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.     

地塞米松磷酸钠在兔眼房水中的药动学研究

目的 探讨地塞米松磷酸钠滴眼液单次滴兔眼后在眼房水内的药动学特征.方法 采用18只新西兰家兔,局部滴入地塞米松磷酸钠滴眼液50μl,以高效液相色谱法测定眼房水中地塞米松磷酸钠的药物浓度,用DASl.0软件计算药动学参数.结果 给药后0.25～6 h,地塞米松磷酸钠在房水中的最高浓度(3.553±0.4287)μg/ml,消除半衰期t1/2,2为(1.44±0.56)h,药时曲线下面积AUC0-6 h为(10.41±2.87)μg·h·ml-1,AUC0-8为(11.47 4-3.64)μg·h·ml-1.空白房水不干扰地塞米松磷酸钠的含量测定.结论 地塞米松磷酸钠滴眼液单次滴兔眼后在眼房水中具有良好的药动学特征和组织通透性.     

多沙普仑在中国回族和汉族健康人体内的药动学

目的:研究汉族和回族健康受试者单次静脉滴注盐酸多沙普仑后的药动学。方法:回族和汉族健康受试者各10名,单次静脉滴注盐酸多沙普仑50 mg,定时采血,用HPLC法测定多沙普仑血药浓度,DAS 2.0软件计算药动学参数。结果:回族受试者的主要药动学参数为:cmax(1.48±0.46)μg/mlt、1/2β(3.91±2.05)h、Vd(1.35±0.45)L/kg、AUC0~12(3.02±0.56)μg·h·ml-1、AUC0~∞(3.49±0.73)μg·h·ml-1。汉族受试者的主要药动学参数为:cmax(1.55±0.52)μg/mlt、1/2β(3.87±2.17)h、Vd(1.35±0.96)L/kg、AUC0~12(3.51±1.26)μg·h·ml-1、AUC0~∞(4.06±1.44)μg·h·ml-1。结论:经统计学分析,回族和汉族健康受试者单次静脉滴注盐酸多沙普仑后药动学参数的差异无统计学意义。     

青霉素V钾片在健康人体内的药动学和生物等效性

建立了LC-MS/MS法测定人血浆中青霉素V钾的浓度,并研究了20名健康志愿者单剂量随机交叉口服青霉素V钾片0.5g后的药动学和相对生物利用度。青霉素V钾受试制剂与参比制剂的主要药动学参数分别为AUC0-7h(9.61±3.94)和(9.69±4.52)μg·h·ml-1,AUC0-∞(9.72±3.96)和(9.79±4.51)μg·h·ml-1,cmax(8.36±4.14)和(8.47±4.47)μg/ml,tmax(0.53±0.15)和(0.54±0.14)h。受试制剂相对于参比制剂的生物利用度为99.3%,两制剂具有生物等效性。     

黄芩苷温敏凝胶在家兔体内的药动学研究

目的：研究黄芩苷温敏凝胶直肠给药后在家兔体内的药动学。方法：家兔经直肠分别给予黄芩苷温敏凝胶剂和水溶性栓剂,采用高效液相色谱法检测血清中的药物浓度,色谱柱为Shim-packVP-ODSC1（8150mm×4.6mm,5μm）,流动相为甲醇-水-磷酸（47∶53∶0.2,V/V/V）,流速为0.8mL·min^-1,柱温为40℃,进样量为10μL,检测波长为274nm。结果：黄芩苷温敏凝胶与黄芩苷水溶性栓剂主要药动学参数Cmax分别为（3.639±0.23）和（2.832±0.18）μg·L^-1;AUC0～∞分别为（796.46±65.35）和（493.86±42.52）μg·h·L^-1。与水溶性栓剂比较,黄芩苷温敏凝胶直肠给药后,Cmax和AUC0～∞均有增加,且有显著性差异,其相对生物利用度为161.2%。结论：黄芩苷制成温敏凝胶直肠给药后,生物利用度显著提高。     

功劳去火片中黄芩苷和小檗碱在大鼠体内的药物动力学

目的 建立同时测定大鼠体内黄芩苷和小檗碱血药浓度的方法,用于研究功劳去火片中两种指标成分的药物动力学.方法 给予大鼠ig功劳去火片制得混悬液,给药前及给药后不同时间采集血样,采用HPLC法测定血样中的黄芩苷和小檗碱,药-时数据经3p97软件分析处理,并与文献比较,判断给药形式的影响.结果 黄芩苷和小檗碱的线性范围分别为0.061～3.910、0.017～1.060 μg·ml-1,最低定量限分别为0.061、0.017 μg·ml-1.两者的平均回收率均大于97.2%,精密度与准确度均符合生物样品分析要求.给药后,黄芩苷在大鼠体内的代谢符合二室模型,主要药动学参数为:K21=0.74±0·301/h,K10 0=0.143±o.035 1/h,K12=1.26±0.80 1/h,t1/2β=13.5±1.0 h,t1/2α=0.40±0.18 h,Tmax=0.352±0.086 h,Cmax=0.944±0.18μg·ml-1.小檗碱符合一室模型,其主要药动学参数为:t1/2(Km)=3.65 ±0.96 h,t1/2(Ka)=0.073±0.019 h,1/2(Km)=0.1076±0.022 h,Tmax=0.60±0.12 h,Cmax0.254±059 μg·ml-1.结论 功劳去火片中黄芩苷和小檗碱的药物动力学受中药复方给药形式的影响,与单指标成份给药有差异.     

注射用比阿培南在健康人体内的药动学

12名健康志愿者分别于30 min内静注比阿培南150、300和600 mg,采用三向交叉拉丁方设计单剂量给药;多剂量给药时12名志愿者分别静注比阿培南300 mg(2次/d),连续给药5d.采用高效液相色谱法测定血浆和尿液中的比阿培南.志愿者单剂量和多剂量给药后,比阿培南体内过程均符合二房室模型,单剂量给药低、中、高剂量的主要药动学参数分别为:t1/2(1.16±0.12)、(1.14±0.11)和(1.17±0.12)h,cmax(9.41±1.64)、(17.75±2.59)和(35.32±4.60) μg/ml,AUC0-6h (11.86±1.61)、(23.45±3.66)和(46.06±7.05) h·μg·ml-1.多剂量末次给药后的主要药动学参数分别为:t1/2(1.19±0.26)h,cmax (19.76±2.83) μg/ml,AUC0-6h (24.47±3.26) h·μg·ml-1,css_av (1.98±0.27)μg/ml,AUCss (23.78±3.22) h·μg·ml-1.中剂量12h尿累积排出率为(49.58±5.36)%.     

双氯芬酸依泊胺凝胶在大鼠体内的药动学

建立了液相色谱-串联质谱法测定大鼠血浆中的双氯芬酸,并考察皮肤局部给予双氯芬酸依泊胺凝胶后大鼠体内的药动学特征.血浆样品用甲醇沉淀蛋白,以布洛芬为内标,采用ESI源负离子模式、多反应监测(MRM)进行定量分析.检测离子对为m/z 295.9→m/z 252.0(双氯芬酸)和m/z 205.1→m/z 161.2(布洛芬).双氯芬酸在1～200 ng/ml浓度范围内线性关系良好,方法回收率为97.80％～104.4％,日内、日间RSD分别小于6.12％和7.51％.SD大鼠经皮给予0.3 g双氯芬酸依泊胺凝胶后,主要药动学参数分别为:cmax(79.90±29.8)ng/ml,AUC0 →,(1 198±349) ng·ml-1·h,AUC0 →∞(1 358±567) ng.ml-1·h,tmax(4.8±23)h,t1/2 (9.208±4.60)h,MRT0→1(11.22±1.06)h.     

姜黄素固体脂质纳米粒在大鼠体内的药动学

目的:研究姜黄素固体脂质纳米粒在SD大鼠体内的口服药动学情况。方法:大鼠单剂量灌胃给予姜黄素固体脂质纳米粒和游离药姜黄素,眼底静脉丛取血,以醋酸乙酯处理血浆样品,尼群地平为内标,高效液相法(HPLC)测定血浆中姜黄素的含量,并用药物与统计(Drug and Statistics,DAS)软件分析处理药动学数据。结果:姜黄素固体脂质纳米粒和游离药姜黄素在大鼠体内的药动学行为均符合二室开放模型,姜黄素固体脂质纳米粒和游离药姜黄素的药动学参数分别如下:药时曲线下面积(AUC0-t)为(798.00±64.44)μg·h·L-1和(108.78±14.22)μg·h·L-1,药时曲线下总面积(AUC0-∞)为(939.49±114.18)μg·h·L-1和(126.99±28.14)μg·h·L-1,峰浓度(Cmax)为(93.84±5.66)μg·L-1和(72.46±2.66)μg·L-1,消除半衰期(t1/2)为(17.16±1.61)h和(4.71±1.18)h,姜黄素固体脂质纳米粒的AUC0-t、AUC0-∞、Cmax和t1/2分别提高了7.34,7.40,1.30和3.64倍。结论:姜黄素固体脂质纳米粒体内消除慢,血药浓度高,且明显提高了姜黄素的口服生物利用度。     

匹伐他汀钙片单、多剂量人体药动学评价

目的:建立LC-MS/MS法测定人血浆中匹伐他汀的浓度,研究其在中国健康受试者体内的单、多剂量药动学过程.方法:20名健康志愿者随机分为2组,每组10人(男女各半),分别口服低、中、高3个剂量(1,2,4 mg)进行单剂量药动学研究,2mg剂量组继续给药(每日1次,连续7 d),进行多剂量药动学研究.采用LC-MS/MS法测定血浆中匹伐他汀的浓度,并采用WinNonLin6.2计算药动学参数.结果:健康受试者单剂量口服1、2、4mg匹伐他汀钙片后的药动学参数:t1/2分别为(11.29±4.28)h、(13.52±5.65)h和(11.87±2.87)h;tmax分别为(0.78±0.32)h、(0.75±0.17)h和(0.93±0.31)h;Cmax分别为(15.80±7.34)ng·ml-1、(36.54±6.29)ng·ml-1和(61.32±15.09)ng·ml-1;AUC(0-48)分别为(36.46±21.86)ng·h·ml-1、(107.90±28.55)ng·h·ml-1和(187.76±62.62)ng·h·ml-1;AUC(0-∞)分别为(40.91±23.20)ng·h·ml-1、(112.97±29.08)ng·h·ml-1和(197.55±68.51)ng·h·ml-1.多剂量组口服2mg匹伐他汀后的药动学参数:t1/2为(13.07±2.16)h,tmax为(0.68±0.12)h,Cmax为(33.88±6.91)ng·ml-1,AUCss为(68.21±20.82)ng·h·ml-1,AUC(0-48)为(77.78±26.50)ng·h·ml-1,AUC(0-∞)为(82.59±26.58)ng·h·ml-1.匹伐他汀钙多次给药达稳态后,药动学参数tmax、t1/2与单次给药一致.结论:在1~4mg剂量范围内匹伐他汀的AUC(0-48)、AUC(0-∞)、Cmax均与剂量呈线性关系;匹伐他汀在连续多次给药后,无体内蓄积现象;匹伐他汀的体内过程在男女性别间无显著差异.     

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.

     

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.     

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.     

Steroidal sapogenin contents in some domestic plants

In order to find out the values of the steroid resources for the future use. the compositions and contents of steroidal sapogenins from 13 domestic plants have been investigated. As a result,Dioscorea nipponica, D. quinqueloba andSmilax china were found to have large amount of diosgenin. And pennogenin inTrillium kamtschaticum andParis verticillata, yuccagenin inAllium fistulosum, hecogenin inAgave americana and neochlorogenin inSolanum nigum were appeared to be major steroidal sapogenins.     

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.