白细胞介素-1受体拮抗剂对卵白蛋白致敏的哮喘豚鼠嗜酸性粒细胞凋亡的影响

目的研究白细胞介素-1受体拮抗剂(IL-1ra)，对慢性哮喘豚鼠肺内嗜酸性粒细胞凋亡及相关机制的影响。方法建立致敏豚鼠模型，连续吸入不同浓度IL-1ra,用卵白蛋白引喘豚鼠，连续8 d，分离血液、肺泡灌洗液(BALF)中嗜酸性粒细胞，计数嗜酸性粒细胞，用放射免疫法测定上清液中阳离子蛋白（ECP），酶连免疫法（ELISA）测血清中IL-5，荧光显微镜观察嗜酸性细胞凋亡。结果IL-1ra能明显减少肺部嗜酸性粒细胞浸润，降低血清、肺泡灌洗液中ECP水平及血清中IL-5的含量，促进嗜酸性细胞凋亡。结论雾化吸入IL-1ra可以通过改变嗜酸性粒细胞的活性及浸润程度，达到治疗哮喘的目的。     

布地奈德纳米混悬剂的制备及药效学评价

目的研究一种新型的布地奈德(BUD)纳米混悬吸入剂,评价其在豚鼠哮喘模型上的治疗作用,以期开发糖皮质激素新剂型用于哮喘长期吸入治疗。方法以HPMC、SLS为基质材料,采用高压乳匀技术制备BUD纳米混悬剂,并进行体外特征评价,体内过敏实验及药效学研究。结果 BUD纳米混悬剂为稳定、均匀的混悬液,纳米粒径呈正态分布,均值为122.5 nm;制备的纳米混悬剂对豚鼠无过敏反应,能明显控制哮喘发作,并呈剂量依赖性;纳米混悬治疗组中白细胞总数和肺泡灌洗液中细胞总数及嗜酸性粒细胞明显低于模型组(P<0.05),且嗜酸性粒细胞减少呈剂量依赖性。结论 BUD纳米混悬液能够提高药物在体内吸收程度,显著抑制气道内炎性细胞浸润,是一种适合哮喘患者吸入的新剂型。     

银杏苦内酯对过敏性豚鼠气道内低密度嗜酸性粒细胞增多的调制作用

用卵蛋白吸入诱导豚鼠哮喘动物模型（哮喘组），然后，进行支气管肺泡灌洗，分析支气管肺泡灌洗细胞学改变。哮喘组支气管肺泡灌洗液中的细胞总数、嗜酸性粒细胞绝对计数及低密度嗜酸性粒细胞比例均显著高于正常对照组（Ｐ＜０．０５、Ｐ＜０．０１）。哮喘动物模型在吸入抗原激发之前，用血小板活化因子特异性拮抗剂银杏苦内酯（ＢＮ５２０２１）预处理后，支气管肺泡灌洗液中细胞总数、分类和嗜酸性粒细胞数量均与哮喘组差异无显著性。但低密度嗜酸性粒细胞比例却显著降低（Ｐ＜０．０５）。用地塞米松预处理动物模型（激素组）后，支气管肺泡灌洗液中的细胞总数、嗜酸性粒细胞数、细胞分类及低密度嗜酸性粒细胞比例均降至正常对照组水平。结果表明：银杏苦内酯能显著减少哮喘动物气道内“活化”状态的低密度嗜酸性粒细胞，可能是一种有用的哮喘抗炎药物。     

罗红霉素与布地奈德干粉吸入剂联用治疗哮喘的临床研究

目的：通过与单纯吸入布地奈德干粉吸入剂（普米克都保）组比较，观察口服罗红霉素联用布地奈德干粉吸入剂治疗哮喘的疗效及对血清可溶性IL-2受体（sIL-2R）、IL-8和血嗜酸性粒细胞（EOS）计数水平的影响。方法：选择门诊轻、中度急性发作哮喘患者45例，随机分组。治疗组口服罗红霉素联合吸入布地奈德干粉吸入剂，对照组吸入布地奈德干粉吸入剂，疗程4周。治疗前、治疗4周后检测肺功能、血sIL-2R、IL-8和EOS计数水平，并按临床症状记分。结果：40例完成了试验。治疗4周后临床症状记分、肺功能一秒钟用力呼气量（FEV1）、FEV1占预计值百分比（FEV1／pred％）、最大呼气流量（PEF）和PEF占预计值百分比（PEF／pred％）改善，血sIL-2R、IL-8和EOS计数水平较治疗前降低，且治疗组较对照组改善更为明显，两组副作用相似。结论：罗红霉素具有抗炎和免疫调节作用，罗红霉素与布地奈德干粉吸入剂联用可以提高疗效。     

新型环索奈德胶囊型干粉吸入剂的研制及其质量研究

目的:研制用于治疗哮喘的环索奈德胶囊型干粉吸入剂,建立其含量测定方法,并对其稳定性进行初步考察。方法:用高效液相色谱-紫外法检测环索奈德干粉吸入剂中主药环索奈德及其有关物质的含量。将主药与辅料混合后,以含量均匀度和肺部沉积率为指标进行处方筛选,考察制剂的有关物质和影响因素,并进行了加速稳定性和长期留样稳定性试验。结果:建立的高效液相色谱法,色谱条件如下:色谱柱为Alltima C18(250 mm×4.6mm,5μm);流动相为乙醇-水(65∶35);流速为1.2 mL.min-1;检测波长为243 nm。最后选择乳糖作为辅料,确定了最佳处方和工艺,获得了较好的含量均匀度和肺部沉积率(约19%)。稳定性结果显示,本制剂应置于阴凉、干燥处保存,在室温下保存至少在1年内稳定,长期放置稳定性在继续考察。结论:建立的高效液相色谱法适合于环索奈德胶囊型干粉吸入剂的日常质量控制,研制的制剂处方稳定。     

孟鲁司特对哮喘豚鼠气道嗜酸粒细胞炎症的抑制作用

目的　研究白三烯受体拮抗剂孟鲁司特 (mon telukast,MK )对哮喘豚鼠气道嗜酸性粒细胞 (Eosinophil,Eos)炎症的影响 ,探讨孟鲁司特拮抗哮喘气道炎症的可能机制。方法　以卵白蛋白致敏豚鼠制备哮喘模型。用密度梯度分离法分离并计数支气管肺泡灌洗液 (BALF)中不同密度的嗜酸性粒细胞 ;采用TUNEL技术原位检测嗜酸性粒细胞凋亡 ;通过ELISA法检测BALF中IL 5的含量 ;采用荧光酶标记法在PharmaciaUnicap 10 0System中测定BALF中嗜酸性粒细胞阳离子蛋白 (ECP)的水平。结果　孟鲁司特能降低哮喘豚鼠BALF中Eos的数量 ;在孟鲁司特治疗组 ,嗜酸性粒细胞凋亡指数明显升高 ,BALF中IL 5和ECP的含量降低 ,与模型组比较差异均有显著性。结论　降低气道IL 5和ECP的水平 ,促进嗜酸性粒细胞凋亡 ,减少嗜酸性粒细胞浸润 ,可能是白三烯受体拮抗剂孟鲁司特拮抗哮喘气道炎症的一个重要机制。     

母牛分枝杆菌菌苗对哮喘豚鼠肺组织嗜酸性粒细胞凋亡的影响

目的 研究母牛分枝杆菌菌苗对哮喘豚鼠肺组织嗜酸性粒细胞凋亡的影响。方法30只豚鼠随机分为对照组、哮喘组及母牛分枝杆菌菌苗组各10只，应用卵清蛋白建立哮喘模型。最后一次激发豚鼠后，计数支气管肺泡灌洗液中炎症细胞，观察肺组织病理改变，应用末端标记法研究肺组织嗜酸性粒细胞的凋亡。结果母牛分枝杆菌菌苗组豚鼠支气管肺泡灌洗液中嗜酸性粒细胞数量为(0.22±0.12)×108·L^-1，显著低于哮喘组的(1.18±036)×108·L^-1 (P＜0.01)；肺组织哮喘炎症反应明显轻于哮喘组；肺组织嗜酸性粒细胞凋亡指数为(23.8±5.4)%，显著高于哮喘组的(4.6±0.7)%( P＜0.01)。结论母牛分枝杆菌菌苗能减少哮喘豚鼠支气管肺泡灌洗液中嗜酸性粒细胞数量，减轻气道哮喘炎症反应，与其诱导哮喘豚鼠肺组织嗜酸性粒细胞凋亡有关。     

孟鲁司特对哮喘豚鼠气道嗜酸性粒细胞凋亡及Fas mRNA表达的影响

目的研究白三烯受体拮抗剂孟鲁司特(montelukast,MK)对哮喘豚鼠气道嗜酸性粒细胞(eosinophil,Eos)凋亡和Fas mRNA表达的影响。方法以卵白蛋白致敏豚鼠制备哮喘模型。用密度梯度离心法分离并计数支气管肺泡灌洗液(BALF)中的嗜酸性粒细胞；采用TUNEL技术原位检测嗜酸性粒细胞凋亡；通过逆转录-多聚酶链反应(RT-PCR)技术检测嗜酸性粒细胞Fas mRNA的表达。结果孟鲁司特能显著降低哮喘豚鼠BALF中Eos的数量；在孟鲁司特治疗组，嗜酸性粒细胞凋亡指数明显升高，Fas mRNA的表达显著增强，与模型组比较均有显著性差异。结论嗜酸性粒细胞凋亡与Fas mRNA表达增加高度相关；增强气道嗜酸性粒细胞Fas mRNA的表达，促进其凋亡，可能是孟鲁司特拮抗哮喘气道炎症的一个重要机制。     

银杏内酯吸入剂对哮喘模型豚鼠气管嗜酸性粒细胞浸润的影响

目的:探讨银杏内酯吸入剂对哮喘模型豚鼠气道嗜酸性粒细胞浸润的影响。方法:将豚鼠随机分为7组,每组8只,分别为哮喘模型组,银杏内酯吸入剂低、中、高剂量组(剂量分别为5、10、20mg·kg-1),银杏内酯腹腔注射(ip)组(剂量为20mg·kg-1),地塞米松组(剂量为10mg·kg-1)和正常对照组,计数肺灌注液(BALF)和支气管中的嗜酸性粒细胞(EOS)数。结果:与正常对照组比较,模型组BALF中的EOS显著增多,银杏内酯吸入剂组可显著减少BALF和支气管中的EOS浸润数(P<0.05)。结论:银杏内酯吸入剂能对抗哮喘豚鼠气道嗜酸性粒细胞浸润,可作为治疗支气管哮喘的一种新方法。     

环孢霉素A治疗哮喘的实验研究

目的 探讨环孢霉素Ａ对哮喘的治疗作用及机制,方法 ２１只豚鼠随机分为正常组,模型组及环孢霉素Ａ组。用卵白蛋白制作豚鼠哮喘模型,用环孢霉素Ａ２５ｍｇ／（ｋｇ．ｄ）连续腹腔注射３ｄ,检测外周血Ｔ淋巴细胞增殖反应,右侧肺脏做支气管肺泡灌洗液中细胞成分分析,左侧肺脏做组织学检查。结果 环孢霉素Ａ组Ｔ细胞增殖刺激指数显著低于模型组（Ｐ〈０．０１）;支气管肺泡灌洗液中细胞总数,嗜酸性粒细胞计数也显著低于模型组     

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.     

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.     

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.