罗红霉素胶囊剂的临床药物动力学及相对生物利用度

目的：进行国产与进口罗红霉素的生物利用度研究。方法：通过交叉试验对８名男性志愿者（２２．６ａ±ｓ２．１ａ）交叉口服罗红霉素３００ｍｇ国产胶囊剂和进口片剂,进行单剂量药物动力学研究。血药浓度采用微生物法进行测定。结果：口服国产胶囊和进口片剂的血药浓度＿时间曲线均符合二室模型,Ｃｍａｘ分别为９．５ｍｇ／Ｌ±１．３ｍｇ／Ｌ与９．０ｍｇ／Ｌ±１．０ｍｇ／Ｌ,Ｔｍａｘ为１．１４ｈ±０．１８ｈ与１．３１ｈ±０．２１ｈ,Ｔ１２β为１３．１ｈ±２．４ｈ与１３．６ｈ±２．２ｈ,ＡＵＣ为１０７ｍｇ·ｈ／Ｌ±２３ｍｇ·ｈ／Ｌ与１０８ｍｇ·ｈ／Ｌ±１４ｍｇ·ｈ／Ｌ。比较２种制剂的药物动力学参数,其差别均无显著意义（Ｐ＞０．０５）。与进口罗红霉素片相比较,国产罗红霉素胶囊剂的相对生物利用度为（９８±１３）％。口服该药４８ｈ尿药回收率为给药量的（１５±５）％。结论：国产罗红霉素胶囊体内过程与进口罗红霉素片剂相仿,２种制剂生物等效。     

氟罗沙星临床药物动力学研究

氟罗沙星在健康志愿者中进行药物动力学研究。全部血、尿药物浓度以高效液相色谱法和微生物法测定。８名志愿者分别单次空腹口服氟罗沙星片剂和胶囊剂４００ｍｇ后的体内过程符合二室模型，Ｃｍａｘ分别为６．５２±１．２０和６．７４±２．３１ｍｇ／Ｌ，并分别于给药后０．９１±０．４３和１．２０±０．６７ｈ到达；其消除半衰期分别为１１．０７±１．７３和１０．８１±２．００ｈ；ＡＵＣ分别为８２．１７±１７．７９和８９．０８±１８．８９ｈｍｇ／Ｌ；给药量的６８．９５％±６．２９％和７７．２３％±６．７６％分别于给药后７２ｈ内自尿中排出。给药后２４ｈ内平均尿药浓度均超过１４０ｍｇ／Ｌ。健康志愿者单次空腹口服国产氟罗沙星片剂和胶囊剂４００ｍｇ后的药动学参数与进口片剂者相仿，平均相对生物利用度相近。根据研究结果，对氟罗沙星的给药方案提出了建议     

国产头孢克罗缓释片的生物等效性研究

比较了１２名健康志愿者单剂量口服７５０ｍｇ国产和进口头孢克罗缓释片的药代动力学和生物利用度,采用ＨＰＬＣ法测定血浆和尿中头孢克罗浓度。结果表明：国产和进口片的血浆峰浓度Ｃｍａｘ为７．２８±１．３４和６．９２±１．４６ｍｇ／Ｌ;Ｔｍａｘ为１．０２±０．５８和２．０８±０．７０ｈ;Ｔ１／２为１．０１±０．２２和０．９６±０．１４ｈ,ＭＲＴ为２．５２±０．３９和２．７０±０．２６ｈ;ＡＵＣ为２１．４１±４．４０和２０．７０±６．０６ｈｍｇ／Ｌ,两种制剂的主要药代动力学参数无显著性差异（Ｐ＞０．０５）,国产片的相对生物利用度为１０６．５０±１７．８４％,ＡＵＣ经三因素方差分析、双单侧ｔ检验和等效界值法证实国产和进口片具有生物等效性。     

氟康唑2种制剂在健康志愿者体内生物利用度和药物动力学比较

目的：比较氟康唑２种制剂在中国健康志愿者体内的药物动力学和生物利用度。方法：１０例中国健康志愿者随机交叉口服氟康唑２种（三维，辉瑞）胶囊各３００ｍｇ，采用反相ＨＰＬＣ法测定血中药物浓度。结果：氟康唑（三维）和氟康唑（辉瑞）ＡＵＣ分别为（２７９±６４）ｍｇ·ｈ／Ｌ和（２８９±５７）ｍｇ·ｈ／Ｌ；Ｃｍａｘ分别为（６．７±１．０）ｍｇ／Ｌ和（７．０±０．８）ｍｇ／Ｌ；Ｔｍａｘ分别为（１．９±０．７）ｈ和（１．９±０．７）ｈ；Ｔ１２β分别为（３７±７）ｈ和（３７±７）ｈ；Ｃｌ分别为（１．１４±０．２７）Ｌ／ｈ和（１．０８±０．２２）Ｌ／ｈ；Ｖｄ分别为（４１±２２）Ｌ和（３５±１１）Ｌ；Ｋｅ分别为（０．０４０±０．０１０）／ｈ和（０．０３０±０．０１０）／ｈ。氟康唑（三维）胶囊的相对生物利用度为９６％。差别无显著意义（Ｐ＞０．０５）。结论：氟康唑２种制剂在中国健康志愿者体内的药动学参数相似，具有生物等效性。     

国产头包克罗缓释片的生物等效性研究

比较了１２名健康志愿者单剂量口服７５０ｍｇ国产和进口头孢克罗缓释片的药代动力学和生物利用度,采用ＨＰＬＣ法测定血浆和尿中头孢克罗浓度。结果表明：国产和进口片的血浆峰浓度Ｃｍａｘ为７．２８±１．３４和６．９２±１．４６ｍｇ／Ｌ;Ｔｍａｘ为１．０２±０．５８和２．０８±０．７０ｈ;Ｔ１／２为１．０１±０．２２和０．９６±０．１４ｈ,ＭＲＴ为２．５２±０．３９和２．７０±０．２６ｈ;ＡＵＣ为２１．４１±     

头孢唑林和头孢他啶在老年人中的药物动力学研究

对头孢唑林和头孢他啶在老年人中的药物动力学进行了研究，并同期在年轻人中进行了比较。老年组单次静滴头孢他啶１ｇ后的高峰血浓度（Ｃ_（ｍａｘ））为１０１．３６±２０．０３ｍｇ／Ｌ，血清消除半衰期（Ｔ_（１／２β））为２．４２±０．３４ｈ，肾清除率（Ｃｌｒ）为６２．９３±１９．２１ｍｌ／ｍｉｎ，药一时曲线下面积（ＡＵＣ）为２４４．３０±６１．５１ｈ·ｍｇ／Ｌ。与年轻组相比，血清Ｔ_（１／２β）延长，Ｃｌｒ降低，ＡＵＣ增大，两者间的差异具统计学显著意义（Ｐ＜０．０１）；Ｃ_（ｍａｘ）则相近。老年组单次静滴头孢唑林后，血清Ｔ_（１／２β）也较年轻者为长，分别为２．４８±０．３７和１．９４±０．２６ｈ；Ｃｌｒ为低，分别为３４．６８±７．１０和４４．５３±１０．９６ｍｌ／ｍｉｎ；ＡＵＣ增大，分别为３８０．７１±６１．３９和３３９．５６±７９．８９ｈ·ｍｇ／Ｌ，上述药动参数间的差异除ＡＵＣ外均具统计学意义（Ｐ＜０．０５）。根据本研究结果，提出头孢他啶和头孢唑林在治疗老年人感染时的给药调整方案。     

健康人口服国产洛美沙星片剂的药代动力学

１２名健康男性志愿者，平均年龄２０ａ，分别交叉口服日本产胶囊和国产片剂盐酸洛美沙星３００ｍｇ。用微生物法测定服药后不同时间点取样的血、尿标本，进行药代动力学和相对生物利用度研究。结果表明：口服两药后均能迅速吸收，达峰时间（Ｔｍａｘ）分别为１．１２±０．２８和１．０８±０．５１ｈ；峰浓度（Ｃｍａｘ）为１．５３±０．５３和１．４９±０．３７ｍｇ·Ｌ－１，消除半衰期（Ｔ１／２β）为９．９２±２．４０和１０．４１±２．１７ｈ；二者的药时曲线下面积（ＡＵＣ）分别为１２．９７±２．８９和１１．８０±２．４８ｍｇ·Ｌ－１·ｈ，国产片剂对日本产胶囊洛美沙星的相对生物利用度为９２．５６±１６．１８％。     

替硝唑胶囊剂的相对生物利用度

目的：研究替硝唑胶囊剂的相对生物利用度。方法：８名健康男性志愿者交叉口服２ｇ替硝唑胶囊和片剂，用高效液相色谱法测定其血药浓度经时过程。结果：替硝唑胶囊与片剂的药时曲线符合一房室模型，胶囊与片剂的Ｔ１／２（Ｋｅ）分别为１３．７±１．５ｈ、１４．２±２．０ｈ、Ｔｍａｘ分别为１．４±０．４ｈ、１．９±０．８ｈ；Ｃｍａｘ分别为５２．１±９．１μｇ·ｍｌ－１、５１．１±１０．３μｇ·ｍｌ－１；ＡＵＣ分别为１０９３．０±１１１．８、１１２３．０±１２８．２（μｇ·ｍｌ－１）·ｈ，胶囊剂的相对生物利用度为９７．６％，经统计学分析处理，差异无显著性（Ｐ＞０．０５）。结论：替硝唑胶囊与片剂具有生物等效性     

环丙沙星3种剂型在62名健康志愿者的药物动力学研究

用微生物测定法对环丙沙星３种剂型在６２名男性健康志愿者身上进行药物动力学研究。在１６名受试者静滴环丙沙星注射液（２００ｍｇ／１００ｍｌ）后，０、１、４、１２ｈ的血药浓度分别为３．６８±０．６３、≤１、０．３３～０．４３及０．１μｇ／ｍｌ，药动学参数Ｔ１／２为３．２４ｈ，总清除率３９３．５ｍｌ／ｍｉｎ，ＡＵＣ０～２４６．２１ｈ·μｇ／ｍｌ，Ｖｓｓ１５５．０±３４．２Ｌ。单次口服环丙沙星１００及５００ｍｇ，体内平均药动学参数Ｃｍａｘ分别为２．３１±０．２８及２．４９±０．２４μｇ／ｍｌ，Ｔｍａｘ分别为１．２６±０．１８及１．４７±０．２１ｈ，Ｔ１／２为２．６９±０．４８及３．８７±０．５３ｈ，ＡＵＣ０～２４为１２．８１±０．８５及１５．０２±２．１１ｈ·μｇ／ｍｌ，结果与文献报道相同。此外，对静滴及口服两种给药途径的血药浓度与临床疗效关系以及统计矩法与房室模型在药物动力学研究中的选用进行了讨论。     

吲哚美辛锌胶囊在兔血浆中药代动力学研究

用ＨＰＬＣ测定了兔口服吲哚美辛锌及吲哚美辛胶囊后血浆中吲哚美辛的浓度，其药－时曲线均符合一室开放模型，数据经３Ｐ８７计算机程序处理拟合得吲哚美辛锌及吲哚美辛药动学参数分别为：Ｃｍａｘ２．０８８ｍｇ／Ｌ，２．６６１ｍｇ／Ｌ；Ｔｍａｘ５．２２７ｈ，３．７０４ｈ；Ｋｅ０．１２３ｈ－１，０．１７２ｈ－１；Ｋａ０．２８９ｈ－１，０．４５９ｈ－１；Ｔ２／２（ａ）２．４０１ｈ，１．５０８ｈ；Ｔ１／２（ｅ）５．６１７ｈ，４．０４０ｈ；ＡＵＣ３１．９０５ｍｇ·ｈ／Ｌ，２７．９０３ｍｇ·ｈ／Ｌ。相对生物利用度为１１４％。     

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.     

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.     

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.     

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.