阿奇霉素分散片药物动力学与生物利用度研究

目的 研究阿奇霉素分散片健康人体的药物动力学与生物等效性。方法高效液相色谱．质谱法（LC-MS）测定20名男性健康志愿者随机交叉口服阿奇霉素分散片受试制剂和参比制剂的药时数值。以DAS2．0软件计算其药动学参数,考察其生物等效性。结果受试制剂和参比制剂的药动学参数：tmax分别为（2．1±0．8）h和（3．1±2．2）h;Cmax分别为（433．5±138．1）μg/L和（425、7±184．3）μg／L;AUC0-120h分别为（4231±1198）μg·L^-1·h^-1和（3881±1154）μg·L^-1·h^-1;AUC0～∞分别为（460911207）μg·L^-1·h^-1和（4287±1268）μg·L^-1·h^-1。以AUC0-120h计算,受试阿奇霉素分散片和参比阿奇霉素分散片比较的人体相对生物利用度为（119．6±52．9）％。结论两种不同厂家的阿奇霉素分散片具有生物等效性。     

吗丁啉片在正常人体内的药动力学及相对生物利用度分析

目的 分析与探讨吗丁啉片在正常人体内的药动力学及相对生物利用度.方法 依照两制剂双周期的自身相对照交叉的试验方法,选择20例身体健康的志愿者,均为男性,使其分别接受单剂量口服试制剂吗丁啉片与参比制剂吗丁啉片,将其随机分为观察组与对照组,每组各10人,观察组先口服受试制剂,之后服用参比制剂;对照组先服用参比制剂,之后服用受试制剂,以7 d为一清洗期.用HPLC法对血药浓度进行测定,并对药代动力学参数加以计算,对两种制剂生物等效性予以评价.结果 口服试制剂吗丁啉片20 mg后,其药代动力学参数：t1/2为（9.15±0.78）h、Tmax为（0.76±0.25）h、Cmax为（28.95±4.07）μg·L^-1、AUC0-t为（144.37±30.95）μg·h^-1·L^-1;服用参比制剂吗丁啉片20 mg之后,其药代动力学参数：t1/2为（8.59±1.11）h、Tmax为（0.78±0.33）h、Cmax为（29.63±5.02）μg·L^-1、AUC0-1为（140.52±31.14）μg·h^-1·L^-1.用AUC0-t计算得出,和参比制剂比较,受试制剂中的吗丁啉片相对生物利用度平均为（103.1±5.5）%.结论 由该次研究可得出,两种吗丁啉存在生物等效性.     

大鼠肝微粒体中有机锡抗癌化合物DBDCT的测定与酶促动力学研究

目的建立测定大鼠肝微粒体中有机锡抗癌化合物DBDCT的方法并研究其相应的酶促动力学。方法采用HPLC测定DBDCT在体外代谢系统中的酶促动力学,用Eadie-Hofstee法分析数据,求算酶促动力学参数Km和Vmax以及肝代谢速率Clin。结果在体外代谢系统中,DBDCT代谢酶促动力学参数Km=159.07μmol·L-1,Vmax=2.813μmol·（min·mg）^-1以及肝清除率Clin=Vmax/Km=0.017L·（min·mg）^-1。结论此分析方法符合方法学验证要求且简单准确,可满足DBDCT体外代谢的研究。     

液相色谱-串联质谱法测定缬更昔洛韦血药浓度及其在健康人体的药代动力学研究

目的研究缬更昔洛韦片剂（抗病毒药）在健康人体内的原药缬更昔洛韦及其活性代谢产物更昔洛韦的药代动力学过程。方法20名健康男性受试者单次口服缬更昔洛韦片900mg，用LC—MS／MS测定给药后不同时间血浆中缬更昔洛韦及其活性代谢产物更昔洛韦的浓度，研究缬更昔洛韦与更昔洛韦的药代动力学特征。结果主要药代动力学参数如下。缬更昔洛韦：AUC0-1为（606．83±245．53）μg·h·L^-1；AUC0-∞为（616．52±247．89）μg·h·L^-1；Cmax为（423．56±178．20）μg·L^-1；tmax为（1．15±0．41）h；t1／2为（0．82±0．25）h；MRT0-1为（1．58±0．37）h；MRT0-∞为（1．66±0．38）h；Ka为（2．57±2．53）h^-1；Ke为（0．91±0．24）h^-1；V／F为（1963．85±920．05）L；CIMF为（1688．77±636．77）L·h^-1。更昔洛韦：AUC0-1为：（24．99±7．78）mg·h·L^-1，AUC0-∞为（26．37±7．80）mg·h·L^-1；Cmax为（7．11±1．96）mg·L^-1；tmax为（1．76±0．59）h；t1／2为（3．49±0．96）h；MRT0-1为（4．04±0．80）h；MRT0-∞为（4．81±0．84）h；琏为（1．13±I．20）h^-1；Ke为（0．21±0．07）h^-1；V／F为（178．55±44．82）L；CL／F为（37．33±11．92）L·h^-1。结论本文建立的测定方法，简单、快速、无干扰，适合人体内血药浓度监测和药代动力学研究。     

大鼠静注苯妥英钠的毒代动力学研究

目的：探讨苯妥英钠（DPH—Na）在大鼠血液的毒代动力学规律及组织分布。方法：大鼠静注中毒剂量DPH-Na后采集血液及组织样品,HPLC法测定其血浆及组织中药物浓度,分别用隔室模型拟合和米曼氏方程计算毒代动力学参数,并比较各组织中药物浓度。结果：DPH-Na静注中毒剂量后,在大鼠体内符合二室模型过程,主要毒代动力学参数：Cmax=（61．31±7．09）ug·ml^-1,t1／2a：（0．18±0．08）h,t1／2 B：（2．60±0．52）h,AUC=（147．22±29．16）（ug·ml^-1）·h,CL=（0．15±0．02）L·h^-1。按米曼氏方程解析所得主要毒代动力学参数：Vm=（10．42±5．33）ug·ml^-1·h^-1,Km=（66．65±13．71）ug·ml^-1,其余毒代动力学参数与二室模型拟合结果无明显差异（P〉0．05）。DPH-Na在各组织中的浓度顺序依次为：肺〉肾〉肝〉心〉脑。结论：DPH-Na在大鼠体内的毒代动力学与药物动力学规律有差异,其中毒后在体内消除减慢,血液及组织中可能大量蓄积。     

非诺贝特缓释片人体药代动力学及生物等效性研究

目的研究非诺贝特缓释片在健康男性志愿者体内的药动学特征及生物等效性。方法20名健康男性志愿者双交叉单次服用0．25g非诺贝特缓释片和非诺贝特缓释胶囊,24名健康男性志愿者双交叉连续服用非诺贝特缓释片和非诺贝特缓释胶囊6d,用HPL-UV测定血浆中的非诺贝特酸浓度,比较单次用药和多次连续用药后体内非诺贝特酸的药代动力学参数,采用DAS2．0进行两制剂的生物等效性检验。结果20名健康男性志愿者双交叉单次服用0．25g非诺贝特缓释片和非诺贝特缓释胶囊后,体内的主要药代动力学参数tmax为（5．25±1．27）h,（4．93±0．71）h;Cmax为（8．58±2．77）mg·L^-1,（9．75±3．44）mg·L^-1;AUC0-96为（188．34±65．66）mg·h^-1·L^-1,（194．02±56．58）mg·h^-1·L^-1。24名健康男性志愿者双交叉连续服用非诺贝特缓释片和非诺贝特缓释胶囊6d后体内的主要药代动力学tmax为（5．06±0．92）h,（5．04±0．93）h;C。,为（7．25±2．32）mg·L^-1,（8．03±3．27）mg·L^-1;AUCss为（174．06±55．67）mg·h^-1·L^-1,（192．66±78．53）mg·h^-1·L^-1。结论连续用药6d体内达到稳定血药浓度,单次用药和多次用药后主要药代动力学参数相似,体内无明显蓄积现象。非诺贝特缓释片和胶囊单次用药和多次用药后均显示生物等效。     

复方替米沙坦胶囊在中国健康志愿者体内的药代动力学

目的：研究中国健康受试者单次和多次口服复方替米沙坦胶囊的药代动力学特点。方法：20名健康受试者随机分为2组,分别单次口服低、高剂量复方替米沙坦胶囊（每粒合替米沙坦40mg,氢氯噻嗪12．5mg）;8名健康受试者口服复方替米沙坦胶囊1粒,连续服用7d,采用LC—MS／MS方法测定血浆药物浓度,并计算药代动力学参数。结果：受试者单次口服复方替米沙坦胶囊1粒或2粒后替米沙坦的主要药代动力学参数：Cmax分别为（130．65±125．97）、（876．22±588．52）μg·L^-1,tmax分别为（1．72±0．96）、（1．03±0．48）h,AUC0-t分别为（1745．22±1634．54）、（4776．26±3703．07）μg·h·L^-1,AUC0-∞。分另1为（1882．11±1704．30）、（5060．78±3955．61）μg·h·L^-1;单次口服复方替米沙坦胶囊1粒或2粒后氢氯噻嗪的主要药代动力学参数：Cmax分别为（70．62±23．05）、（120．42±51．41）μg·L^-1,tmax分别为（1．95±1．01）、（2．30±1．14）h,AUC0-t分别为（498．99±162．45）、（888．83±384．29）μg·h·L^-1,AUC0-∞分别为（511．32±161．02）、（910．67±390．77）μg·h·L^-1.连续7d口服复方替米沙坦胶囊1粒后替米沙坦和氢氯噻嗪的主要药代动力学参数：Cmax分别为（199．27±133．79）、（53．52±11.54）μg·L^-1,tmax分别为（1．33±1．14）、（2．38±1．03）h,AUC∞分别为（1211．13±774．94）、（405．80±142．41）μg·h·L^-1,Cav分别为（50．46±32．29）、（16．91±5．93）μg·L^-1,DF分别为（3．61±1．61）、（3．18±0．59）。结论：单次口服复方替米沙坦胶囊后,替米沙坦在40,80mg时的AUC和C一的增加比例显著高于剂量增加比例,呈非线性药代动力学特征;氢氯噻嗪在12．5,25mg时的AUC和Cmax的增加与剂量增加成正比,呈线性药代动力学特征。连续给药与单次给药相比,其药代动力学特征未发生显著变化。     

五味子甲素对大鼠肝微粒体CYP3A活性的影响

目的：通过体外药物代谢实验探讨五味子甲素对CYP3A活性的影响。方法：以大鼠肝微粒体为载体,选取咪达唑仑（MDZ）作为药物“探针”,建立高效液相色谱（HPLC）检测方法,体外给药测定五味子甲素对MDZ的IC50值以及相关酶动力学参数。结果：孵育体系内源性物质不干扰测定,方法快捷、稳定、灵敏度高。在肝微粒中,五味子甲素对MDZ的IC50浓度为6．26μmol／mL,相关酶动力学参数：Km=15．77μmol／L,K1=5．50μmol／mL。结论：五味子甲素对大鼠肝微粒体CYP3A活性具有抑制作用,其抑制作用为混合型,即：非竞争与反竞争抑制。     

探针药物法测定大黄对大鼠肝细胞色素CYP2E1酶的影响

目的用探针药物法测定大黄对大鼠肝细胞色素CYP2E1酶的影响。方法将SD舍大鼠随机分组,给药组予大黄灌胃,以生理盐水组为空白对照,尾静脉给予CYP2E1探针药物氯唑沙宗,HPLC法检测体内药动学参数来评价各组的CYP2E1酶活性。结果氯唑沙宗代谢符合二室模型,给药组t1/2β（1．18±0．28）h、AUC（20．09±12．11）mg·h·L^-1、V（c）（0．30±0．21）L、CL（s）（0．94＋0．59）L·h^-1,对照组t1/2β（1．49±0．14）h、AUC（38．87±8．35）mg·h·L^-1、V（c）（0．21±0．06）L、CL（s）（0．12±0．02）L·h^-1.结论大黄对大鼠肝细胞色素CYP2E1有诱导作用。     

激动α1B—肾上腺素受体对DDT1 MF—2细胞生长的刺激作用及途径

目的 研究激动α1B－肾上腺素受体（α1B－AR）对DDT1MF－2细胞生长的影响及其机制。方法 用^3H^-胸腺嘧啶参入法测定细胞的DNA合成速率;用流式细胞计测定细胞周期。结果 去甲肾上腺（NE,0.1－1μmol.L^-1)可刺激DDT MF－1细胞DNA的合成。磷脂酶C抑制剂（U73122,10μmol.L^-1)、Ca^2 /ATP酶抑制剂（CPA,10μmol.L^-1)、胞内Ca^ 络合剂（BATPTA／AM,10μmol.L^-1)、PKC抑制剂（RO－31－8220,0．1μmol.L^-1或calphostin C,0.1μmol.L^-1)、酷氨酸激酶抑制剂（tyrphostin A25,10μmol.L^-1或genis-tein,10μmol.L^-1)、MEK1／2抑制剂（P98059,100μmol.L^-1)均可阻断NE刺激细胞DNA合成的作用。结论 激动α1B－AR可刺激DDT1MF－2细胞增殖,其信号转导途径可能与PLC激活、Ca^2 释放、PKC、TK和ERKs的激活有关。     

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.     

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.     

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.