尿液NGAL作为药物诱导急性肾毒性生物标志物的研究进展

寻找能早期、灵敏、特异地诊断肾毒性的新型生物标志物已成为目前药物临床前研究的热点。大量研究发现尿液中性粒细胞明胶酶相关脂质运载蛋白（NGAL）对肾损伤的诊断效能优于传统生物标志物血清肌酐和尿素氮。2018年尿液NGAL获得了美国食品药品监督管理局的批准，可用于I期临床试验中药物对肾小管损伤作用的监测，但其在临床前试验中的应用和推广仍有待进一步研究。就NGAL特性、作为药物诱导急性肾损伤生物标志物研究进展及其应用面临的挑战进行综述，以期为NGAL在我国新药研发中对急性肾毒性评价的应用奠定基础。     

药物性肝损伤组学生物标志物新进展

药物性肝损伤(drug-induced liver injury, DILI)是引起药物不良反应和药物停产或药物撤市的主要原因。临床前药物肝毒性评价和临床患者DILI诊断主要依赖于生物标志物的检测。随着组学技术的发展,人们发现了一些具有更高特异性和敏感性的新型DILI生物标志物。基于蛋白质组学、转录组学、基因组学和代谢组学的新型生物标志物可为临床前药物潜在肝毒性的评价和临床DILI的预测、早期诊断提供参考和依据。     

肝毒性生物标志物研究进展

药物肝毒性是医药界关注的重要问题。及时准确地评价药物的肝毒性,寻找特异性强、灵敏度高的肝毒性生物标志物对新药研发及保证临床用药安全具有重要意义。针对传统的肝毒性生物标志物（包括谷氨酸氨基转移酶、天冬氨酸氨基转移酶、谷氨酸脱氢酶等）,以及新发现的生物标志物（血清F蛋白、嘌呤核苷磷酸酶、激肽原对氧磷酶）进行综述,为药物肝毒性的研究及防治提供参考。     

生物标志物在药品生命周期中的应用与相关法规

生物标志物（biomarker）是一种能客观测量并评价正常生物过程、病理过程或对药物干预反应的指示物，可有效提高新药研究开发决策，指导候选药物早期临床试验，降低新药研发失败的风险。其在新药开发与临床治疗中的关键作用受到世界各国（地区）的关注，纷纷出台相应的支持政策。本文通过对生物标志物的定义与分类、各国对生物标志物在药品研究开发中应用的政策法规以及生物标志物分析检测技术规范等进行分析和综述，提出和制订《药物生物标志物分析检测验证技术指导原则》（草案），提交国家药典委员会，以期为生物标志物的发现、检测、验证及其在医药行业的应用提供技术指导。     

髓质海绵肾的诊断研究进展

髓质海绵肾（MSK）是一种肾脏畸形,通常表现为肾钙质沉着症和复发性肾结石等,同时需要使用昂贵且耗时的静脉尿路造影（IVU）进行诊断。尽管IVU仍然是目前诊断MSK的金标准,但其他方法如多层螺旋CT（MDCT）、核磁共振成像（MRI）、乃至生物标志物正在迅速崛起,为MSK的早期检测和诊断提供了希望。本文对MSK最新的影像...     

血清胱氨酸蛋白酶抑制剂C在顺铂肾毒性早期诊断中的临床意义

胱氨酸蛋白酶抑制剂C（CysC）是一个反映肾小球滤过率（GFR）改变的灵敏的标志物,对于发现早期肾功能损伤具有重要意义。顺铂是临床上常用的广谱抗癌药物,对乳腺癌、肺癌、卵巢癌及胃肠癌等均有较好的效果,其疗效与用药剂量成正比,但其剂量的增加却受顺铂肾毒性的限制。为探讨血清胱氨酸蛋白酶抑制剂C对顺铂造成的早期肾损伤的诊断价值,我们对50例患者血清CysC结果进行分析,报告如下。     

蛋白质组学技术在药物性肝损伤生物标志物研究中的应用

临床前药物性肝损伤的评价存在灵敏性低和特异性差的问题,常产生假阴性结果和出现意外的毒性,是导致药物终止开发甚至退市的重要原因之一。在药物肝毒性临床前研究中,可以利用蛋白质组学技术的快速、灵敏、高通量等优点,寻找和发现新的肝毒性生物标志物,使药物开发过程更为安全有效。本文对肝毒性生物标志物的研究现状,蛋白质组学在生物标志物的发现及验证等方面的技术发展进行了综述分析,并且着重归纳了该技术在中药致肝损伤方面的生物标志物研究中的应用。与传统评价方法相比,蛋白质组学技术对于发现新型肝潜在毒性生物标志物具有不可替代的优势。随着蛋白质组学技术结合其他组学技术的发展,其在药物肝毒性早期筛选、生物标志物的临床桥接等方面将取得突破性的进展。     

生物标志物在药物性肝损伤中应用的研究进展

摘 要药物性肝损伤是伴随着药物使用而出现的最常见不良反应之一,也是药物研发失败及药物撤市或限制使用的主要原因。生物标志物检测是临床前药物肝毒性评价和临床患者潜在肝损伤诊断的重要技术手段,而传统的肝损伤指标因缺乏特异性和灵敏性等因素,限制了其在早期评价中的应用。因此,寻求及验证新的生物标志物势在必行。本文主要对结合现代组学等技术探索出具有科研及临床价值的新型生物标志物研究现状予以概述。以期为科研人员、临床医师、新药研发机构等预测药物的肝毒性及可能的发展趋势,判断药物引起的肝损伤程度等提供参考。     

老年患者医院获得性急性肾损伤相关因素分析

目的 探讨老年患者医院获得性急性肾损伤（HA-AKI）的相关危险因素,为老年HAAKI患者的早期诊断及治疗提供理论及临床依据.方法 对我院2010年5月至2012年5月住院的385例老年HA-AKI患者的病因和临床特点进行回顾性分析.结果 导致老年HA-AKI的主要原因为肾毒性药物（88例,占22.85％）,感染（76例,占19.74％）,肾前性血灌注不足（71例,占18.44％）,各种手术（68例,占17.66％）,肾后性梗阻（42例,占10.91％）.结论 老年HA-AKI的病因复杂,危险因素较多,主要为肾毒性药物、感染、肾前性灌注不足、各种手术及肾后性梗阻,提示对老年住院患者应密切观察,以期早期发现、积极预防.     

马兜铃酸类物质的生物标记物与减毒策略研究进展

马兜铃酸类物质(aristolochic acids,AAs)广泛存在于马兜铃科植物,是马兜铃科中药的重要毒性成分.作为致癌数据库(CPDB)中最强的致癌物之一,AAs能够产生肝毒性、肾毒性、致癌和致突变等毒副作用,在体内能够产生AA-DNA加合物等一系列代谢物,其特异的代谢物可作为生物标志物,用于相关疾病的早期诊断与...     

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.

     

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.     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.     

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.