(2β,3α,16β,17β)-3,17-双乙酰氧基-2,16-双哌啶基-5α-雄甾烷的合成

目的合成泮库溴铵和维库溴铵的中间体(2β,3α,16β,17β)-3,17-双乙酰氧基-2,16-双哌啶基-5α-雄甾烷。方法以表雄酮为原料,经磺酰化、消除、乙酰化、环氧化、取代、乙酰化反应合成目标化合物。结果所得产物及中间体经核磁共振谱确认。结论所设计合成路线可行,总收率30.4%,可用于工业生产。     

维库溴铵的合成

目的合成维库溴铵。方法以5α-雄甾-2-烯-17-酮为原料经酯化、氧化、开环、还原、乙酰化、最后与溴甲烷成盐等6步反应合成维库溴铵。结果与结论维库溴铵的结构经红外光谱、差热分析、核磁共振谱、质谱确证,总收率为13.7%。     

哌库溴铵的合成研究

目的 合成哌库溴铵。方法 以5α-表雄酮为原料，经磺酰化、消除、烯醇酯化、双环氧化、N-甲基哌嗪开环、乙酰化、与甲磺酸甲酯成季铵盐、与溴化锂进行阴离子交换共9步反应合成哌库溴铵。结果与结论 产物结构经核磁共振谱、红外光谱、高分辨率质谱等确认，总收率为17％，该合成方法适用于工业生产。     

罗库溴铵的合成研究

目的合成罗库溴铵。方法以表雄酮为起始原料,经酯化、消除、溴代、环氧化、氨解、还原、开环、选择性乙酰化,最后与烯丙基溴成盐等9步反应合成目标物罗库溴铵。结果与结论罗库溴铵的结构经红外光谱、核磁共振氢谱、质谱、元素分析确证,总收率达24.9%。     

哌库溴铵的合成工艺

目的 合成哌库溴铵并改进其工艺.方法 以5α-雄甾-2-烯-17-酮为原料,通过酯化、环合、开环、还原等六步反应合成得到哌库溴铵.结果 和结论通过工艺优化,使总收率由24.3%提高到44.6%,产物经1HNMR、IR、元素分析确证结构,经HPLC检测纯度>99.5%,并全检合格.优化后的工艺参数易于控制,生产工序便于操作,有利于工业化生产.     

格隆溴铵合成方法的改进

目的改进格隆溴铵的合成方法。方法苯乙酮酸经格氏反应、酯化反应制得α-环戊基扁桃酸甲酯,再与N-甲基吡咯烷-3-醇经酯交换、季铵化反应制得格隆溴铵。结果与讨论合成的格隆溴铵总收率为13.9%,其结构经过熔点测定及1H-NMR、13C-NMR确证。     

阿曲库铵和维库溴铵量──效关系和恢复时相的比较性研究(英)

比较性观察阿曲库铵和维库溴铵量-效关系和恢复时相特征。选择60例ASAI级,年龄17～50岁,施择期整形外科手术的中国患者,分层随机平均分成阿曲库铰组和维库溴铵组。用60％NO2-O2-硫喷妥钠-芬太尼维持麻醉。用加速度仪监测神经肌肉功能,采用TOF刺激方式,以T1抑制的百分比为研究指标。用累计给药方法建立阿曲库铵和维库溴铵的量-效关系曲线。根据用最小二乘法建立的量-效关系曲线,阿曲库铵的神经肌肉阻滞作用强度仅为维库溴铵的17％。两药的ED50、ED90和ED95均有明显差别。应用等效剂量（1.5×ED95）后,两药的高峰时间、临床肌松时间、恢复时间和体内作用时间均无明显差别。结论：阿曲库铵是一弱效能的肌松药,而维库溴接为一强效能肌松药。阿曲库按和维库溴铵的作用强度比率为1／6。应用等效剂量后,两药的恢复时相无明显差别。     

阿地溴铵原料药有关物质的合成

目的研究阿地溴铵原料药中有关物质来源及合成方法,为产品质量控制提供依据和杂质对照品。方法通过对阿地溴铵原料药制备过程可能产生的杂质推测,以(R)-(-)-3-奎宁醇和3-苯氧基溴丙烷为原料合成杂质A;以R-2,2-二(2-噻吩基)-2-羟基乙酸奎宁-3-基酯和1,3-二溴丙烷为原料,控制不同反应条件合成杂质B和杂质C。结果与结论合成的3种杂质经~1H-NMR、HRMS谱确证,HPLC测定纯度在98%以上,可作为阿地溴铵原料药的杂质对照品,其中杂质B和杂质C为首次报道;建立了专属性好、灵敏度高的阿地溴铵杂质分析方法,为阿地溴铵原料药的质量控制提供帮助。     

联合应用顺阿曲库铵与维库溴铵后ED50和ED95的改变

目的：观察顺式阿曲库铵联合维库溴铵用药后ED50和ED95的变化。方法将75例择期手术患者（ASAⅠ~Ⅱ级）随机分为3组：顺式阿曲库铵组、维库溴铵组和顺式阿曲库铵＋维库溴铵组,每组各25例。麻醉诱导后,以单次给药法观察起效时间和T1达到最大抑制的时间,描绘3组患者的量-效曲线,求得各自的ED50和ED95值,并运用等效图法和代数法对两药相互作用进行分析。结果单用顺式阿曲库铵组、维库溴铵组ED50值分别为32.35、28.78μg/kg,ED95值分别为52.67、51.20μg/kg。联合用药时ED50值为16.81、12.17μg/kg,ED95值为23.49、22.16μg/kg,与单独用药相比,差异均有统计学意义。联合用药时ED50和ED95的合用代数值分别为0.942、0.879。结论联合使用顺式阿曲库铵和维库溴铵具有协同作用,且量-效曲线产生左移。     

罗库溴铵的合成工艺研究

目的研究罗库溴铵的合成工艺。方法以2β-（4-吗啉基）-16β-（1-毗咯烷基）-3α,17β-二羟基-5α-雄甾烷为原料,经乙酰化,再选择性水解得到17p乙酰化物,然后与烯丙基溴成盐得到罗库淡铵。考察了乙酰化、选择性水解的条件,同时分离得到3a,17β-二乙酰化物。结果与结论罗库决铵及其中间体的结构经核磁共振氢谱（1H-NMR）、碳谱（^13C-NMR）,质谱（ESI-MS）确证,总收率59．6％。     

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.