氯苯扎利钠对正常大鼠及佐剂性关节炎大鼠IL－1活性及大鼠腹腔巨噬细胞H_2O_

研究了氯苯扎利钠（ＣＣＡ）对正常大鼠和佐剂性关节炎大鼠ＩＬ－１活性及大鼠腹腔巨噬细胞Ｈ＿２Ｏ＿２释放的影响。经ＣＣＡ（１０．２００μｇ／ｍｌ）作用后所制备的含ＩＬ－１上清液（正常大鼠腹腔巨噬细胞１．５×１０￣７／ｍｌ，ＬＰＳ８μｇ／ｍｌ）使小鼠胸腺细胞在体外增殖活性（［３￣Ｈ］ＴｄＲ参入法）降低。ＣＣＡ对佐剂性关节炎大鼠ｉｐ￣７天后可使升高的ＩＬ－１活性降低。采用酚红法测定Ｈ＿２Ｏ＿２释放，可见ＣＣＡ５～１００μｇ／ｍｌ对腹腔巨噬细胞Ｈ＿２Ｏ＿２释放抑制作用明显。这些结果表明，ＣＣＡ抗炎和治疗ＲＡ的机制之一可能是通过干扰ＲＯＳ的释放及抑制ＩＬ－１活性，使ＩＬ－１作为肽类炎症介质参与反应和参与免疫调节的过程受阻而达到的。     

组胺H_2受体激动剂和拮抗剂及抗癌药对正常人造血祖细胞和HL－60白血病细胞生长的作用

采用体外微量克隆培养体系研究了组胺Ｈ＿２受体激动剂４－甲基组胺（４－ＭＨ）和拮抗剂雷尼替叮（ｒａｎｉｔｉｄｉｎｅ）及抗癌药阿糖胞苷分别对正常人外周血粒－巨噬系祖细胞（ＰＢＣＦＵ－ＧＭ）和ＨＬ－６０白血病细胞生长的作用。当４－ＭＨ的浓度为１０￣（－９）～１０￣（－６）ｍｏｌ·Ｌ￣（－１）时，可促进ＰＢＣＦＵ－ＧＭ的增殖，４－ＭＨ的浓度增加至１０￣（－１）ｍｏｌ·Ｌ￣（－１）时则表现为抑制ＰＢＣＦＵ－ＧＭ的增殖。Ｒａｎｉｔｉｄｉｎｅ的浓度为１０￣（－９）～１０￣（－５）ｍｏｌ·Ｌ￣（－１）时，表现出对ＰＢＣＦＵ－ＧＭ增殖的抑制作用，但在１０－６ｍｏｌ·Ｌ￣（－１）剂量时对ＰＢＣＦＵ～ＧＭ的抑制率低于５０％，而在该剂量时对ＨＬ－６０白血病细胞的抑制率已达１００％，具有一定的选择性。抗癌药阿糖胞苷（Ａｒａ－Ｃ）对ＨＬ－６０白血病细胞的抑制作用比对ＰＢＣＦＵ－ＧＭ的抑制作用较强，但两者的ＩＣ＿（５０）值处于同一个数量级。在强化化疗剂量１０￣（－５）ｍｏｌ·Ｌ￣（－１）时，Ａｒａ－Ｃ对ＨＬ－６０白血病细胞和ＰＢＣＦＵ－ＧＭ正常造血祖细胞的抑制率均达１００％。     

环孢菌素A阻断人HL－60抗药性细胞于G_1期而诱导敏感细胞凋亡

进一步研究了抗三尖杉酯碱的ＨＬ－６０细胞（ＨＲ２０）抗细胞凋亡的机制及该抗性和抗药性的关系。结果表明，环孢菌素Ａ（ＣｓＡ）２０，１０μｇ·ｍｌ￣（－１）诱导ＨＬ－６０细胞发生凋亡，而阻断ＨＲ２０细胞于Ｇ＿１期，就不能诱导细胞发生凋亡。低浓度的ＣｓＡ明显增加柔红霉素在ＨＲ２０细胞内的积聚，其逆转抗药性作用与阻断细胞周期运行无关。ＣｓＡ１０μｇ·ｍｌ￣（－１）处理ＨＲ２０细胞，可引起５０ｋＤａ的蛋白质高度磷酸化。结果提示：环孢菌素Ａ阻断抗三尖杉酯碱的ＨＬ－６０细胞于Ｇ＿１期，而诱导敏感的ＨＬ－６０细胞发生凋亡，其阻断作用与抗药性无关     

常咯啉在实验性心律失常狗的药代动力学－药效动力学分析

用Ｈａｒｒｉｓ冠脉结扎法诱发的心律失常狗研究常咯啉药代动力学－药效动力学。７只狗按８３．３３μｇ·ｋｇ￣（－１）·ｍｉｎ￣（－１）静脉滴注６０ｍｉｎ，在给药期间和停药后不同时间记录ＥＣＧ及测定血药浓度。Ｃ－Ｔ数据用药代程序计算药代参数；药效数据用药代－药效同步分析模型计算药效动力学参数，Ｋ１０，Ｔ１／２，Ｖｄ，Ｃｌ分别为０．００８７ｍｉｎ￣（－１），７８．０３ｍｉｎ，４０．５５ｍｌ·ｋｇ￣（－１）和０．４２１ｍｌ·ｋｇ￣（－１）·ｍｉｎ￣（－１）；Ｋｅ０和Ｃｅ（５０）分别为０．００４８ｍｉｎ￣（－１）和２．０１μｇ·ｍｌ￣（－１）.     

商陆多糖Ⅰ联合白细胞介素2对小鼠脾细胞杀瘤活性的影响

商陆多糖Ⅰ（ＰＡＰ－Ｉ），０．３～３μｇ·ｍｌ－１和小鼠脾细胞培养３～５ｄ可显著增强其杀伤Ｐ８１５肿瘤细胞活性及ＩＬ－２（２５０～５００ＩＵ·ｍｌ－１）诱导的ＬＡＫ细胞活性，最适浓度为１μｇ·ｍｌ－１。ＰＡＰ－Ｉ及ＩＬ－２和脾细胞培养的上清液对Ｐ８１５肿瘤细胞无细胞毒作用，但能增强脾细胞及ＬＡＫ细胞杀瘤活性。ＰＡＰ－Ｉ，５，１０及５０ｍｇ·ｋｇ－１，ｉｐ可增强脾细胞杀伤Ｐ８１５和Ｌ９２９细胞的活性及ＩＬ－２诱导的ＬＡＫ细胞活性。     

乌苯美司体外对人单核细胞功能的活化作用

观察了国产乌苯美司（乌比美克）体外对人单核细胞功能的影响：①０．０１￣１００μｇ／ｍｌ乌苯美司能直接诱导人单核细胞生成ＩＬ－１；②经０．１μｇ／ｍｌ乌苯美司作用４ｈ后，人单核细胞即开始分泌ＩＬ－１，２４ｈ达到高峰，以后逐渐下降；③经１０￣１００μｇ／ｍｌ乌苯美司预处理，单核细胞可促进ＮＫ细胞活性，而经０．０１￣０．１μｇ／ｍｌ乌苯美司处理，单核细胞则抑制ＮＫ细胞活性。     

乌苯美司对体外人白细胞介素—2生成及受体表达的促进作用

乌苯美司（乌比美克）１０￣１００μｇ／ｍｌ能促进人外周血淋巴细胞分泌ＩＬ－２；而０．０１￣０．１μｇ／ｍｌ则能增强人外周血淋巴细胞表达ＩＬ－２受体以及对ＩＬ－２发生反应的能力；在０．０１￣１００μｇ／ｍｌ范围内，乌苯美司对人血清中ＩＬ－２抑制物活性无明显影响。     

怀牛膝总皂甙对离体大鼠子宫的兴奋作用及机理研究

研究表明，怀牛膝总皂甙（ＡＢＳ０．１～０．４ｍｇ／ｍｌ）对离体大鼠子宫产生明显的浓度依赖性兴奋作用，５－ＨＴ（１０μｇ／ｍｌ）可明显增强ＡＢＳ的作用。ＡＢＳ和５－ＨＴ均使高Ｋ＋去极化后的高体大鼠子宫产生依细胞内Ｃａ２＋性和依细胞外Ｃａ２＋性收缩；氯两嗪（０．５μｇ／ｍｌ）或氟丙嗪（０．４μｇ／ｍｌ）和消炎痛（２０μｇ／ｍｌ）合用均明显拮抗ＡＢＳ的作用。     

吡罗昔康凝胶的兔透皮吸收及药物动力学

作者采用高效液相色谱法研究了吡罗昔康（Ｐｉｒ）凝胶剂２０、３０ｍｇ／ｋｇ在１０只家兔的透皮吸收过程及药物动力学。药－时曲线符合一房室模型特征，两组的吸收和消除参数无明显差异（Ｐ＞０．０５），平均值（ｎ＝１０）Ｋａ为０．４３５ｈ￣（－１），Ｋｅ为０．１０９ｈ￣（－１），Ｔ＿（１／２）Ｋａ为２．０５ｈ，Ｔ＿（１／２）Ｋｅ为６．７４ｈ，Ｔ＿（ｍａｘ）为５．５７ｈ。Ｃ＿（ｍａｘ）和ＡＵＣ随给药剂量增加呈比例增高。两组的Ｃ＿（ｍａｘ）分别为５．４２和８．９５μｇ／ｍｌ，ＡＵＣ为８３．７５和１３４．４０（μｇ·ｈ）／ｍｌ，表明该Ｈｒ凝胶剂透皮性能较好。     

多抗甲素对人免疫功能的影响

本文应用［３Ｈ］ＴｄＲ参入法研究多抗甲素（ＰＡＡ）对人的淋巴细胞增殖反应和ＮＫ细胞活性的影响，结果表明：１．１０００μｇ·ｍｌ－１ＰＡＡ对正常人和食道癌患者外周血淋巴细胞（ＰＢＬ）增殖有直接刺激作用。在促细胞分裂剂ＰＨＡ作用下，ＰＡＡ促进正常人和食道癌患者ＰＢＬ增殖反应的浓度分别为１００～１０００μｇ·ｍｌ－１和１０～１００μｇ·ｍｌ０－１，提示ＰＡＡ有免疫调整作用。２．食道癌患者ＰＢＬ的ＮＫ细胞活性明显低于正常人。ＰＡＡ对正常人和食道癌患者ＮＫ细胞活性有明显的增强作用，分别上升１２．３９±４．５％和１９．６６±５．４％，ＰＡＡ对ＮＫ细胞活性的增强作用表现为时间和剂量依赖性。     

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.     

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.     

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.