大鼠血浆中补阳还五汤及总苷元的阿魏酸药物动力学研究

目的:对补阳还五汤及总苷元在大鼠血浆中阿魏酸的含量进行测定,并研究其药物动力学。方法:采用反相高效液相色谱法,色谱柱:C_(18)柱(250 mm×4.6 mm,5μm),检测波长:322 nm,流动相:甲醇-水-冰醋酸(35:65:0.47),流速:1 ml·min~(-1),柱压:(2200±60)psi;温度:35℃。药物动力学参数采用3P87软件处理。结果:血浆样品中阿魏酸线性范围为1.01～5.05 ng(r=0.999 8),平均方法回收率为98.85%,RSD为1.3%。补阳还五汤中阿魏酸的t_(1/2α)为1.31 min;t_(1/2β)为58.9 min;CL为(2.83±0.12)ml·min~(-1)·kg~(-1);AUC为(531.6±67.9)μg·min·ml~(-1);总苷元中阿魏酸的t_(1/2α)为1.39 min;t_(1/2β)为52.3 min;CL为(3.43±0.22)ml·min~(-1)·kg~(-1);AUC为(593.3±45.7)μg·min·ml~(-1),两组药动学参数中B(μg·ml~(-1))、t_(1/2)β(min)和V_c(ml·kg~(-1))存在显著差异(P<0.05)。结论:补阳还五汤复方及总苷元中阿魏酸药物动力学为二室模型。中药复方成分组合对药物动力学参数有一定影响。     

异丙酚全麻下瑞芬太尼在手术患者的药代动力学

目的研究瑞芬太尼(麻醉药)复合异丙酚靶控输注静脉全麻的临床药代动力学。方法选择24例靶控输注异丙酚全麻手术患者,以不同速度0.50,0.75,1.00μg·(kg·min)-1输注瑞芬太尼,取桡动脉血浆,用高效液相色谱-紫外法检测瑞芬太尼浓度,用DAS计算药代动力学参数。结果瑞芬太尼符合二室模型,3组患者的t1/2α、t1/2β、V1、V、CL比较无显著性差异(P>0.05),AUC(0-∞)、V、t1/2β和CL的RSD分别为33.42%,67.38%,51.22%和68.10%。结论瑞芬太尼不同输注速率对药代动力学无明显影响,但应注意个体化给药。     

单次口服硫辛酸胶囊在中国健康志愿者体内的药物动力学研究

目的:研究硫辛酸胶囊在中国健康人体内的药物动力学。方法:22名健康志愿者单剂量口服硫辛酸胶囊200 mg,用HPLC-MS法测定硫辛酸血浓度,并拟合药动学参数。结果:主要的药动学参数Ka为(0.109±0.117)min~(-1),t_(1/2)为(24.42±9.51)min,t_(max)为(16.59±4.47)min,C_(max)为(1489.93±358.65)ng·ml~(-1),AUC_(0-1)为(59558.64±18456.17)ng·min·ml~(-1),MRT_(0-t)为(46.46±14.73)min,Vc/F为(129.09±59.59)L,Cls/F为(3646.83±1110.76)ml·min~(-1)。结论:健康志愿者口服硫辛酸胶囊后的体内过程呈线性动力学特征,符合一级消除过程。     

家兔静注蝮蛇抗栓酶的药物动力学

以家兔凝血时间的延长作为分级定量的药理指标,测定了蝮蛇抗栓酶 iv 给药的药动学参数和 ig给药的生物利用度。按二室开放模型拟合的结果如下:t_(1/2α)=1.12h;t_(1/2β)=3.8h;k_(12)=0.039h~(-1);k_(21)=0.56h~(-1);k_(10)=0.21h~(-1);CL=0.021kg/kg·h;V_c=0.098kg/kg;V_p=0.0069kg/kg;V_(ss)=0.105kg/kg;F=10.9%。     

体内药物累积法研究白血康的表观药物动力学

采用体内药物累积法测定小鼠 ip 白血康后的体内过程和药动学参数,白血康在小鼠体内的过程符合二室开放模型,模型方程为:体存率%=87.1711e~(-1.0952t) 138.1771e~(-0.0272t),t_(1/2)α=0.6328h,t_1/2β=25.48h,k_(21):0.6821h~(-1),k_(12)=0.3966h~(-1),k_(10)=0.0437h~(-1),Vc=3.55L/kg.     

HPLC-MS／MS法研究盐酸右美托咪定注射液的人体药物代谢动力学

目的:研究盐酸右美托咪定注射液在健康成年志愿者体内的药代动力学。方法:采用单次给药的开放、平行实验设计。将受试者随机分入3个剂量组,每组包含5名男性和5名女性,分别静脉注射盐酸右美托咪定0.5,1.0,1.5μg·kg~(-1),采用HPLC—MS/MS 法测定给药后不同时间的血药浓度,用 DAS Ver 2.0和 SPSS 进行药动学参数计算和统计分析。结果:健康受试者在10 min 内静脉注射不同剂量盐酸右美托咪定0.5,1.0,1.5μg·kg~(-1)后,盐酸右美托咪定的主要药代动力学参数 C_(max)(ng·L~(-1))分别为105.2±28.3,148.7±35.9,287.1±62.3;t_(1/2α)(min)分别为:3.2±0.7,5.5±3.2,4.0±0.6;t_(1/2β)(min)分别为:92.4±19.0,106.9±20.9,99.8±9.7。结果表明在上述剂量范同内 AUC_(0-360)、AUC_(0-∞)与给药剂量呈线性关系;t_(1/2β)、CL 和MRT 在上述不同剂量组间无显著性差异(P>0.05);t_(1/2α)和 V_d 在上述不同剂量组间差异有显著性(P<0.05),但与给药剂量无关。结论:在0.5～1.5μg·kg~(-1)的剂量范围内,盐酸右美托咪定注射液在健康成年志愿者体内呈线性动力学特征。     

盐酸阿芬太尼在手术病人中的药代动力学研究

本文进行了两组不同剂量的阿芬太尼在14例手术病人中药代动力学研究。7例一次性iv 80μg·kg~(-1)阿芬太尼,另7例一次性iv 40μg·kg~(-1)。用RIA方法测定0-8 h阿芬太尼的血浆浓度和0-48 h尿中的回收率。研究表明:阿芬太尼在两组病人体内的药代动力学过程均为3室模型。阿芬太尼的初级消除很快,给药后30 min内90％的原型药被消除。病人血浆浓度未发现2次上升现象。二者药-时曲线接近平行,说明阿芬太尼的代谢过程为1级消除。两组阿芬太尼的药代动力学数据经t检验无显著差异(P>0.05)。阿芬太尼的快、慢分布相和消除相的半衰期t_(1/2)π,t_(1/2)α和t_(1/2)β分别为0.71 min±s 0.37 min,11.66 min±s 3.46 min和86.12 min±s 19.15 min;平均总体和中心室的分布容积Vd、Vc分别为34.22L±s 8.27L和4.23L±s 1.72L;平均总体清除率Cl为0.29 L·min~(-1)±s 0.08L·min~(-1)。另外,k_(12)/k_(21)为1.5,k_(13)/k_(31)为3.5,k_(10)大于k_(31)。用药后48 h以内,40μg·kg~(-1)组和80μg·kg~(-1)组的病人尿中排出的原形阿芬太尼分别占总给药量的0.68％±s 0.72％和0.66％±s 0.54％。其肾清除率分别为0.0016 L·min~(-1)±s 0.0011 L·min~(-1)和0.0021 L·min~(-1)±s 0.0015 L·min~(-1)。     

地奥司明片在健康人体内的药物动力学

目的:建立测定人血浆中地奥司明苷元浓度的液相色谱-串连质谱检测法,并研究地奥司明片在健康人体内的药物动力学特征。方法:用LC/MS/MS法测定,色谱柱为CAPCELL PAK UG120柱,流动相为乙腈-0.1%甲酸溶液(80:20,v/v),流速0.6 ml·min~(-1),柱温为24℃,对12名健康志愿者口服地奥司明片后不同时间点的血药浓度进行测定,并用统计矩法计算药动学参数。结果:地奥司明片中地奥司明苷元在健康受试者体内的主要药动学参数t_(max)为(12.1±0.9)h,C_(max)为(8.88±2.69)ng·ml~(-1),t_(1/2)为(11.9±2.5)h,AUC_(0-48h)为(183±55)ng·h·ml~(-1),AUC_(0-∞)为(200±61)ng·h·ml~(-1)。结论:本方法具有良好的准确性、精密度和较高的灵敏度、简便快速,能满足地奥司明的血药浓度测定和药动学研究。     

复方纳米雄黄中砷在大鼠体内的药动学*

目的:研究复方纳米雄黄中砷在大鼠体内的药动学行为。方法:用氢化物发生-双道原子荧光光谱法测定血清中砷元素的浓度,并计算药动学参数。结果:低、中、高(35,70,140 mg·kg~(-1))三剂量组主要药动学参数分别为t_(1/2)Ka:0.34,0.30,0.29 h;t_(1/2)Ke:19.0,21.6,22.1 h;CL/F:7.1,6.5,6.0 mL·kg~(-1)·h~(-1);V_d/F:188.6,200.1,191.0 mL·kg~(-1);C_(max):180.9,334.4,693.1 ng·mL~(-1);AUC:5069,10650,23393 ng·mL~(-1)·h。除C_(max)和AUC外,其他药动学参数在3种剂量组间比较和雌雄性别之间比较,差异均无统计学意义(P>0.05),而C_(max)和AUC则与剂量呈正比。结论:复方纳米雄黄中砷在大鼠体内的药动学行为符合开放性血管外给药一室模型一级速率过程。     

米索前列醇片在健康人体内的药动学特征

目的建立人血浆中米索前列醇浓度的LC-MS/MS检测方法,研究米索前列醇片在健康志愿者体内的药动学特征。方法采用K-MS/MS C_(18)分析色谱柱(150 mm×4.6 mm,5μm);流动相为甲醇-水-1%氨水(55:45:0.075,V/V/V);流速为0.5 mL·min~(-1);柱温为室温。结果该测定方法的线性范围为10～3000 ng·L~(-1)(r=0.9964),最低检测浓度为10.0 ng·L~(-1)(按R_(S,N)≥3计),提取回收率为80%～90%,日内和日间RSD均<10%。药动学研究表明,米索前列醇片在体内代谢过程符合一室模型,主要药动学参数t_(1/2)、ρ_(max)、t_(max)、AUC_(0-360)分别为:(1.15±0.26)h,(1 209±973)ng·L~(-1),(32±13)min,(1 359±1 015)ng·h·L~(-1)。结论本法具有良好的准确性和较高的灵敏度,简便快速,适用于米索前列醇片血药浓度的测定和药动学研究。     

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.     

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.