不同剂量黄芩素在大鼠体内的药动学差异*

目的:比较不同给药剂量下黄芩素在大鼠体内的药动学差异。方法:采用HPLC-ECD技术,对灌胃给予黄芩素药低、中、高剂量(20,100,200 mg.kg-1)后,大鼠血浆中黄芩苷的浓度进行测定,比较了不同给药剂量下,黄芩苷的血药浓度-时间曲线图。结果:黄芩苷的血药浓度-时间曲线均存在双峰现象。黄芩素低剂量组:黄芩苷的Tm ax=1和9 h,Cm ax,1 h=3.74μg.mL-1,Cm ax,9 h=2.18μg.mL-1,AUC0~24 h=30.44μg.mL-1.h;黄芩素中剂量组:黄芩苷的Tm ax=1和13 h,Cm ax,1 h=15.32μg.mL-1,Cm ax,13 h=6.76μg.mL-1,AUC0~24 h=123.77μg.mL-1.h;黄芩素高剂量组:黄芩苷的Tm ax=1.5和9 h,Cm ax,1.5 h=14.63μg.mL-1,Cm ax,9 h=10.92μg.mL-1,AUC0~24 h=149.63μg.mL-1.h。与低剂量(20 mg.kg-1)相比,中、高剂量组的剂量分别增加了4和9倍,但AUC0~24值仅提高了3.1和4倍。结论:黄芩素给药剂量在20~100 mg.kg-1间,代谢产物黄芩苷的药动学行为呈线性关系;黄芩素给药剂量在100~200mg.kg-1间,黄芩苷的药动学行为呈非线性关系。     

黄芩提取物中有效成分黄芩苷和汉黄芩苷在糖尿病大鼠中的药动学研究

目的比较黄芩提取物中主要成分黄芩苷和汉黄芩苷在糖尿病大鼠和正常大鼠体内的药动学.方法腹腔注射链脲佐菌素建立糖尿病大鼠模型,灌胃黄芩提取物后取血分离血浆,采用HPLC-Uv法检测血浆中黄芩苷和汉黄芩苷浓度,以矩量法计算药动学参数,AUC(0-τ)的计算采用梯形法.采用黄芩提取物与大鼠粪便温孵,从肠道代谢研究黄芩苷和汉黄芩苷动力学改变的初步机制.结果与正常大鼠比较,糖尿病大鼠给予黄芩苷和汉黄芩苷后体内Cmax1明显增加[黄芩苷(6.07±0.95)vs.(17.01±3.60)μg·mL-1,P＜0.01;汉黄芩苷(3.50±0.72)vs.(9.34±2.04)μg·mL-1,P＜0.01],Cmax2明显增加[黄芩苷(1.61±0.18)vs.(7.39±3.04)μg·mL-1,P＜0.01;汉黄芩苷(1.95±0.52)vs.(6.72±2.60)μg·mL-1,P＜0.01],AUC(0-τ)也明显增加[黄芩苷(38.72±7.25)vs.(86.70±20.91)μg·mL-1·h,P＜0.01;汉黄芩苷(39.20±12.10) vs.(69.40±24.20)μg·mL-1·h,P＜0.01],粪便悬浮液中黄芩苷降解也加快(Ke0.087 vs.0.173 min-1).结论黄芩苷和汉黄芩苷在糖尿病大鼠与正常大鼠之间存在明显的药动学差异,在糖尿病大鼠肠道内代谢加快.     

汉黄芩素固体脂质纳米粒在大鼠体内的药动学及组织分布

摘 要 目的:研究汉黄芩素固体脂质纳米粒在大鼠体内的药动学及组织分布情况。方法: 大鼠随机分成汉黄芩素注射液组和汉黄芩素固体脂质纳米粒组,分别于给药后不同时间采血测定汉黄芩素含量,并测定两组大鼠心、肝、脾、肺、肾中汉黄芩素含量,计算靶向效率以评价其在大鼠体内的组织分布及靶向性。结果:汉黄芩素固体脂质纳米粒在大鼠体内的药动学模型符合二室模型,主要药动学参数为：t_1/2α=（0.551 0±0.124 7）h, t_1/2β=(14.589 1±1.563 8)h, CL=(0.006 4±0.001 4) ml·h·Kg^-1, AUC_0→∞=(125.76±9.5728) mg·h·L^-1,其在肝脏、脾脏、心脏、肺脏及肾脏的靶向效率分别为2.003、1.789、0.634、0.707、0.259。结论:与汉黄芩素溶液相比,汉黄芩素固体脂质纳米粒能提高对肝脏、脾脏的趋向性,有利于提高其治疗作用。     

鸡西产黄芩药材及其须根的质量评价与溯源研究

目的:建立黄芩药材和须根的质量控制方法,考察生长年限和施肥情况对鸡西产黄芩药材和须根中主要成分含量的影响.方法:采用HPLC,C18色谱柱;以甲醇-0.4％磷酸水溶液为流动相进行梯度洗脱;检测波长277nm;柱温25℃;流速1.0mL·min-1.结果:黄芩苷、黄芩素和汉黄芩素的线性范围分别为2.705～108.2μg·mL-1、0.5465～21.86μg·mL-1和0.4660～18.64μg·mL-1,r≥0.9996;平均回收率分别为98.78％、97.17％和97.16％,3年生且施加有机肥黄芩药材及须根各项指标含量较高.结论:本法操作简便,专属性强,准确度高,可用于黄芩药材与须根的质量评价,鸡西地区栽培黄芩种植年限选择3年并施加有机肥有利于提高黄芩的品质且能节约种植成本.     

高效液相色谱法测定大鼠血浆内厄洛替尼的浓度及其药动学研究

目的 建立以高效液相色谱法测定大鼠血浆中厄洛替尼浓度的方法,并研究其在大鼠体内的药物动力学.方法 色谱柱为Dikma Diamonsil C18,流动相为乙腈-水=60∶40(pH=2.0),流速为1.2 mL· min-1,柱温为35℃;检测波长331nm.结果 厄洛替尼血药浓度在80～4 000 ng·mL-1与峰面积线性关系良好(r=0.997 7),最低检测限为80 ng·mL-1;日内、日间RSD均≤10％,提取回收率在83.77％～85.68％.6只SD大鼠单剂量静脉给予厄洛替尼(10 mg·kg-1)后药动学参数分别为:Cmax=(1.203×103士118.2)ng·mL-1; t1/2=(23.24±2.33)h;AUC0-r=(4.713×103士213.6) ng· h· mL-1;AUC0-∞=(5.363×103±323.6) ng· h· mL-1;MRT=(25.91±2.34)h;Vd=(28.44±1.58)L.结论 本方法简便、准确、灵敏、专属性强,同样适用于人血浆中厄洛替尼浓度的测定及其药动学研究,对于评价厄洛替尼疗效和安全性有重要意义.     

新型钙离子拮抗剂DY-9836在大鼠体内的药动学

目的建立测定大鼠血浆中新型钙离子拮抗剂DY-9836浓度的高效液相色谱-荧光检测(HPLCFl)法,研究DY-9836在大鼠体内的药动学。方法以维拉帕米为内标,色谱柱:Extend C18(4.6 mm×150 mm,5μm);流动相:乙酸钠(pH=6.5)-乙腈(50∶50,V/V);流速:1 mL·min-1;柱温:35℃;λex=304 nm,λem=335 nm。大鼠灌胃后,测定血浆中DY-9836的浓度,采用WinNonLin 5.2软件计算药动学参数。结果 DY-9836的血药浓度线性范围为0.327～4.083μg·mL-1;方法回收率分别为93.35%～98.08%;DY-9836在大鼠体内的主要药动学参数:Ke为(0.05±0.01)h-1、t1/2为(14.20±0.92)h、tmax为(1.25±0.42)h、ρmax为(2.98±0.56)μg·mL-1、AUC0-t为(37.74±2.00)μg·h·mL-1、AUC0-∞为(41.71±1.90)μg·h·mL-1、CL为(480.3±22.0)mL·h-1·kg-1、MRT0-t为(19.30±0.60)h。结论本实验所建立的测定血浆中DY-9836的HPLC-Fl方法简便、快速、灵敏、准确、可靠。     

注射用头孢拉定对双黄连粉针药动学的影响

目的测定双黄连粉针中绿原酸在大鼠体内的药动学参数。方法利用建立的高效液相色谱法测定大鼠单独静脉注射双黄连粉针及与头孢拉定合用后绿原酸在大鼠体内的血药浓度,采用药动学程序Topfit2.0进行统计处理,计算非室模型药动学参数。结果单用双黄连粉针后绿原酸的药动学参数:t210.5h,ke1.37h-1,AUC0-t6.98μg.h.mL-1,MRT0.43h,Cltot111.0mL.min-1.kg-1,Vz5.01L.min-1.kj-1;合用头孢拉定后绿原酸的药动学参数:t210.53h,ke1.33h-1,AUC0-t8.07μg.h.mL-1,MRT0.45h,Cltot99.3mL.mL-1.kg-1,Vz4.50L.min-1.kg-1。结论头孢拉定不影响大鼠体内绿原酸的药动学过程。     

黄芩素在小鼠体内的药动学及其组织分布研究

建立了HPLC法测定小鼠血浆和组织中的黄芩素,并研究了小鼠静脉注射黄芩素后的药动学及组织分布特征.黄芩素在0.05～50 μg/ml浓度范围内线性关系良好,提取回收率74.2%～104.2%,方法回收率88.9%～113.5%,日内、日间RSD均小于15%.静脉注射后,黄芩素在小鼠体内的药-时曲线符合二室模型,主要药动学参数:t1/2β 16.42 min,AUC0-∞ 128.97 mg·min·L-1,CI 0.14 L·min-1·kg-1.组织分布结果表明,黄芩素主要分布在肝脏和肺部组织,其次为心、肾和骨骼肌,脑和脾分布最少.     

LC-IT-MS/MS法测定大鼠体内商陆皂苷甲浓度及其药动学研究

目的:建立测定SD大鼠体内商陆皂苷甲(EsA)血药浓度的高效液相-离子阱串联质谱方法;研究EsA在SD大鼠体内的药动学特征。方法:采用Diamonsil C18色谱柱(50 mm×2.1 mm,3μm),流动相为甲醇-水(含0.1%冰醋酸)(70∶30),流速为0.2 mL.min-1,采用ESI源,正离子检测模式,以人参皂苷Rg1为内标,血浆样品经正丁醇液液萃取后进样分析,测定大鼠血浆中EsA浓度,BAPP软件计算主要药动学参数。结果:在选定的色谱条件下,EsA和内标分离良好,没有内源性物质干扰。EsA在5～500 ng.mL-1范围内线性良好(r=0.998 3),最低定量限为5 ng.mL-1,提取回收率大于70%,日内和日间精密度小于10%。SD大鼠灌胃给予EsA 15 mg.kg-1后,其主要药动学参数AUC0～24 h为(1 013.85±82.73)ng.h.mL-1,AUC0-∞为(1 076.31±92.70)ng.h.mL-1,t1/2为(6.16±0.63)h,Cmax为(218.80±38.33)ng.mL-1,Tmax为(0.8±0.1)h。结论:本方法简便快捷、灵敏准确;本研究所获得的EsA在SD大鼠体内的药动学参数为EsA的临床应用提供了依据。     

山柰酚静脉注射后在大鼠体内的药动学研究

目的:研究静脉注射山柰酚后大鼠体内药动学特点。方法:将60只大鼠随机分为10个时间组,每组6只。均静脉注射给药,给药容积0.1mL·kg-1,剂量5mg·kg-1。于给药后1、3、5、10、20、40、80、120、180、240min分别从相应时间组每只大鼠取血0.5mL(n=6),采用高效液相色谱法检测大鼠血浆中山柰酚浓度;色谱柱为PhenomenexC1(8100mm×4.6mm,6μm),预柱为DikmaEasyⅡGuardC18Kit(8mm×4mm),流动相为乙腈-水(1∶2,V/V),流速为0.5mL·min-1,检测波长为370nm,柱温为35℃,进样量为80μL;采用3p97软件计算药动学参数。结果:大鼠静脉注射山柰酚的浓度-时间曲线符合二室模型,t1/2α=(0.95±0.35)min;t1/2β=(5.68±0.94)min;AUC0～t=(155.10±7.43)μg·min·mL-1;AUC0～∞=(199.84±14.07)μg·min·mL-1;CL=(45.90±1.90)mL·kg-1·min-1。结论:山柰酚原型在大鼠体内消除迅速,血药浓度下降快,30min后消除95%以上。     

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.     

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.