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     

进口和国产索他洛尔片剂的相对生物利用度研究

目的：本文对进口和国产索他洛尔片剂在１２名男性健康志愿者中的药物动力学和相对生物利用度进行了研究。方法：建立了一个检测血清中索他洛尔浓度的反相高效液相色谱－荧光检测法。结果：单剂量口服索他洛尔１６０ｍｇ后的血药浓度数据用３Ｐ８７药物动力学程序进行模型拟合，国产片剂ＡＵＣ、Ｃｍａｘ、Ｔｍａｘ、Ｔ１／２分别为１６．２±３．６ｈ·μｇ·ｍｌ－１，１．２±０．２μｇ·ｍｌ－１，２．１±０．７ｈ，１７．０±７．２ｈ；进口片剂ＡＵＣ、Ｃｍａｘ、Ｔｍａｘ、Ｔ１／２分别为１５．９±３．５ｈ·μｇ·ｍｌ－１，１．２±０．４μｇ·ｍｌ－１，２．１±０．６ｈ，１８．６±９．４ｈ。国产片剂的相对生物利用度为１０３．５％。结论：两种片剂的所有药动学参数经统计学（ＳＰＳＳ软件）处理差异均无显著性（Ｐ＞０．０５）。     

对乙酰氨基酚凝胶在人体的药动学和生物利用度

８名健康男性志愿者交叉服用５００ｍｇ剂量的对乙酰氨基酚凝胶剂和片剂。血药浓度采用ＨＰＬＣ测定。对乙酰氨基酚凝胶剂的药动学参数：Ｔ１／２（Ｋａ）０．３０±０．２２ｈ，Ｔ１／２（Ｋｅ）２．１±０．４ｈ，Ｔｍａｘ１．０±０．４ｈ，Ｃｍａｘ５．１±１．５μｇ／ｍｌ，ＡＵＣ２１±５（μｇ／ｍｌ）·ｈ。这些参数与片剂的相似，凝胶剂相当于片剂的生物利用度为１０５．１％     

盐酸特拉唑嗪胶囊人体生物利用度及药物动力学研究

目的：对盐酸特拉唑嗪胶囊的人体内生物利用度进行研究。方法：单剂量口服盐酸特拉唑嗪胶囊和片剂２ｍｇ。血药浓度采用ＨＰＬＣ测定，数据用３Ｐ８７计算药动学参数。结果：盐酸特拉唑嗪胶囊剂的药动学参数：Ｋａ为８．２±４．０ｈ－１，Ｔ１／２为８．２±２．５ｈ，Ｔｍａｘ为０．６１±０．１１ｈ，Ｃｍａｘ为４３．５±８．５ｎｇ·ｍｌ－１，ＡＵＣ为３６７．４±３４．６ｎｇ·ｈ·ｍｌ－１；盐酸特拉唑嗪片剂的药动学参数：Ｋａ为６．４±７．４ｈ－１，Ｔ１／２为７．４±２．１ｈ，Ｔｍａｘ为０．９±０．４ｈ，Ｃｍａｘ为４３．１±４．８ｎｇ·ｍｌ－１，ＡＵＣ为３７１．３±４４．４ｎｇ·ｈ·ｍｌ－１。结论：两种剂型的药物动力学参数之间差异均无显著性（Ｐ＞０．０５），胶囊剂的相对生物利用度为９９．８８％。     

克拉霉素两种制剂的生物等效性研究

采用微生物管碟检定法，以短小芽孢杆菌ＣＭＣＣ（Ｂ）６３２０２为检定菌，测定了１２名男性健康受试者口服克拉霉素（ＣＲＭ）胶囊（被试制剂）和片剂（标准对照制剂）后不同时刻血浆中活性药物的浓度，绘制了血药浓度－时间曲线。受试者交叉口服含ＣＲＭ５００ｍｇ的被试制剂和标准对照制剂后，血浆药物浓度达峰时间分别为１．３９±０．７４和１．１６±０．４１ｈ，血浆药物浓度峰值分别为２．５４±０．６２和２．７１±０．６１μｇ／ｍｌ，消除半衰期分别为４．５９±０．９９和４．７２±０．８５ｈ，用梯形法计算，ＡＵＣ０→∞分别为２１．７０±２．７１和２２．４２±３．５３ｈμｇ／ｍｌ。被试制剂中ＣＲＭ的相对生物利用度平均为（９９．３±１０．３）％，经统计学分析与对照制剂生物等效。两种制剂中ＣＲＭ的药动学过程均符合一室开放模型     

两种布洛芬缓释制剂在健康人体内的药物动力学

目的：本文对布洛芬缓释片和胶囊在健康志愿者中的药物动力学进行研究。方法：建立了一个测定人血中布洛芬的高效液相色谱法。结果：口服单剂量６００ｍｇ片剂和胶囊的ＡＵＣ分别为１５０．２±３４．８和１５１．８±３４．５μｇ·ｈ·ｍｌ－１；Ｃｍａｘ分别为２２．７±５．３和２２．２±３．９μｇ·ｍｌ－１；Ｔｍａｘ分别为３．５±０．７和３．８±０．８ｈ。口服多剂量６００ｍｇ达稳态后片剂和胶囊的ＡＵＣ分别为１５６．０±３８．７和１６３．２±４４．７μｇ·ｈ·ｍｌ－１；Ｃｍａｘ分别为２４．６±５．５和２３．８±４．４μｇ·ｍｌ－１；Ｔｍａｘ分别为３．０２±０．２９和３．２±０．５ｈ。达稳态后片剂和胶囊的波动系数分别为１．４±０．３和１．４２±０．２３。经统计学处理，上述各参数间差异均无显著性（Ｐ＞０．０５）。结论：双单侧ｔ检验（ＮＤＳＴ程序）的结果表明，布洛芬两种缓释制剂具有生物等效性。     

国产氧氟沙星颗粒剂生物利用度的研究

本文在８名男性健康志愿者中，对国产氧氟沙星颗粒剂与进口氧氟沙星片剂进行了生物利用度的比较研究。交叉试验设计，口服给药２００ｍｇ，用专一性强、灵敏度高的反相ＨＰＬＣ－荧先检测法，测定氧氟沙星血药浓度。氧氟沙星口服给药的药时曲线均符合二室模型，其主要药动力学参数，国产颗粒剂和进口片剂分别为：ＡＵＣ１７．２１±１．５３５和１６．６４±１．７２３μｇ·ｈ／ｍｌ、Ｃ（ｍａｘ）２．９７８±０．５４５６和２．５８８±１．１９１μｇ／ｍｌ、Ｔ（ｍａｘ）０．３７００±０．２２２９和０．８１６１±０．５７８４ｈ，其相对生物利用度为１０３．４３％。经统计学处理，二者的ＡＵＣ、Ｃ（ｍａｘ）、Ｔ（ｍａｘ）均无显著性差异（ｐ＞０．０５）。结果表明，国产氧氟沙星颗粒剂在人体内的生物利用度与进口氧氟沙星片剂相似。     

安乃近代谢物4-甲氨基安替比林的HPLC测定及其鼻腔滴剂在人体的相对生物利用度

安乃近进入血液后，迅速、完全地被代谢为４甲氨基安替比林（ＭＡＡ），血浆中检测不出安乃近原型药，故血浆ＭＡＡ水平可反映安乃近的吸收情况。本文建立了ＭＡＡ的ＨＰＬＣ测定法，并用于安乃近鼻腔滴剂人体内药代动力学和肌内注射剂及口服片剂的相对生物利用度研究。结果表明鼻腔滴剂较口服片剂吸收快，较肌内注射剂生物利用度高。     

阿奇霉素分散片的人体药物动力学及相对生物利用度研究

８ 名健康男性志愿者交叉单剂量口服５００ ｍ ｇ 阿奇霉素分散片及片剂,采用微生物法测定不同时间的血药浓度,求得分散片和普通片的药物动力学参数分别如下：ｋａ 为１．２８±０．２３、１．２１±０．１８ ｈ－ １;ｔ１／２（（β）为４６．２７±８．１６、４９．８１±８．８２ ｈ;Ｃｍ ａｘ 为０．６２±０．１１、０．５８±０．１１ μｇ／ｍ ｌ;Ｔｍ ａｘ 为１．７３±０．１５、１．８２±０．１５ ｈ;ＡＵＣ为１０．１６±２．３５、１０．６５±３．４３ μｇ·ｈ／ｍ ｌ。经统计学处理,两制剂的ｋａ、Ｃｍ ａｘ、Ｔｍａｘ、ｔ１／２（β）均无显著性差异（Ｐ＞ ０．０５）。分散片相对生物利用度Ｆ为９５．０９±４．９８％ 。经方差分析、配对ｔ检验,均得出两制剂具有生物等效性的结论。     

口服甲苯咪唑微丸的药物动力学及生物利用度

目的：比较５ 只家兔单剂量口服甲苯咪唑微丸及片剂后的药动学与生物利用度。方法：采用ＲＰＨＰＬＣ 法测定血药浓度,３Ｐ８７ 程序计算药动学参数。结果：微丸的Ｃｍａｘ、Ｔ１／２ 、ＡＵＣ分别为６４３．４９ ｎｇ·ｍｌ－ １ 、１ ．０５ ｈ、８ １７０ ．９４ ｈ·ｎｇ·ｍｌ－１ 。结论：微丸与片剂的ＡＵＣ有统计学显著性差异（ Ｐ＜０ ．０５）,相对生物利用度为５２８ ．６０ ％ 。     

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.     

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.     

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.

     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

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.