大鼠对阿魏酸哌嗪的在体肠吸收

目的考察阿魏酸哌嗪(PF)在大鼠各肠段的吸收。方法采用在体肠吸收实验,在浅麻醉状态下,分肠段考察大鼠对PF的吸收动力学。采用RP-HPLC测定循环液中药物的浓度。结果大鼠胃、十二指肠、小肠、结肠对PF均有较好的吸收,2h后的吸收百分率分别为62.04%±11.62%、70.02%±5.21%、72.08%±3.91%和12.68%±1.22%,其中十二指肠、小肠、结肠对PF的吸收速率常数分别为0.561±0.006、0.630±0.071、0.098±0.007 h-1。结论PF在大鼠胃至结肠各部位均有较好的吸收,吸收最佳部位是胃、十二指肠和小肠,在结肠部位也有少量的吸收。     

牡荆素鼠李糖苷的大鼠在体肠吸收动力学

目的 研究牡荆素鼠李糖苷(RHV)的大鼠在体肠吸收动力学特征.方法 采用HPLC法测定RHV在肠循环液中的药物浓度;采用UV法测定肠循环液中酚红浓度;以大鼠原位灌注模型考查RHV的肠吸收动力学情况.结果 RHV 浓度为20、10、5μg·ml-1的吸收速率常数(Ka)分别为0.0416、0.0478、0.0312 h-1;肠循环液pH4、6、8时RHV的Ka分别为0.0253、0.0478、0.0588 h-1;RHV在十二指肠、空肠、回肠和结肠时的Ka分别为0.0479、0.0308、0.0322、0.0305 h-1.结论 RHV 浓度对RHV的Ka无显著性影响;在pH4～8时,随肠循环液pH的增大,RHV的Ka增加;RHV在大鼠十二指肠、空肠、回肠和结肠的吸收无显著性差异(P＞0.05);RHV在大鼠肠道的吸收呈一级动力学过程,吸收机制为被动扩散.     

川芎嗪大鼠在体肠吸收动力学

目的:探讨川芎嗪在大鼠各肠段的吸收动力学特征.方法:采用大鼠在体小肠回流装置,以UV法和HPLC法分别测定酚红和川芎嗪的含量.结果:川芎嗪在小肠的吸收速率常数(Ka)于不同药物浓度2.5,5,10,25 mg·L-1时分别为0.360 8,0.388 1,0.444 6,0.385 9 h-1;不同pH值7.8,6.8,5.4时分别为0.466 4,0.413 9,0.270 5 h-1;在十二指肠,空肠,回肠和结肠时分别为0.291 3,0.220 9,0.172 8,0.133 3 h-1.结论:药物浓度对Ka无影响;在pH 7.8～5.4范围内,随药液pH值的增大,药物的Ka显著增加;药物在十二指肠、空肠和回肠的吸收较好,在结肠的吸收较差;川芎嗪在肠道的吸收呈一级动力学过程,吸收机制为被动扩散.     

吗替麦考酚酯大鼠在体肠吸收动力学研究

目的:研究吗替麦考酚酯(MMF)、麦考酚酸(MPA)在大鼠肠道的吸收特性。方法:采用大鼠在体肠吸收实验模型,考察不同药物浓度、不同肠段、不同pH对MMF、MPA肠吸收特性的影响。结果:MMF在十二指肠、空肠、回肠、结肠的吸收速率常数分别为0.0176,0.0219,0.0311,0.0333 h-1,统计结果显示,不同肠段间吸收有明显差异(P<0.05);在pH 5.4～7.4范围内,药物吸收不受pH影响;65,135,200,300μg·mL-1不同浓度MMF的吸收速率常数分别为0.0964,0.1325,0.1655,0.1222h-1,而不同浓度MPA的吸收速率常数基本不变(P>0.05)。结论:MMF在整个肠段均有吸收,剂型设计时可考虑缓控释制剂。     

普拉克索的大鼠在体肠吸收

采用大鼠在体灌流法,以灌流液中剩余药物浓度为指标,考察普拉克索(1)在不同吸收部位的吸收动力学特征以及不同pH、不同药物浓度对1全肠段吸收的影响.结果显示,1在不同肠段的吸收速率常数(h-1)分别为:十二指肠0.295、结肠0.513、回肠0.480 h和空肠0.808 h.药物在大鼠全肠道内的吸收量随药物浓度的增大而升高,药物浓度和pH对吸收速率常数无显著性影响.1在肠道的吸收符合一级动力学特征,吸收机制为被动吸收.采用大鼠在体胃灌注法,以胃灌注液中药物前后浓度变化计算1在胃部吸收情况.结果表明1几乎不吸收.     

盐酸洛美沙星大鼠在体肠吸收动力学研究

目的研究盐酸洛美沙星在大鼠各肠段吸收的药代动力学特征。方法采用大鼠在体肠段灌流实验装置,利用紫外分光光度法和HPLC分别测定酚红和盐酸洛美沙星的含量。结果盐酸洛美沙星在十二指肠、空肠、回肠、结肠的吸收速率常数分别为0.204 5、0.321 0、0.183 9、0.129 2 h-1;在不同药物浓度1.5、15、150μg/mL小肠的吸收速率常数分别为0.192 7、0.219 2、0.230 9 h-1;在不同pH值(6.29、6.79和7.4)时的吸收速率为0.163 1、0.181 9、0.160 2 h-1。结论盐酸洛美沙星在大鼠全肠段均有吸收,吸收符合一级动力学特征,吸收机制为被动转运。     

吲达帕胺大鼠在体胃、小肠的吸收动力学研究

目的研究吲达帕胺在大鼠胃、小肠的吸收特性。方法采用大鼠在体方式 ,对吲达帕胺进行了大鼠胃、小肠的吸收动力学实验。结果大鼠胃部为吲达帕胺的不良吸收部位 ,2h的吸收百分率为 9 8% ;胆管结扎与不结扎对吸收速率无明显影响 ;吲达帕胺在小肠各部位吸收良好 ,吸收速率常数按十二指肠、空肠、回肠、结肠顺序依次下降 ,吸收速率常数分别为 0 1 5 6、0 1 4 0、0 1 30、0 0 73h-1。药物在肠道的吸收呈现一级吸收动力学 ,吸收机制为被动吸收。结论结肠的吸收速率常数大约是小肠段的十分之三 ,提示适于制备日服一次 ( 2 4h)缓释给药系统。     

法莫替丁大鼠在体小肠吸收动力学研究

应用大鼠在体肠吸收实验方法研究了法莫替丁各肠段的吸收动力学特征。实验表明 :法莫替丁在肠道各部位的吸收速率按十二指肠、空肠、回肠、结肠顺序下降 ,吸收速率常数分别为0 0 5 0 8,0 0 44 6 ,0 0 415 ,0 0 2 87h-1。药物在肠道内的吸收呈现一级吸收动力学过程 ,其吸收机制为被动扩散     

去甲基斑蝥素纳米粒大鼠体肠吸收动力学研究

目的:考察去甲基斑蝥素(NCTD)及其壳聚糖纳米粒(NCTD-CS-NP)制剂的大鼠在体吸收特征与相关动力学。方法:采用大鼠在体回流试验,并用紫外分光光度法和HPLC分别测定酚红和NCTD的质量浓度;并采用在体循环法比较不同质量浓度NCTD及NCTD-CS-NP在大鼠小肠区段内的吸收规律。结果:NCTD在十二指肠、空肠、回肠、结肠的吸收速率常数(ka)分别为:0.0306,0.0278,0.0151,0.0044h-1,NCTD-CS-NP在对应肠段的ka分别为:0.0689,0.0592,0.0353,0.0095h-1;质量浓度分别为140,160,180μg/mL的NCTD小肠ka分别为:0.0499,0.0525,0.0489h-1;对应质量浓度的NCTD-CS-NPka分别为:0.0814,0.0764,0.0734h-1。结论:NCTD的质量浓度对其大鼠全肠道的吸收无显著影响,吸收呈一级动力学过程,且以肠道中上部的吸收为主,NCTD-CS-NP可有效促进药物在肠粘膜的吸收。     

氟他胺大鼠在体肠吸收动力学研究

目的:研究氟他胺在大鼠小肠各段的吸收动力学特征,为其剂型设计提供依据.方法:采用在体试验法,分别用紫外可见分光光度法及高效液相色谱法(HPLC)测定酚红和氟他胺的浓度.结果:在体全小肠段吸收实验中,药液在体循环6h后,43.58％的药物被肠道吸收;氟他胺在十二指肠、空肠、回肠、结肠的吸收百分率分别为(10.66±2.98)％·cm-1·h-1、(10.12±3.05)％·cm-1·h-1、(10.47±3.1)％·cm-1·h-1、(10.11±3.02)％·cm-1·h-1,四个肠段的肠壁通透系数分别为:(0.587±0.208) cm2·h-1、(0.571±0.193) cm2·h-1、(0.593±0.197) cm2·h-1、(0.539±0.192) cm2·h-1;药物浓度为15.48～68.48 μg· mL-1时,小肠的吸收速率在(0.092±0.010) h-1～(0.090±0.012)h-1之间基本相似;供试药液中聚山梨酯-80的含量分别为1％、2％、5％时,肠的吸收速率分别为:(0.097±0.017)h-1、(0.078±0.012)h-1、(0.073±0.009) h-1.结论:氟他胺在大鼠肠道各部分均有吸收,且吸收呈一级动力学过程,吸收机制为被动扩散;实验范围内,药物浓度和聚山梨酯-80含量对药物的吸收速率无影响;大鼠各肠段的吸收速度无显著性差异,说明氟他胺在整个肠段均有较好的吸收.     

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.