新型双氯芬酸钠缓释片的人体相对生物利用度研究

８名健康男性志愿者单剂量交叉口服１００ｍｇ受试双氯芬酸钠缓释片、扶他林或ＶｏｌｔａｒｅｎＳＲ１００后,Ｔｍａｘ分别为２．４±１．０、２．１±０．５和４．４±１．８ｈ;Ｃｍａｘ分别为６０２．６±９２．８、３３３７．６±１０８８．２　７６１．０±３４２．０ｎｇ／ｍｌ;ＭＲＴ分别为１３．２±４．８、２．９±０．８和７．９±１．９ｈ;ＡＵＣ０分别为４８６６．２±６４４．６、５３１４．３±５３４．３和４８２９．１±５８２．８ｎｇ／（ｍｌ－１·ｈ）;双氯芬酸钠缓释片和ＶｏｌｔａｒｅｎＳＲ１００相对于扶他林的生物利用度分别为８８．３±１３．２％和８６．３±１２．６％。另８名志愿者交叉口服受试双氯芬酸钠缓释片（１００ｍｇ,ｐｄ）和扶他林（５０ｍｇ,ｂｉｄ〕,连服５天。Ｃｍａｘ分别为５９３．９±１３４．１、１２４７．８±５２７．５ｎｇ／ｍｌ,峰谷波动率（ＰＴＦ）分别为３．３±１．２、５．３±２．１。本研究将为新型双氯芬酸钠缓释片的临床应用提供依据。     

异丙酚临床药物动力学研究

本文采用高效液相色谱法测定血浆中异丙酚浓度，研究８例异丙酚诱导静脉麻醉手术患者的药物动力学特征。结果表明：异丙酚诱导静脉麻醉符合开放性三室模型特征，具有分布快，分布广，清除率高等特性。其药物动力学参数分别为：Ｔ１／２α＝０．０１１±０．００２ｈ，Ｔ１／２β＝０．１９±０．１１ｈ，Ｔ１／２γ＝２．６±１．０ｈ，Ｖ＝５．０±２．５Ｌ／ｋｇ，Ｃｌ＝１．５７±０．２４Ｌ／（ｋｇ·ｈ）     

双氯芬酸缓释片的生物利用度研究

以ＨＰＭＣ为主要辅料制备双氯芬酸缓释片。其溶出符合零级动力学模型，ｔ１／２＝２６３．９５ｍｉｎ，而国产肠溶衣片ｔ１／２＝７４．５８ｍｉｎ。８名健康志愿受试者交叉口服自制缓释片及肠溶衣片各１００ｍｇ后测定血药浓度，结果表明两者起效速度和生物利用度无显著差异，而消除半衰期前者明显大于后者。     

咪哒唑仑在两个年龄组的药物动力学

对健康男性较高年龄及青年志愿者各７例，分别单次快速静滴０．０８ｍｇ／ｋｇ及０．１２ｍｇ／ｋｇ咪哒唑仑后，进行了药物动力学研究。结果两组药物动力学均成二室模型。较高年龄组比青年组的室间转运速率常数Ｋ１２、末相半衰期Ｔ１／２β和平均滞留时间ＭＲＴ０－∞均明显增大，两组Ｋ１２分别为７±６ｈ和２．８±１．４ｈ（Ｐ＜０．０５），Ｔ１／２β为４．０±１．７ｈ和２．１±０．６ｈ（Ｐ＜０．０１），ＭＲＴ０－∞为５．２±１．８ｈ和２．５±０．７ｈ（Ｐ＜０．０１）；而总清除率ＣＬｓ较高年龄组比青年组明显减小，分别为０．１７±０．０３Ｌ／（ｋｇ·ｈ）和０．２８±０．０８Ｌ／（ｋｇ·ｈ）（Ｐ＜０．０１）。且中国人ＣＬｓ较欧洲人为低。提示年龄增大对咪哒唑仑的清除能力下降，中国男性老年人给药剂量和给药间隔应适当调整。     

氟康唑的药物动力学和生物利用度的研究

采用高效液相色谱柱切换法，研究了单剂口服国产氟康唑胶囊剂２００、１５０ｍｇ与进口氟康唑１５０ｍｇ胶囊剂的志愿受试者体内药物动力学过程。结果表明：单剂口服不同剂量的两种胶囊血药浓度－时间曲线符合二至模型。国产氟康唑胶囊２００、１５０ｍｇ及进口氟康唑胶囊剂１５０ｍｇ的药物动力学参数依序如后：消除半衰期（Ｔ１／２β）分别为３４．５５±５．９７、３４．７６±２．６８及３１．０７±２．４２ｈ。达峰时间（Ｔｍａｘ）分别为１．５５±０．２８、１．６１±０．８９及１．９７±０．４４ｈ。峰浓度（Ｃｍａｘ）分别为４．６３±０．３３、３。７７±０．５３及３．９２±０．５２ｍｇ／Ｌ。曲线下面积（ＡＵＣ）分别为１９９．５４±２３．５２、１６８．２４±１３．８２及１６４．３１±１４。９１ｍｇ·ｈ／Ｌ。Ｖ／Ｆ（ｃ）值分别为３２．９７±４．３６、３１．３２±７．６７及３０．１２±２．４６Ｌ。清除率（Ｃｌ（ｓ））分别为１．０１±０．１１、０．９０±０．０７及０．９２±０．０９Ｌ／ｈ。国产胶囊剂对美国进口胶囊剂的平均相对生物利用度为１０２．８７％。     

健康人应用4种不同剂型茶碱的药代动力学及生物利用度研究

通过荧光偏振免疫法测定１０名健康人血清中茶碱浓度，对口服茶碱控释片、茶碱缓释片、氨茶碱片及静脉注射氨茶碱进行了药代动力学及生物利用度的研究。结果：控释片达峰时间（ｔｐ＝６．００±０．９３ｈ）与缓释片达峰时间（ｔｐ＝６．００±１．１１ｈ）均慢于氨茶碱片（ｔｐ＝１．８３±０．３８ｈ）；清除率（Ｃｌ＝０．４０±０．１１、Ｃｌ＝０．４１±０．０９ｍｌ／ｍｉｎ·ｋｇ）也均小于氨茶碱片（Ｃｌ＝０．６４±０．１２ｍｌ／ｍｉｎ·ｋｇ），控释与缓释片的生物利用度分别为９４．０±１５．７％、９４．８±１７．２％，高于氨茶碱片（Ｆ＝８７．７±１９．５％）。控释片、缓释片与普通片各药代动学参数及绝对生物利用度间差异均有显著性，而控释片与缓释片间无显著性差异，说明茶碱控释片与缓释片具有满意的缓释特性，保证可靠的完全吸收，减小峰谷浓度落差，并可减少给药次数，降低毒副反应的发生率，提高临床治疗效果。     

高效液相色谱法与紫外法测定慢性阻塞性肺病患者茶碱血药浓度的评价

本文用高效液相色谱法（ＨＰＬＣ）和双波长紫外分光光度法（ＵＶ）平行测定了２ｌ例慢性阻塞性肺病（ＣＯＰＤ）患者的血清茶碱浓度，共１２３例次。两种方法之间有良好的线性关系（ｒ＝０．９７６１，Ｐ＜０．０ｌ），但ＵＶ法较ＨＰＬＣ法测得的血清茶喊浓度低（△Ｃ＝－０．６±１．６ｍｇ／Ｌ，ｎ＝１２３，Ｐ＜０．０５）。药物动力学研究表明：两种方法所得药＋时曲线均符合一房室模型，血药浓度的差异并不影响茶碱的主要药动学参数值及由此预测的给药剂量。Ｋａ为３±５／２．５±２．８ｈ~(－１)；Ｋ为０．４±０．０７／０．１５±０．０５ｈ~(－１)；Ｔ１／２为５．７±２．４／５．０±１．８ｈ；Ｃｌ为０．０９±０．０５／０．０８±０．０４Ｌ／（ｋｇ·ｈ）；Ｄ为１．０±０．６／０．９±０．４ｍｇ／（ｋｇ·ｈ），Ｐ＞０．０５。     

环丙沙星在老年慢性阻塞性肺病患者多次给药的药动学研究

应用微生物法测定６名老年慢性阻塞性肺病患者（ＣＯＰＤ）多次口服环丙沙星片后的血清药物浓度，药物体内过程符合一室模型，其主要药动学参数分别为：Ｔ１／２＝５．１±１．１ｈ；Ｖｄ／Ｆ＝７±４Ｌ／ｋｇ；（Ｃ∞）ｍａｘ＝２．７±１．０μｇ／ｍｌ；Ｔ′ｐ＝１．０±０．４ｈ，测定方法平均回收率为１０１．６％     

氧氟沙星和环丙沙星在老年人中的药物动力学

对氧氟沙星和环丙沙星在老年和年轻健康志愿者中的药物动力学进行同期比较研究。上述两药全部血、尿浓度均以高效液相色谱法测定。老年组单剂口服氧氟沙星３００ｍｇ后的平均血清Ｔ＿（１／２β）为７．０８±０．８１ｈ，Ｃｌ＿ｒ为９５．９±２１．０ｍｌ／ｍｉｎ，ＡＵＣ为３２．６±４．１ｈ·ｍｇ／Ｌ，与年轻组相比，血清Ｔ＿（１／２β）延长，Ｃｌ＿ｒ降低以及ＡＵＣ增大。老年组与年轻组的Ｃ＿（ｍａｘ）则相近，分别为４．６７±０．９８和４．７２±０．５１ｍｇ／Ｌ。老年组每１２ｈ口服氧氟沙星３００ｍｇ连续７天后的Ｃ＿（ｍａｘ）和ＡＵＣ较单剂者明显增高。老年组和年轻组单剂口服环丙沙星５００ｍｇ后的Ｔ＿（１／２ｋｅｌ）分别为３．３２±０．４３和２．７６±０．４３ｈ，Ｃｌ＿ｒ分别为２３１．４±６８．８和２５６．９±６４．０ｍｌ／ｍｉｎ，ＡＵＣ分别为１７．７±４．９和１５．９±３．５ｈ·ｍｇ／Ｌ。根据本研究结果，对上述两药在治疗老年人感染时给药方案的调整提出了建议。     

氧氟沙星在健康人体的药动学研究

应用微生物法测定６名健康志愿者多次口服氧氟沙星片达稳态后的血清药物浓度，药物体内过程符合一室模型，其主要药物动力学参数分别为：Ｔ＿（１／２）＝３．７４±０．４６ｈ；Ｖｃ＝１．５９±０．４５Ｌ／ｋｇ；Ｃ＿（ｍａｘ）＝２．６２±０．４２μｇ／ｍｌ；Ｔｐ＝１．２±０．５５ｈ。测定方法平均回收率为９９．２％。     

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.     

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.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.     

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.