中枢苯二氮受体正电子示踪剂-[~(11)C]氟马西尼的自动化合成

目的:建立简便的全自动化生产正电子放射性示踪药物-[11~C]氟马西尼([11~C]flumazenil)的方法,满足临床诊断需要。方法:首先采用全新的气相反应法制备出[11~C]CH3I,合成的[11~C]CH3I先被吸附浓集,然后与去甲氟马西尼在70℃发生反应,反应混合液经半制备HPLC分离后再通过SPE C18分离柱进行纯化,最后用无菌0．9％氯化钠溶液洗脱得到[11~C] flumazenil注射液。结果:合成时间从加速器轰击结束开始共28 min,放化产率经过衰减校正后为20％,化学纯度大于97％,放化纯度大于99％。产品的无菌及无热原要求均符合规定。结论:通过计算机远程控制实现了[11~C]flumazenil注射液的全自动生产,简化了生产步骤,而且保证了生产的可靠性和重现性,可完全满足临床需要。     

表皮生长因子受体正电子显像剂-[~(11)C]PD153035的自动化合成

目的建立全自动化生产正电子放射性示踪药物-[11C]PD153035(表皮生长因子受体酪氨酸激酶抑制剂)的方法,为临床肿瘤检测提供新的手段。方法首先采用全新的气相反应法制备出[11C]CH3I,合成的[11C]CH3I先被吸附浓集,然后由氦气流推动进入反应器与前体在70℃发生反应,反应混合液经半制备HPLC分离纯化后用无菌生理盐水稀释得到[11C]PD153035注射液。结果合成时间从加速器轰击结束开始共28min,放化产率经过衰减校正后为20%,化学纯度大于95%,放化纯度大于99%。产品的无菌及无热原要求均符合规定。结论通过计算机远程控制实现[11C]PD153035注射液的全自动合成,简化了操作步骤,而且保证了生产的可靠性和重现性,可完全满足临床需要。     

阿尔茨海默病正电子显像剂11C-PIB的自动化合成

目的：建立简便的全自动化生产正电子放射性示踪药物2-（4＇-N-11C-甲胺基苯）-6-羟基苯并噻唑（11C-PIB）的方法,满足临床诊断需要。方法：采用气相法制备11C-CH3I,11C-CH3I通过灼热的三氟磺酸银粉末转换成11C-Triflate-CH3,然后与前体2-（4＇-氨基苯基）-6-羟基苯并噻唑在室温发生反应,反应混合液经半制备HPLC分离后再通过Sep-Pak C18分离柱进行固相萃取,并用0.9%无菌氯化钠溶液稀释,最后通过0.22μm的微孔无菌滤膜过滤得到注射液。结果：合成时间从加速器轰击结束开始共35 min,放化产率经过衰减校正后为48.6%（n=25）,化学纯度大于97%,放化纯度大于99%。产品的无菌及无热原要求均符合规定。结论：通过计算机远程控制实现了11C-PIB注射液的全自动生产,简化了生产步骤,保证了生产的可行性和重现性,可完全满足临床需要。     

正电子放射性示踪剂—[~(11)C]氟马西尼注射剂的质量控制研究

目的研究电子放射性示踪药物—[11C]氟马西尼([11C]Flumazenil)的质量控制方法,保证临床用药安全。方法应用高效液相色谱法(HPLC)对[11C]Flumazenil注射剂的化学纯度和放射化学纯度进行检测,并按药典规定对无菌及细菌内毒素等项检查进行测定。结果[11C]Flumazenil注射剂的化学纯度和放射化学纯度分别大于97%和99%,其它各项检测指标也全部合格。结论[11C]Flumazenil注射液的质量符合药用要求,可满足临床安全使用的要求。     

心脏神经受体显像剂11C标记羟基麻黄素合成方法优化

目的：建立简便实用的正电子放射性示踪药物11C标记的羟基麻黄素（11C-mHED）自动化生产的方法,满足临床诊断需要.方法：首先使用加速器通过14N（p,α）11C核反应来生产11C-CO2,然后使用TRACERlab FXc合成模块将11C-CO2还原为11C-CH4,进一步反应生成11C-CH3I,以此作为甲基化试剂,与间羟胺前体反应得到11C-mHED的混合液,经HPLC进行纯化并用0.9%氯化钠溶液稀释,通过0.22 μm的微孔无菌滤膜过滤得到所需的注射液.结果：合成时间从加速器轰击结束开始共33 min,放化产率经过衰减校正后为12%±1%（n=5）,化学纯度大于97%,放射化学纯度大于99%.产品的无菌及无热原要求均符合规定.结论：通过对比不同文献的方法和修改多个反应参数,简化了生产流程,节省了合成时间,实现了11C-mHED注射液的计算机远程控制全自动生产,保证了生产的可行性和重现性,可完全满足临床需要.     

氨基酸代谢PET-CT探针L-[S-11C-甲基]-蛋氨酸的全自动合成及质量控制

目的 研究氨基酸代谢显像剂L-[S-11C-甲基]-蛋氨酸([11C]-MET)全自动合成、质量控制以及影响因素.方法 运用医用回旋加速器轰击氮氧混合气体,生产出的[11C-]与57％氢碘酸生成[11C]-碘代甲烷,高纯氮气推动[11C]-碘代甲烷与[11C]-MET前体L-高胱氨酸硫内酯反应,生成[11C]-MET,经纯化,灭菌最终得到[11C]-MET注射液.薄层色谱法对[11C]-MET进行放射化学纯度(RCP)检测.肿瘤患者行[11C]-MET PET-CT扫描.结果 最终合成产物[11C]-MET的RCP＞ 95％,3 mg的L-高胱氨酸硫内酯可获得未校正合成效率约为35％.结论 使用国产碳-11碘代甲烷合成模块以及碳-11多功能合成模块的组成化学合成模块实现液相法转移[11C-]两步法合成[11C]-MET,合成时间短,合成稳定.     

碳-11标记的6-羟基哒嗪酮衍生物在小鼠体内的生物学分布研究

摘要：目的:研究碳-11标记的6-羟基哒嗪酮衍生物[11C]HCC923在小鼠体内和脑内的分布情况。方法:加速器中产生的[11C]CO2通过TRACERlab FX-MeI模块中的两步反应生成[11C]CH3I,然后与前体化合物反应生成放射性示踪剂[11C]HCC923。在快速纯化和制剂后,用尾静脉注射的方式给正常小鼠注射[11C]HCC923,每只注射100～150μCi。然后经PET/CT成像得到影像数据,并分析各个时间点[11C]HCC923在体内重要脏器以及在脑内亚结构脑区的放射性摄取分布。结果:通过[11C]CH3I的11C-甲基化反应成功制备了[11C]HCC923,从加速器开启到制备完成的合成时间为60～80 min,放射化学产率约为12%（未经时间校正）,放射化学纯度大于95%。小鼠PET/CT的影像数据表明,注射[11C]HCC923后在体内主要脏器都有分布,其在肝脏和肾脏中代谢较快,无明显蓄积。[11C]HCC0923能较快地通过血脑屏障达到脑内,在5～10 min后放射性摄取达到最大,并在脑中持续稳定的的结合;对各个脑内亚结构脑区的放射性摄取分析中可看到,[11C]HCC0923在海马和下丘脑中有相对较高的吸收,其中在海马中%ID/cc为7.65,而在大脑皮质,脑干中则分布较少。结论:[11C]HCC923的放射合成方法可靠有效;[11C]HCC923在体内分布和代谢正常,且能快速通过血脑屏障在脑内特异性的分布,其中主要分布在海马内,并能在扫描时间范围内维持一定的平衡,表明其原型化合物HCC0923具有较高的靶向Sigma-1受体的中枢神经系统小分子药物的研发潜力。     

氟马西尼药物伍用下在5%葡萄糖注射液中的稳定性

氟马西尼（flumazenil）为一种咪哇苯二氮注类衍生物，可竞争性地与苯二氮近受体结合，从而桔抗或逆转苯二氮a类药物的中枢抑制作用。临床常用于苯二氮这类药物镇静，全身麻醉后或特护（ICU）病人的催醒，经常与其它药物合用。本文报道在室温下氟马西尼与氨条碱、盐酸多巴酚丁胺、盐酸多巴胺、盐酸西咪替丁、法莫替丁、盐酸雷尼替丁、肝素钠、盐酸利多卡因和盐酸普鲁卡因胺在5％葡萄糖注射液中的配伍稳定性。将氟马西尼！．0mg分别加入50mL5％葡萄糖注射液和各含有上述9种药物的SOmL50葡萄糖注射液中。室温下（23℃）放置24h，于0，2，48…     

用于多巴胺D_4受体体内研究的3-[4-(4-[~(18)F]氟苯甲基)哌嗪-1-基]甲基-1H-吡咯并[2,3-b]吡啶的合成及生物学评价

目的　 7 氮杂吲哚的衍生物L 74 5 ,870是一个新的、高亲和性 (Ki=0 4 3nmol·L-1)的多巴胺D4受体选择性配体 ,我们放化合成了其类似结构的新化合物 3 [4 (4 [18F]氟苯甲基 )哌嗪 1 基 ] 甲基 1H 吡咯并 [2 ,3 b]吡啶 ([18F]C) ,并作了大鼠体内生物学评价。方法　 ([18F]C)的放化合成是通过 3 (哌嗪 1 基 )甲基 1H 吡咯并 [2 ,3 b]吡啶和 4 氟[18F]苯甲醛的胺烷基化反应完成 ,放化产率为 9 0 %～12 0 % ,放化纯度大于 98% ,比活度高于 37GBq·mol-1。结果　额叶皮质、海巴和延髓等脑区有较高的放射性摄取率 ,分别为 0 4 3%ID/ g和 0 35 %ID/g ;而纹状体、小脑处放射性摄取率较低。结论　大鼠体内的组织分布和代谢物研究表明 :[18F]C在大鼠脑组织区域有特异性分布 ,暗示其可能作为适合的显像剂用于多巴胺D4受体的体内研究     

新型18F-脱氧葡萄糖注射液的制备与质量控制

目的 研究^18F-脱氧葡萄糖(^18F-FDG)注射液的制备和质量控制方法。方法应用小型回旋加速器,通过^18O(p,n)^18F核反应生产出^18F离子,由亲核取代反应制备^18F-FDG,并对所制备的^18F-FDG注射液进行质量控制。结果采用新型^18F-FDG化学合成方法后,放射化学产率可达72％,HPLC法测定的化学纯度大于99％,TLC测定放化纯度大于95％,^18F-FDG注射液的各项质量控制指标均符合《美国药典》的要求。结论 新型^18F脱氧葡萄糖注射液可应用于临床PET的检查。     

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.