多价态结合药物研究进展

生物体系多价态结合理论认为,生物实体(分子,表面)之间的结合是瞬间的多配体与多受体的多价态结合,这种多价态结合在生物体系中普遍存在,并具有单价态结合所没有的一些特点,特别是多价态结合的结合力更强。现对生物体系多价态结合理论的发展、多价态结合的基本特点及其机制,以及在药物研究方面的应用进行了综述。生物体系多价态结合理论为药物设计提供了新的策略,在抗耐药菌抗生素、抗流感病毒、抗艾滋病毒(H IV)、抗霍乱菌和抗肿瘤等方面都得到广泛应用。     

泛硫乙胺临床应用进展

泛硫乙胺(pantethine),又称潘特生,是组成辅酶A(CoA)的重要前体物质.CoA是生物体内最重要的酶之一,是生物体内众多代谢途径的辅助因子,包括脂肪酸氧化、糖分解代谢、氨基酸分解、血红素合成、乙酰胆碱合成等.     

多价的抑制剂有望成为抗流感药物

在流感病毒表面的酶位点选择性释放一种聚合物，可以增加该聚合物防止病毒粘附于红细胞的能力，这项研究将设计出生物界面相互作用的有效抑制剂。目前研究集中于合成多价的聚丙酷胺，这种聚合物与覆盖于流感病毒表面的两种蛋白质结合。其中绝大多数是血凝素，它与称为唾液酸的糖结合，而唾液酸是细胞表面受到病毒攻击的点；另一种蛋白质是神经氨酸青酶，可粘住唾液酸，使病毒通过粘液分泌（富含于唾液酸中），克服运行阻力，弓没感染效应；该酶还帮助新合成的流感病毒逃离受感染细胞，而去感染其他细胞。早期合成的聚合物与神经氨酸音酶和血…     

两种抗粘附活性乳糖苷及其荧光和生物素标记物的合成(英文)

白细胞与内皮细胞的粘附在炎症相关的疾病中起着重要作用,前期研究发现的多价乳糖苷可以很好地抑制该过程而发挥抗炎活性。我们以2-氨基-1,3-丙二醇、谷氨酸为连接臂,采用收敛法合成了二价乳糖苷An-2及四价乳糖苷Gu-4,这两个化合物显示了良好的抗粘附活性,对重症烧伤休克大鼠具有较好的治疗效果。利用An-2及Gu-4的荧光标记物Yan-2和YGu-4进行的抗粘附机制研究表明,多价乳糖苷的作用靶点是白细胞上的整合素CD11b。本文将报道这两种新的多价乳糖苷及其荧光和生物素标记物的合成。     

1,3-二羟基丙酮生物技术法生产及其在生物体内的代谢

目的介绍了微生物转化甘油生产二羟基丙酮的作用机理,以及二羟基丙酮在生物体内的代谢情况.方法综合最新国内外文献资料,阐述了甘油作为微生物发酵底物,逐步转化为二羟基丙酮的过程,以及二羟基丙酮在生物体内随着糖和脂肪代谢途径进入,从而分解代谢.结果和结论目前发现微生物转化甘油生产二羟基丙酮的合成途径有两条;而二羟基丙酮在生物体内也至少有两条分解代谢途径.     

在合成培养基中头孢菌素C生物合成的某些特点

本文用顶孢头孢霉菌(cephlaosporiam acremonium)281A为研究对象研究了头孢菌素C在合成培养基中生物合成的某些特点。首先考察了糖和多元醇对生长及头孢菌素-C生物合成的影响,证明该菌株能很好地同化各种糖和醇,在培养24小时,所有碳源(除蔗糖以外)都能使生长达到很高的速度,但抗生素的合成水平却有所不同。在利用蔗糖、淀粉和麦芽糖时,该菌合成头孢菌素C能力最强,因此这三种糖均可作为头孢霉菌培养基的碳源。     

生物防御性沙门菌重组疫苗

一些病原体有可能被错用于生物恐怖行为或生物战,因而需要有对这些病原体的预防性疫苗,生物防御疫苗应该既安全又容易免疫,并能在肺表面快速诱导抗各种气源性病原体的黏膜免疫.本文就研制基于沙门菌的多价生物防御疫苗所用的技术、必须考虑的事项、已取得的进步以及今后的展望等方面进行综述.     

夫西地酸钠的理化配伍禁忌

目的 探讨夫西地酸钠的配伍禁忌,以利临床合理用药.方法 收集2000年1月至2010年1月国内公开发表的相关文献,并进行归纳整理和分析.结果 夫西地酸钠与盐酸川芎嗪、维生素C、维生素B、酚磺乙胺、氨溴索、果糖二磷钠、门冬氨酸钾镁、转化糖、免疫球白蛋白、奥硝唑、庆大霉素、喹诺酮类等药物有配伍禁忌.结论 夫西地酸钠具有弱碱性、鳌合物性质,忌与弱酸性、多价金属离子化合物配伍用.     

海洋细胞毒药物与抗体偶联物的制备及生物活性评价

目的 以抗体N-糖链为偶联位点,制备曲妥珠单抗与海洋细胞毒药物单甲基澳瑞他汀E(MMAE)偶联物,并研究其对乳腺癌细胞BT474的杀伤作用。 方法 合成含叠氮和炔基修饰的唾液酸化寡糖,采用化学酶法制备含叠氮或炔基修饰的曲妥珠单抗,利用生物正交反应分别制备相应的抗体药物偶联物。利用SDS-PAGE 对转糖基及偶联过程进行监测,表面等离子共振技术(SPR)对叠氮或炔基修饰前后抗体与FcγRIIIa亲和力进行检测。利用CCK-8法评价两种抗体药物偶联物对乳腺癌细胞株BT474的杀伤作用。结果 成功制备了含叠氮或炔基修饰的曲妥珠单抗及N-糖链糖基位点抗体药物偶联物,修饰抗体与FcγRIIIa的亲和力较曲妥珠单抗增加,相比曲妥珠单抗,两种抗体MMAE偶联物对BT474有更明显的生长抑制作用。结论 基于抗体糖链末端唾液酸位点偶联的方法可有效应用于海洋细胞毒抗体偶联药物的开发。     

新霉胺类似物的合成与RNA结合和生物活性评价

为了提高新霉胺对16S rRNA的亲和力，合成了Ⅱ环5位修饰的新霉胺类似物。以新霉素B为原料，经水解，保护，亲核取代，脱保护，叠氮还原多步反应得到氨基或氨基链修饰的新霉胺类似物。用表面等离子共振法测定了所合成的化合物与大肠杆菌（E.coli．）核糖体A位点rRNA（16S RNA）的相互作用。合成了6个Ⅱ环5-位修饰的新霉胺类似物，发现Ⅱ环5位氨基链修饰可以增强化合物对16S RNA的亲和力，其中一些化合物在10^-3M有体外细菌抑制活性。在新霉胺的Ⅱ环5位引入氨基或脂肪胺可以增加与16S RNA的亲和力。Ⅱ环5位上羟基的构型改变对于药物／16S RNA复合物稳定性的影响较低。     

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.     

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.

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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.

     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

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.     

Alzheimer’s disease – current trends in basic and clinical research. Highlights from the 16th ECNP

Advances in the molecular biological knowledge of neuronal nicotinic acetylcholine receptors (nAChRs) have led to a growing interest by the pharmaceutical industry in the development of novel compounds that selectively modulate nAChR function. The ability of (-)-nicotine, an activator of nAChRs, to enhance attentional aspects of cognition in animals and humans, to exert neuroprotective and anxiolytic-like effects, and presumably to mediate the negative correlation between smoking and Alzheimer's (and Parkinson's) Disease, has focused interest on the potential therapeutic utility of modulators of nAChR function for treatment of some of the deficits associated with these progressive, neurodegenerative conditions. Numerous compounds are known which activate nAChRs and which might serve as lead compounds toward the development of such agents. The pharmacologic diversity of neuronal nAChR subtypes suggests the possibility of developing selective compounds which would have more favourable side-effect profiles than existing agents. This broader class of agents, collectively called cholinergic channel modulators (ChCMs), is anticipated to encompass compounds which would have more favourable side-effect profiles than existing agents, which generally exhibit low selectivity. This selectivity may be achieved by preferentially activating some subtypes of nAChRs (i.e., Cholinergic Channel Activators, ChCAs) or inhibiting the function of other subtypes (Cholinergic Channel Inhibitors, ChCIs). An overview of the biology of nAChRs and the rationale for the use of ChCMs for the treatment of dementia related to neurodegenerative diseases are presented, followed by a discussion of lead compounds and compounds under consideration for clinical evaluation.