20-7 一种新的对乙型肝炎病毒具有活性的抗病霉药物BMS-200475的代谢情况

ＢＭＳ－２００４７５原是作为抗疱疹病毒药物（ＳＱ－３４６７６）而合成的,对Ｉ型单纯性疱疹病毒（ＨＳＶ－１）、Ⅱ型单纯性疱疹病毒（ＨＳＶ－２）和水痘一带状疱疹病毒具有中度活性,对人巨细胞病毒也有活性,但对ＲＮＡ病毒如人免疫缺陷病毒或流感病毒没有活性。最近发现ＢＭＳ－２００４７５对乙型肝炎病毒（ＨＢＶ）具有高度活性,５０％有效浓度为３．７ｎｍｏｌ／Ｌ,５０％细胞毒浓度为３０μｍｏｌ／Ｌ。用对数生长期细胞检测核苷类药物的胞内代谢,而ＨＢＶ活性的检测则使用停滞期的２．２．１５细胞。在ＭｅｐＧＺ细胞和ＨＢ…     

维拉帕米、硝苯地平对人成纤维细胞增殖、胶原和透明质酸合成的抑制作用

研究维拉帕米（Ｖｅｒ）和硝苯地平（Ｎｉｆ）对人胚肺成纤维细胞（ＨＬＦ）增殖、胶原与透明质酸（ＨＡ）合成的作用，为应用钙通道阻滞剂防治器官纤维化提供实验依据。分别采用四氮唑蓝（ＭＴＴ）比色法、３Ｈ－脯氨酸参入和放射免疫法测定细胞增殖、胶原和ＨＡ合成。Ｖｅｒ和Ｎｉｆ在２０～４０μｍｏｌ·Ｌ－１浓度范围内均以浓度依赖方式抑制ＨＬＦ增殖及胶原和ＨＡ合成。Ｖｅｒ和Ｎｉｆ具有抗纤维化作用。     

人巨细胞病毒蛋白酶及其抑制剂的研究进展

人巨细胞病毒（ＨＣＭＶ）属于β家族疱疹病毒,ＨＣＭＶ蛋白酶在装配蛋白产生和病毒壳体成熟中具有重要作用,抑制ＨＣＭＶ蛋白酶可产生抗疱疹病毒药物,ＨＣＭＶ蛋白酶属丝氨酸蛋白酶类,以均二聚体为其唯一活性形式,其活性位点催化三联体的构成与典型的已知丝氨酸蛋白酶有明显不同。晶体结构数据显示ＨＣＭＶ蛋白酶单体只有一个结构域,由一个丝氨酸（Ｓｅｒ１３２）和两个组氨酸（Ｈｉｓ６３和Ｈｉｓ１５７）构成催化三联体,ＨＣＭＶ蛋白酶对序列Ｐ５－Ｐ５′肽段（ＧＶＶＮＡ／ＳＣＲＬＡ）水解活性最级;仍维持显著活性的最小肽段为Ｐ４－Ｐ４′。目前有关ＨＣＭＶ蛋白酶抑制剂的研究报道还比较少,其中以底物抑制剂较引人注目。     

强啡肽A－（1－13）类似物的合成及生物活性

用固相多肽合成方法，合成了强啡肽Ａ－（１－１３）（Ｉ）及其类似物［Ａｌａ８，Ｄ－Ｐｒｏ１０］－ＤＹＮＡ－（１－１３）－ＮＨ２（ＩＩ）和［Ｄ－Ａｌａ２，Ａｌａ８，Ｄ－Ｐｒｏ１０］－ＤＹＮＡ－（１－１３）－ＮＨ２（ＩＩＩ），并对其进行了镇痛活性试验和ＭＶＤ及ＲＶＤ试验。结果表明，合成产物均有镇痛活性，其中类似物ＩＩＩ的镇痛活性是１的３．６倍，ＲＶＤ试验活性比１强１３５倍，比已知的ｋ－受体强激动剂Ｕ５００４８８强１１倍。     

慢性活动性乙型肝炎的HBV和HCV重叠感染及其抗—HCV抗体的临床意义

应用酶免疫法检测天津地区９０例慢性活性乙型肝炎患者的抗丙型肝炎病毒（抗－ＨＣＶ）抗体。对抗－ＨＣＶ阳性患者的血清进行了Ｎｅｓｔｅｄ－ＰＣＲ检测。９０例患者有２４例为抗－ＨＣＶ阳性，阳性率为２６．７％；２４例抗－ＨＣＶ阳性患者经ＰＣＲ检测，８例为ＨＣＶ ＲＮＡ阳性。本组研究表明，天津地区慢性活动性肝炎患者血清中存在高水平的抗－ＨＣＶ。在一定数量的患者中抗－ＨＣＶ与ＨＣＶ ＲＮＡ并存，揭示确有ＨＢＶ和     

间硝苯地平对血管紧张素Ⅱ促进血管平滑肌细胞增殖和蛋白质合成的影响

以培养血管平滑肌细胞（ｖａｓｃｕｌａｒｓｍｃｏｔｈｍｕｓｃｌｅｃｅｌｌ，ＶＳＭＣ）为模型，观察了间硝苯地平（ｍ－ｎｉｆｅｄｉｐｉｎｅ，ｍ－Ｎｉｆ）对血管紧张素Ⅱ（ａｎｇｉｏｔｅｎｓｉｎⅡ，ＡＮＧⅡ）促进ＶＳＭＣ增殖和蛋白质合成的影响。结果表明，ｍ－Ｎｉｆ抑制ＡＮＧⅡ（１００ｎｍｏｌ·Ｌ￣（－１））引起ＶＳＭＣ［￣３Ｈ］ｔｈｙｍｉｄｉｎｅ和［￣３Ｈ］ｌｅｕｃｉｎｅ参入，并呈剂量依赖性。ｍ－Ｎｉｆ（２×１０￣（－６）ｍｏｌ·Ｌ￣（－１））可抑制ＡＮＧⅡ对ＶＳＭＣ的刺激、ＤＮＡ及蛋白质合成速率，分别降低了４６％，５８％，５３％。提示ｍ－Ｎｉｆ可抑制ＡＮＧⅡ对ＶＳＭＣ增殖和蛋白合成的促进作用     

蜕皮甾酮对人脐静脉内皮细胞增殖的影响

目的：研究一种植物成分——蜕皮甾酮（ＥＤＳ）是否能影响人脐静脉血管内皮细胞（ＨＵＶＥＣ）增殖。方法：采用血管内皮细胞（ＶＥＣ）体外培养的方法，以ＭＴＴ法及流式细胞术观察细胞增殖的情况。结果：（１）ＤＥＳ能够影响ＨＵＶＥＣ代谢ＭＴＴ；（２）ＤＥＳ的浓度对ＨＵＶＥＣ的ＭＴＴ代谢物—ｆｏｒｍａｚａｎ的生成量有影响：在２５～４００ｍｇ·Ｌ－１，ＥＤＳ促进线粒体代谢ＭＴＴ、形成ｆｏｒｍａｚａｎ，并且在２００ｍｇ·Ｌ－１时可使ｆｏｒｍａｚａｎ的形成量达到最高值；在８００ｍｇ·Ｌ－１以上浓度时，ｆｏｒｍａｚａｎ的形成量减少，并低于正常培养的ＨＵＶＥＣ的ｆｏｒｍａｚａｎ的形成量。（３）在２００ｍｇ·Ｌ－１时，流式细胞术显示，ＥＤＳ能够影响ＨＵＶＥＣ的细胞周期：ＥＤＳ可促进ＨＵＶＥＣ由静止期和（或）ＤＮＡ合成前期进入ＤＮＡ合成期、由ＤＮＡ合成期进入ＤＮＡ合成后期和（或）分裂期。结论：ＥＤＳ能够刺激ＶＥＣ分裂、增殖，并且ＶＥＣ的增殖状况与ＥＤＳ的浓度有关。     

107例静脉药瘾者丙型肝炎、庚型肝炎病毒重叠感染的研究

目的 了解海洛因静脉药瘾者ＨＧＶ／ＨＣＶ重叠感染状况。方法 用酶联免疫间接法,逆转录套式聚合酶链反应（ＲＴ－ｎＰＣＲ）分别检测１０７例静脉药瘾者抗－ＨＣＶ、ＨＣＶ ＲＮＡ、ＨＧＶ ＲＮＡ。结果 抗－ＨＣＶ（＋）者ＨＧＶ ＲＮＡ（＋）检出率达４８．１５％,而抗－ＨＣＶ（－）者则为２２．６４％,两组比较,差异有极显著意义（Ｘ＾２＝７．５９,Ｐ〈０．０１）。在ＨＧＶ／ＨＣＶ重叠感染者中,单项抗－ＨＣＶ（     

N－（4－甲氧羰基－4－邻苯二甲酰亚氨基丁酰基）－N－取代甘氨酸、脯氨酸和焦谷氨酸的合成

报道ｌｌ个预期有血管紧张素转化酶抑制活性的Ｎ－（４－甲氧羰基－４－邻苯二甲酰亚氨基丁酰基）－Ａ－取代甘氨酸（ＶＩＩ１－９）、脯氨酸（ＶＩｌ１０）和焦谷氨酸（ＶＩｌ１１）的合成和鉴定。所有上述化合物以及与ＶＩＩ１－９相应的叔丁酯（ＶＩ１～９）均未见文献报道。药理初试结果显示，化合物ＶＩＩ８，ＶＩＩ９和ＶＩｌ１０均有明显降压活性。     

慢性丙型肝炎患者血清TNF/Stnf-R的变化及其临床意义

目的 探讨慢性丙型肝炎（ＨＣＶ）患者血清肿瘤坏死因子（ＴＮＦ）和可生肿瘤坏死因子受体（ＳＴＮＦ－Ｒ）的变化及其临床意义。方法 应用酶联免疫吸附试验（ＥＬＩＳＡ）检测慢性ＨＣＶ患者血清ＴＮＦ和ＳＴＮＦ－Ｒ水平；同时采用速率法在全自动生化分析仪上测定血清丙氨酸转氨酶（ＡＬＴ）和天冬氨酸转氨酶（ＡＳＴ）的活性。结果 慢性ＨＣＶ患者血清ＴＮＦ和ＳＴＮＦ－Ｒ显著高于下沉脸；血 ＳＴＦ－Ｒ２与ＡＳＴ、ＡＬＴ显     

Efficacy of gut lavage,hemodialysis, and hemoperfusion in the therapy of paraquat or diquat intoxication

Clinical and in vitro investigations were carried out to test the efficacy of gut lavage, hemodialysis, and hemoperfusion in the treatment of poisoning with paraquat or diquat. In a patient suffering from diquat intoxication 130 times more diquat was removed by gut lavage 30 h after ingestion than was removed by complete aspiration of the gastric contents.Determination of in vitro clearances for paraquat and diquat by hemodialysis showed that, at serum concentrations of 1–2 ppm, such as are frequently encountered in poisoning in man, toxicologically relevant quantities of herbicide cannot be removed from the body. At a concentration of 20 ppm, on the other hand, hemodialysis proved to be effective, the clearance being 70 ml/min at a blood flow rate of 100 ml/min. The efficacy of hemoperfusion with coated activated charcoal was on the whole better. Especially at concentrations around 1–2 ppm, the clearance values for hemoperfusion were some 5–7 times higher than those for hemodialysis.In a patient suffering from paraquat poisoning, both hemodialysis as well as hemoperfusion were carried out. The in vitro results could be confirmed: At serum concentrations of paraquat less than 1 ppm no clearance could be obtained by hemodialysis while by hemoperfusion with activated charcoal quite high clearance values were measured and the serum level dropped down to zero.

---

Zusammenfassung Klinische Untersuchungen und Laboratoriumsversuche wurden durchgeführt, um die Wirksamkeit von Darmspülung, Hämodialyse und Hämoperfusion bei Paraquat- und Deiquat-Vergiftungen zu prüfen.Bei einem Patienten wurde 30 Std nach Deiquat-Aufnahme durch Darmspülung 130mal mehr Deiquat entfernt als durch vollständige Aspiration des Mageninhaltes. In vitro-Versuche ergaben, daß bei Blutserumkonzentrationen von 1–2 ppm, die bei Vergiftungen oft gemessen werden, durch Hämodialyse keine toxikologisch relevanten Paraquat- oder Deiquat-Mengen entfernt werden können. Dagegen erwies sich die Hämodialyse bei 20 ppm und einer Blutumlaufgeschwindigkeit von 100 ml/min mit einer Clearance von 70 ml/min als wirksam. Die Hämoperfusion mit beschicheter Aktivkohle war in diesen Versuchen aber eindeutig überlegen, denn insbesondere bei Konzentrationen um 1–2 ppm waren die Clearance-Werte 5–7mal höher als bei der Hämodialyse.Die in vitro-Ergebnisse wurden bei einem Patienten mit einer Paraquat-Vergiftung bestätigt: Bei Konzentrationen unter 1 ppm war die Hämodialyse wirkungslos, während durch Hämoperfusion relativ hohe Clearance-Werte erreicht wurden, so daß der Serumspiegel rasch unter die Nachweisgrenze abfiel.

     

In vitro studies on sterically stabilized liposomes (SL) as enzyme carriers in organophosphorus (OP) antagonism

This study describes a new approach for organophosphorous (OP) antidotal treatment by encapsulating an OP hydrolyzing enzyme, OPA anhydrolase (OPAA), within sterically stabilized liposomes. The recombinant OPAA enzyme was derived from Alteromonas strain JD6. It has broad substrate specificity to a wide range of OP compounds: DFP and the nerve agents, soman and sarin. Liposomes encapsulating OPAA (SL)* were made by mechanical dispersion method. Hydrolysis of DFP by (SL)* was measured by following an increase of fluoride ion concentration using a fluoride ion selective electrode. OPAA entrapped in the carrier liposomes rapidly hydrolyze DFP, with the rate of DFP hydrolysis directly proportional to the amount of (SL)* added to the solution. Liposomal carriers containing no enzyme did not hydrolyze DFP. The reaction was linear and the rate of hydrolysis was first order in the substrate. This enzyme carrier system serves as a biodegradable protective environment for the recombinant OP-metabolizing enzyme, OPAA, resulting in prolongation of enzymatic concentration in the body. These studies suggest that the protection of OP intoxication can be strikingly enhanced by adding OPAA encapsulated within (SL)* to pralidoxime and atropine.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

Aquatic Insects and Trace Metals: Bioavailability,Bioaccumulation, and Toxicity

Abstract

The uptake of metals from food and water sources by insects is thought to be additive. For a given metal, the proportions taken up from water and food will depend both on the bioavailable concentration of the metal associated with each source and the mechanism and rate by which the metal enters the insect. Attempts to correlate insect trace metal concentrations with the trophic level of insects should be made with a knowledge of the feeding relationships of the individual taxa concerned. Pathways for the uptake of essential metals, such as copper and zinc, exist at the cellular level, and other nonessential metals, such as cadmium, also appear to enter via these routes. Within cells, trace metals can be bound to proteins or stored in granules. The internal distribution of metals among body tissues is very heterogeneous, and distribution patterns tend to be both metal and taxon specific. Trace metals associated with insects can be both bound on the surface of their chitinous exoskeleton and incorporated into body tissues. The quantities of trace meals accumulated by an individual reflect the net balance between the rate of metal influx from both dissolved and particulate sources and the rate of metal efflux from the organism. The toxicity of metals has been demonstrated at all levels of biological organization: cell, tissue, individual, population, and community. Much of the literature pertaining to the toxic effects of metals on aquatic insects is based on laboratory observations and, as such, it is difficult to extrapolate the data to insects in nature. The few experimental studies in nature suggest that trace metal contaminants can affect both the distribution and the abundance of aquatic insects. Insects have a largely unexploited potential as biomonitors of metal contamination in nature. A better understanding of the physico-chemical and biological mechanisms mediating trace metal bioavailability and exchange will facilitate the development of general predictive models relating trace metal concentrations in insects to those in their environment. Such models will facilitate the use of insects as contaminant biomonitors.