头孢地尼的合成

头孢地尼的合成用2－（2－氨基噻唑－4－基）－2－（Z）－（乙酰氧亚氨基）乙酰N－羟基丁二酰亚胺酯于7－氨基－3－头孢烯－4－羟酸二苯甲酯盐酸进行缩合，优化反应条件后，总收率为80％。     

盐酸尼非卡兰的合成

以1，3－二甲基脲为原料，经环合、氯化、胺解和磺酸酯化反应合成中间体6－[[2－（p－甲苯磺酰基氧基）乙基]氨基]－1，3－二甲基－2，4（1H，3H）－嘧啶二酮，再与中间体2－[3-(4-硝苯基）再基氨基]乙醇缩合、成盐得盐酸尼非卡兰，总收率26．6％。     

萘普生中间体2-氨基-2-(5-溴-6-甲氧基-2-萘基)丙酸的合成

采用1，3－二溴－5，5－二甲基乙丙酰脲作催化剂，在丙酮溶剂中，以盐酸作催化剂，于室温快速(8min)、高收率（96％）地对2－甲氧基萘的萘环进行溴化，再经乙酰化、Bucherer-Berg环化和水解反应，制得萘普生中间体2－氨基－2－（5－溴－6-甲氧基－2－萘基）丙酸。并对环化反应的条件进行了优化，反应总收率68％。     

头孢噻呋的合成

头孢噻呋可以7－ACA为原料,先与2－呋喃甲硫羟酸缩合得到7－氨基－3[(2-呋喃基羰基）硫甲基]-3－头孢烯－4－羧酸,再以活性硫酯（5）取代需用三苯甲基保护氨基的2－氨基噻唑－4－羧酸的1H－苯并三唑－1－基活性酯,进行7－位酰胺化反应制得。5为反应剂可缩短反应时间（3h）,简化操作,收率可由34％提高至64．6％。产品质量较好,成本较低,易于工业化生产。     

盐酸特拉唑嗪的合成

分别以四氢糠醇和藜芦醛为原料，经多步反应制得Ｎ－（２－四氢糠酰）哌嗪（４，收率３３％）和２－氯－４－氨基－６，７－二甲氧基喹唑啉（８，收率２４％），再由两者缩合后成盐得盐酸特拉唑嗪（１），收率８０％。     

（S）—（＋）—2—氨基丙醇合成工艺改进

对（S）－（＋）－2－氨基丙醇的合成工艺进行了改进。以L－丙氨酸为起始原料，经缩合、KBH4还原两步反应，制得本品，工艺简单、易操作，收率82％。     

β-内酰胺酶抑制剂他唑巴坦的合成

目的：合成他唑巴坦。方法：以6－氨基青霉烷酸（6－APA）为原料，经溴化，酯化，氧化并脱溴成亚砜后，与三唑反应，再氧化，脱保护基得他唑巴坦。结果：使用30％双氧水氧化生成亚砜，与2－三甲基硅－1，2，3－三唑反应生成2α－甲基－2β－（1，2，3－三唑－1－基）甲基青霉烷－3α－羧酸二苯甲酯，结论：该方法缩短了反应路线，操作简便，总收率24％。     

3－氨基吡咯烷及其N－乙酰物的合成

３－苄胺基丙酸乙酯（４）经Ｎ－烷基化、Ｄｉｅｃｋｍａｎｎ环合、脱羧、成肟与催化氢化５步反应得到３－氨基－１－苄基吡咯烷（９），收率３７．５％。由９分别合成了３－氨基吡咯烷二盐酸盐（１）与３－乙酰胺基吡咯烷（２），总收率从丙烯酸乙酯计分别为３０％与２０％。     

加替沙星的合成工艺研究

以3－环丙氨基－2－（3－甲氧基－2，4，5－三氟苯酰）丙烯酸乙酯为起始原料，经环合、鳌合、醇解合成加替沙星，总收率为45％；通过对环合剂及鳌合剂的选择，本实验路线具有原料易得、操作简便、收率高、纯度高等优点。     

氯诺昔康的合成

以2，5－二氯噻吩为原料，经氯磺化、甲胺化、N－烷基化、环合、氨基取代等反应合成氯诺昔康。甲胺化时，以30％甲胺水溶液代替气体甲胺，简化了操作；N－烷基化时以相转移催化剂／氯乙酸甲酯代替钠氢／碘乙酸甲酯，提高了收率；环合反应更换溶剂系统使收率可达77％。工艺操作简便、安全，条件温和，成本低，总收率可由0．45％提高至12．3％。     

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.