环丙沙星在老年慢性阻塞性肺患者多次给药的药动学研究

应用微生物法测定６名老年慢性阻塞肺病患者多次口服环沙星片后的血清药物浓度，药物体内过程符合一定模型，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＾Ｄ１ｐ＝１．０±０．４ｈ，测定方法平均回收率为１０１．６％。     

氨氯地平片在健康人和高血压患者中的药物动力学

采用反相高效液相色谱法测定了健康志愿者及高血压患者共３３名单剂量口服５ｍｇ苯磺酸氨氯地平片后的血清药物浓度，研究了该药在中国人体内的药物动力学。经ＰＫＢＰ－Ｎ１程序拟合表明，氨氯地平主要呈现二房室模型。其主要药动学参数分别为：健康人Ｔ１／２α＝０．６±０．５ｈ，Ｔ１／２β＝３５±９ｈ，Ｔｍａｘ＝８±４ｈ，Ｃｍａｘ＝２．４±０．８ｎｇ／ｍｌ；中青年高血压患者Ｔ１／２α＝０．６±０．４ｈ，Ｔ１／２β＝３６±９ｈ，Ｔｍａｘ＝１１±４ｈ，Ｃｍａｘ＝２．３±１．２ｎｇ／ｍｌ；老年高血压患者Ｔ１／２α＝０．４９±０．３３ｈ，Ｔ１／２β＝４２±１４ｈ，Ｔｍａｘ＝１０±４ｈ，Ｃｍａｘ＝２．８±１．４ｎｇ／ｍｌ。结果表明，中国人体内的氨氯地平药动学参数与报道的外国人相似。     

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％。     

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。     

健康人单剂量口服茶碱控释胶囊的药物动力学

目的：研究７ 名健康志愿者单剂量口服茶碱控释胶囊（ 简称ＣＲＴＣ）４００ ｍｇ 后的药物动力学。方法：用紫外法测定健康人血清中茶碱的血药浓度。结果：ＣＲＴＣ的药物动力学参数分别为：Ｔｍａｘ ＝ （７ ．９ ±１．１）ｈ,Ｃｍａｘ ＝ （４．０ ±０ ．９）μｇ·ｍｌ－１ ,Ｔ１／２ｅ ＝（１７ ．２±２ ．６）ｈ,Ｋｅ ＝（０．０４±０．０６）ｈ－１ ,Ｔ１／２ａ＝ （２ ．１±０ ．９）ｈ,Ｋａ＝（０．２３±０．０４）ｈ－ １ ,ＡＵＣ０７２ ＝ （１３８ ．０±１７ ．６）μｇ·ｈ·ｍｌ－ １ 。结论：ＣＲＴＣ的药物动力学参数与国产茶碱控释片（ 简称ＤＣＲＴＴ）［１］ 相比：其吸收减慢,导致达峰时间延长,达峰浓度降低。但其消除减慢,ＣＲＴＣ在体内蓄积,致使其药时曲线下的面积较ＤＣＲＴＴ 大。     

应用Bayesian反馈法预测阿替洛尔药物动力学参数及血药浓度

应用Ｂａｙｅｓｉａｎ反馈法预测２１例高血压病人，口服阿替洛尔的个体药动学参数及稳态血药浓度（Ｃｐｓｓ）并与经典药动学方法估算结果作比较，结果表明本法的Ｔ１／２为６．０±１．７ｈ，Ｖｄ为１．４３±０．１３Ｌ／ｋｇ，ＣＬ为１７２±３４ｍｌ／（ｈ·ｋｇ）；经典法的Ｔ１／２为６．８±２．４ｈ，Ｖｄ为１．４５±０．５６Ｌ／ｋｇ，ＣＬ为１６４±８５ｍｌ／（ｈ·ｋｇ）。两者无显著性差异（Ｐ＞０．０５）。两法所测得Ｃｐｓｓ有较好相关性（ｒ＝０．９９３）。     

口服茶碱缓释胶囊的药物动力学

采用荧光偏振免疫法（ＦＰＩＡ），对１２名老年慢性阻塞性肺病（ＣＯＰＤ）患者口服单剂量和多剂量茶碱缓释胶囊（ＰＴ）测定经时血药浓度并计算药物动力学参数。结果表明，单剂量组口服ＰＴ后Ｔｍａｘ＝７．０±６．０ｈ，Ｃｍａｘ＝６．８±２．６ｍｇ·Ｌ－１；多剂量组连续口服ＰＴ后Ｔｓｓｍａｘ＝４．０±１．８ｈ，Ｃｓｓｍａｘ＝１６．５±２．６ｍｇ·Ｌ－１。     

盐酸伪麻黄碱在人体中的药物动力学

采用反相高效液相色谱外标法测定人血清中伪麻黄碱浓度，并测定８例志愿受试者伪麻黄碱血药浓度，并计算分析药物动力学参数，结果单剂量口服９０ｍｇ盐酸伪麻黄碱后，药时曲线呈一室模型。Ｔｍａｘ＝１．７±１．１ｈ，Ｃｍａｘ＝３６４±９４ｎｇ·ｍｌ－１，ＡＵＣ（０～∞）＝２６６２±３０３（ｎｇ·ｈ·ｍｌ－１），Ｔ１／２＝４．０±１．０ｈ，Ｋａ＝２．４±１．４ｈ－１，Ｋｅ＝０．１９±０．０４ｈ－１，Ｖｄ＝０．１９±０．０５ｍｇ，Ｃｌ＝０．０３±０．０１ｍｇ·ｈ－１。     

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。     

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）     

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.

     

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.     

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.     

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.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.