor-increasing effect in adolescent rats. Conclusions These results suggest that THC can have greater anxiogenic, aversive, and locomotor-reducing effects in adult rats than in adolescent rats. These findings suggest an explanation for reduced marijuana use in adult humans compared to teenagers.     

Evaluation of flushing of a high-selenium backwater channel in the Colorado River

Concern has been raised that selenium contamination may be adversely affecting endangered fish in the upper Colorado River basin. The objective of the study was to determine if operation of a water control structure (opened in December 1996) that allowed the Colorado River to flow through a channel area at Walter Walker State Wildlife Area (WWSWA) would reduce selenium and other inorganic elements in water, sediment, aquatic invertebrates, and forage fish. Endangered Colorado pikeminnow were collected and muscle plug samples taken for selenium analysis. Selenium concentrations in filtered water were 21.0 microg/L in 1995, 23.5 microg/L in 1996, 2.1 microg/L in 1997, and 2.1 microg/L in 1998. Selenium concentrations in sediment cores and sediment traps were 8.5 microg/g in 1995, 8.2 microg/g in 1996, 4.8 microg/g in 1997, and 1.1 microg/g in 1998. Selenium concentrations in aquatic invertebrates were 27.4 microg/g in 1996, 15.5 microg/g in 1997, and 4.9 microg/g in 1998. Selenium concentrations in forage fish were 27.2 microg/g in 1996, 20.2 microg/g in 1997, and 8.6 microg/g in 1998. Selenium concentrations in muscle plugs of Colorado pikeminnow were 9.8 microg/g in 1995, 9.5 microg/g in 1996, 9.0 microg/g in 1997, and 10.3 microg/g in 1998. Although selenium concentrations in water, sediment, aquatic invertebrates, and forage fish decreased substantially after operation of the water control structure, a corresponding change in Colorado pikeminnow did not seem to occur. Selenium concentrations in muscle plugs decreased with increasing fish total length and weight, did not change between repeat sampling in the same year or recapture in subsequent years, and seemed to be most closely associated with the mean monthly river flow for the March-July period.     

Influence of cadmium and copper on tissue element levels of pregnant rats

In the current study, we examined the effects of Cd on Cd, Cu, Zn and Fe levels in placenta and maternal and fetal plasma and tissues, the placental weight, total fetal and maternal body weights, and fetal and maternal tissue weights during pregnancy. A total of 21 adult female rats were treated during gestation with drinking water containing one of the following: 70 mg/L of CdCl₂, a combination of 70 mg/L of CdCl₂ and 70 mg/L of CuSO₄, or no addition (control). Placenta Cu and Fe levels, fetal liver and kidney Cu levels, and fetal liver tissue weights were lower in the group administered Cd than in the control group. Also, Cd levels in the placenta, maternal and fetal liver, and maternal kidney were higher in the group treated with Cd than in controls. In the group administered both Cd and Cu, fetal body and tissue weights did not change, but Cd levels in the placenta, maternal and fetal liver, and maternal kidneys were higher than in controls. Zn and Fe levels in the maternal kidney and fetal liver were also lower in this group. Cd exposure during pregnancy resulted in Cd accumulation in maternal and fetal tissues during pregnancy and a decrease in the total weight of fetuses, and the combination of Cd and Cu caused some changes in the both maternal and fetal levels of Cu, Zn, and Fe, but it did not cause changes in the total fetal body weight or the weights of individual tissues.     

A review of poisonous plants that cause reproductive failure and malformations in the ruminants of Brazil

The objective of this review is to provide a report on toxic plants causing reproductive problems in ruminants in Brazil. Aspidosperma pyrifolium causes abortion or stillbirth in goats, as well as most likely in sheep and cattle, in the semiarid regions of Northeastern Brazil. Intoxications by Ateleia glazioveana, Tetrapterys acutifolia and T. multiglandulosa result in abortion and neonatal mortality in cattle and sheep, and the same signs have been experimentally observed in goats. These three plants can also cause cardiac fibrosis and a nervous disease with spongiosis of the central nervous system. Other plants known to cause abortion include Enterolobium contortisiliquum, E. gummiferum, Stryphnodendron coriaceum, S. obovatum and S. fissuratum. These plants can also cause digestive signs and photosensitization. Abortions have been reported in animals intoxicated by nitrates and nitrites as well. Infertility, abortions and the birth of weak offspring have been reported in animals intoxicated by plants containing swainsonine, including Ipomoea spp., Turbina cordata and Sida carpinifolia. Trifolium subterraneum causes estrogenism in cattle. Mimosa tenuiflora and, most likely, M. ophthalmocentra cause malformations and embryonic mortality in goats, sheep and cattle in the semiarid regions of Northeastern Brazil.     

Contribution of serum and cellular semicarbazide-sensitive amine oxidase to amine metabolism and cardiovascular toxicity.

Semicarbazide-sensitive amine oxidase (SSAO) plays a role in the in vivo and in vitro toxicity of several environmental and endogenous amines. We investigated the role of SSAO as a component of cell culture medium (through addition of fetal calf serum (FCS)) compared to intracellular SSAO in the in vitro cytotoxicity of three amines and metabolites. Smooth muscle cells and beating cardiac myocytes were grown in 96-well plates and exposed to various concentrations and combinations of FCS in medium, amines (allylamine, AA; benzylamine, BZA; and methylamine, MA), and amine metabolites (aldehydes: acrolein, benzaldehyde, and formaldehyde; hydrogen peroxide, H2O2; ammonia, NH3). Amine and amine metabolite cytotoxicity was quantified by monitoring cell viability. SSAO activity was measured in FCS, cardiovascular cells, or rat plasma by a radioenzymatic assay using [14C]BZA. Our data show that AA and its aldehyde metabolite, acrolein, were the most toxic compounds to both cell types. However, AA toxicity was FCS-dependent in both cell types, while BZA, MA, and amine metabolite (i.e., aldehydes, H2O2, and NH3) cytotoxicity showed little FCS dependence. In these experiments, medium containing 10% FCS had a calculated amine metabolic capacity that was 30- to 50-fold that of the cultured smooth muscle cellular content in a single well of a 96-well plate. Our study demonstrates that SSAO in FCS contributes to amine metabolism and cytotoxicity to rat cardiovascular cells in vitro and how critical it is to evaluate serum for its role in mechanisms of amine toxicity in vitro and in vivo.