咪唑立宾在亲属肾移植术后患者的应用

目的探索咪唑立宾（MZR）在亲属肾移植术后抗排斥治疗的效果及其不良反应。方法选择2007年1月～2008年12月间共62例亲属肾移植病例,其中28例接受环孢素（CsA）或他克莫司（FK506）、MZR和强的松（Pred）治疗的患者作为观察组,34例接受CsA或FK506、吗替麦考酚酯（骁悉,MMF）和Pred治疗的患者作为对照组。随访6-24个月．观察两组患者的急性排斥反应（AR）、术后感染及其他不良反应发生率。结果MZR组与MMF组比较．术后6个月内AR发生率差异无显著性（P〉0．05）;术后肺部感染等严重感染发生率低于MMF组．但差异无显著性意义;除尿酸升高外两组不良反应发生率无显著差异。结论与MMF比较,MZR抗排斥作用肯定,不良反应小．费用相对低廉,适合在临床尤其是亲属活体受者中应用。     

肾移植患者应用咪唑立宾与麦考酚酸酯2种三联免疫抑制方案的疗效比较

目的:观察咪唑立宾(MZR)的免疫抑制效果及安全性,采用MZR替代麦考酚酸酯(MMF),比较环孢素A(CsA)+MZR/MMF+泼尼松龙(Pre)两种三联免疫抑制治疗的疗效。方法:尸体肾移植患者70例,按手术顺序交替登记MZR组和MMF组。移植后采用CsA+MZR/MMF+Pre三联免疫抑制疗法,MZR组剂量为200mg.d-1(体重>60kg)或150mg.d-1(体重<60kg);MMF组剂量为1500mg.d-1(体重>60kg)或1000mg.d-1(体重<60kg)。观察肾移植术后1年的人/肾存活率、急性排斥反应发生率及治疗逆转率、感染发生情况及药物毒副作用。结果:全部病例术后随访至少1年,MZR组和MMF组的急性排斥反应发生率分别为17.1%和11.4%,两组之间无显著性差异。MZR组和MMF组肺部感染的发生率分别为8.6%和48.6%,MMF组的发生率显著升高。血尿酸升高的发生率两组之间比较未见显著性差异,MZR组在术后24,36,48周时血尿酸的水平要高于MMF组。MZR组的持续用药率显著高于MMF组。结论:MZR可以与钙调神经素阻滞剂、激素联合应用于肾移植患者,具有一定的安全性和有效性,不良...     

心脏死亡器官捐献供者肾移植的近期效果评价

目的研究捐献心脏死亡器官供者肾移植后的近期临床效果。方法选取我院DCD供肾移植43例为DCD组,SCD供肾移植31例为SCD组,术前均对两组受者采用口服吗替麦考酚酯联合他克莫司的免疫抑制方案。术中通过静脉注射泼尼松,术后观察比较两组受者肾移植半年存活率、DGF发生率、血肌酐值(SCr)、肾小球e GFR滤过率、排斥反应发生率以及感染并发症率。结果 (1)两组受者在移植肾术后半年内存活率分别为90.1%,90.3%,差异无统计学意义(P>0.05);(2)DCD组肾移植延迟恢复功能发生率为20.9%(9/43),SCD组发生率为19.3%(6/31),两组差异无统计学意义(P>0.05)。(3)术后1、3、6、2个月后检测DCD组血肌酐值明显高于SCD组,差异具有统计学意义(P<0.05);(4)两组受者肾移植肾小球滤过率在术前及术后1、3、6、2个月的检测结果显示P>0.05,差异无统计学意义;(5)DCD组排斥反应发生率为9.1%低于SCD组排斥反应发生率为11.4%,DCD组感染并发症率7.0%明显低于SCD发生率22.5%,两组差异具有统计学(P<0.05)。结论心脏死亡器官捐献供者肾移植的近期效果与司法途径SC相比差异不大,有望成为在今后成为肾移植主要来源,但仍需在不断的观察中研究远期存活率为我国器官移植工作取得更大的突破。     

二重血浆置换及免疫吸附联合IL-2受体单抗方案处理致敏肾移植受者的临床研究

目的:评估应用二重血浆置换(DFPP)、免疫吸附(IA)联合IL-2受体单抗方案处理致敏肾移植受者的临床效果。方法:将56例致敏肾移植受者分为2组,35例试验组应用DFPP、IA联合IL-2受体单抗方案,21例对照组未进行上述处理。采用酶联免疫吸附(ELISA)方法检测肾移植受者体内群体反应性抗体(PRA)水平,比较2组急性排斥反应(AR)和肾功能延迟恢复(DGF)的发生率,随访2组人/肾1a存活率及术后6个月和12个月的血肌酐情况。结果:试验组PRA明显下降,PRA降为阴性者14例;试验组与对照组术后AR发生率分别为28.6%、42.9%(P<0.05),DGF发生率分别为8.6%、14.3%(P>0.05),1a人存活率分别为100.0%、95.2%(P>0.05),移植肾1a存活率分别为94.3%、76.2%(P<0.05),随访6个月/12个月血肌酐分别为(115.2±16.6)/(121.2±28.6)μmol.L-1和(128.4±27.4)/(134.6±33.7)μmol.L-1(P<0.05)。结论:DFPP、IA联合IL-2受体单抗方案可选择性去除受者体内的致敏抗体,可降低致敏受者术后AR的发生率,提高术后肾移植受者1a移植肾存活率,术后6个月和12个月的血肌酐水平也较低。     

前列地尔在肾移植术后早期应用的临床研究

目的:观察前列地尔在肾移植术后早期的应用对促进移植肾功能恢复的效果。方法:比较93例肾移植受者术后2周内给予前列地尔20μg.d-1(治疗组),同期85例术后未使用前列地尔的肾移植受者(对照组),比较2组术后尿量、血肌酐、彩色多谱勒监测移植肾血流阻力指数、肾功能延迟恢复和急性排斥反应的发生率以及1a人/肾存活率。结果:治疗组术后1d的24h尿量(9.40±1.9)L明显高于对照组(8.11±1.8)L(P<0.01),而术后1d血肌酐、术后5d血流阻力指数、肾功能延迟恢复的发生率((553.4±51.8)μmol·L-1、0.642±0.035、7.53%)则明显低于对照组((624.6±65.2)μmol·L-1、0.689±0.037、14.12%)(P<0.01);2组之间急性排斥反应发生率(9.68%,10.59%)和1a人/肾存活率(98.9%/95.7%,98.8%/95.3%)无明显差异。结论:肾移植受者术后早期应用前列地尔有利于术后移植肾功能的恢复,但对术后急性排斥反应率和1a人/肾存活率的影响不明显。     

巴利昔单抗联合鼠抗人CD3单克隆抗体在高致敏受者肾移植中的临床应用

目的:探讨巴利昔单抗与鼠抗人CD3单克隆抗体(OKT3)联合诱导在高致敏受者肾移植临床应用中的有效性及安全性。方法:术前2个月内群体反应性抗体(PRA)检测值均>50%的尸体供肾肾移植受者20例,其中9例受者接受巴利昔单抗联合OKT3免疫诱导(联合诱导组),11例受者接受OKT3常规免疫诱导(OKT3诱导组),均以他克莫司(Tac)+吗替麦考酚酯(MMF)+泼尼松(Pred)为基础免疫抑制方案,评估术后移植肾功能恢复情况、3个月内急性排斥反应发生率、1年内肺部感染发生率、1年人/肾存活率及移植肾功能。结果:联合诱导组、OKT3诱导组肾移植术后3个月内急性排斥反应发生率及术后1年内肺部感染发生率分别为11.1%vs.36.4%(P=0.319),11.1%vs.63.6%(P=0.028);联合诱导组患者术后1周内移植肾功能恢复正常比例明显高于OKT3诱导组(88.9%vs.27.3%,P=0.010);联合诱导组术后1年人/肾存活率均为100%,与OKT3诱导组(分别为90.9%、81.8%)比较,差异不显著(P=1.00和P=0.100);术后1年联合诱导组、OKT3诱导组血肌酐值分别为(105±24)、(97±22)μmol·L-1(P=0.437)。结论:巴利昔单抗联合OKT3进行免疫诱导,在预防高致敏受者术后早期排斥反应的同时,缩短了移植肾功能的恢复时间,是一种安全、有效的防治策略。     

肾移植术后应用咪唑立宾和吗替麦考酚酯的有效性和安全性Meta分析

目的：评价肾移植术后应用咪唑立宾（MZR）和吗替麦考酚酯（MMF）的有效性和安全性。方法：计算机检索 PubMed、OVID、EMbase、Cochrane Library、中国生物医学文献数据库（CBM）、中国期刊全文数据库（CNKI）、维普及万方数据库,纳入肾移植术后应用MZR与MMF的随机对照试验（RCT）,检索时间范围为建库至2017年6月。由2位评价者按照纳入与排除标准筛选文献、提取资料并评价纳入研究的质量后,采用Rev Man 5.3统计软件进行Meta分析。结果：共纳入12项RCT研究。Meta分析结果显示：MZR组与MMF组肾移植受者术后急性排斥反应发生率、受者存活率、移植肾存活率的比较,差异无统计学意义（RR=1.21,95%CI 0.88~1.65,P=0.25;RR=1.00,95%CI 0.96~1.04,P=0.97;RR=1.00,95%CI 0.96~1.04,P=0.99）。2组间不良反应发生率比较,差异无统计学意义（RR=0.82,95%CI 0.61~1.10,P=0.18）,进一步亚组分析结果显示MZR较少引起胃肠道反应和肺部感染（RR=0.36,95%CI 0.19~0.71,P=0.003;RR=0.49,95%CI 0.29~0.84,P=0.009）,但更易导致高尿酸血症的发生（RR=2.17,95%CI 1.69~2.78,P<0.05）。骨髓抑制、肝功能异常和巨细胞病毒感染发生率2组无显著差异（RR=0.59,95%CI 0.30~1.19,P=0.14;RR=1.42,95%CI 0.79~2.54,P=0.24;RR=0.58,95%CI 0.3~1.12,P=0.1）。结论：肾移植术后应用MZR预防排斥反应的疗效与MMF无显著差异,且较少引起胃肠道反应和肺部感染,但更易导致高尿酸血症的发生;骨髓抑制、肝功能异常和巨细胞病毒感染发生率与MMF无显著差异。     

肾移植受者术后咪唑立宾血药浓度监测及肌酐清除率对其影响

目的：建立肾移植受者术后咪唑立宾浓度的高效液相色谱串联质谱（HPLC-MS/MS）分析方法,测定咪唑立宾浓度并探讨肌酐清除率对咪唑立宾血药浓度的影响。方法：HPLC色谱柱XDB-C₁₈（150 mm×4.6 mm,5 μm）;流动相0.1%甲酸水溶液（A）-乙腈（B）,梯度洗脱：0~2 min 70% A,2~4 min 40% A,4~7 min 70% A;流速0.6 mL·min^-1;电喷雾离子源ESI负离子模式。肾移植受者术后口服咪唑立宾（100 mg bid）,在初次服药后第10日与第15日分别于服药前半小时和服药后3 h测定血药浓度,观察肌酐清除率对药物浓度的影响。结果：目标化合物咪唑立宾与内标BA-TPQ的离子质荷比（m/z）分别为258.2→126.1和278→91.1。二者分离完全,保留时间分别为2.14 min和2.74 min,提取回收率稳定,日内、日间精密度RSD低于15%,血浆样品在低温环境中稳定。肾移植受者血药浓度监测表明,咪唑立宾浓度与肌酐清除率高度相关,随肌酐清除率降低而升高,不良反应可能与峰浓度高有关。结论：肾移植术后监测咪唑立宾血药浓度,根据肌酐清除率调整给药剂量,有助于降低排异反应,减少不良反应的发生。     

咪唑立宾治疗药物监测在肾移植术后患者中的应用进展

咪唑立宾(mizoribine,MZR)作为口服免疫抑制剂,在临床上用于预防肾移植术后排斥反应的发生。MZR的生物利用度个体差异大,因此需要个体化给药。但相对其他免疫抑制剂,MZR的治疗药物监测(therapeutic drug monitoring,TDM)工作在我国开展相对滞后。目前国内外尚未见针对MZR的TDM的综述报道。该文首先分析MZR的药动学特征,然后针对MZR的检测方法、监测指标与治疗窗选择予以总结和建议,最后评价目前的MZR基因多态性与群体药动学研究。该文可为后续在肾移植术后患者中开展MZR的TDM工作提供方案制定参考。     

咪唑立宾用于肾移植患者的不良反应观察

目的：观察咪唑立宾在肾移植术后的安全性及不良反应。方法：选取40例肾移植患者，在使用环孢素及泼尼松的基础上加用咪唑立宾，观察咪唑立宾对肾移植患者的用药情况及引起的不良反应。结果：40例肾移植患者中死亡3例，急性排斥反应共3次。尿酸值升高者为26人。白细胞降低者为8人。肝功能异常者为8人。肺部感染为4人。血糖升高者为3人。结论：咪唑立宾有一定的副作用，尿酸值升高为其特有的不良反应。     

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.     

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.     

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.