法罗培南钠多剂量静脉滴注在中国健康人体的药代动力学

目的研究多剂量静脉滴注法罗培南钠(β内酰胺类抗生素)在中国健康人体的药代动力学。方法 11名健康志愿者接受多剂量静脉滴注法罗培南钠(600 mg,tid×7 d),用高效液相色谱-紫外检测法,测定法罗培南的血药浓度、尿药浓度,用3P87软件计算药代动力学参数。结果血药浓度-时间曲线符合二房室模型,体内过程呈线性动力学特征。主要的药代动力学参数:单剂量给药后,Cmax为(62.54±10.58)μg.mL-1;t1/2α为(0.39±0.12)h;t1/2β为(1.40±0.68)h;AUC0-8为(67.34±11.80)μg.h.mL-1;尿药累积排泄率为(26.24±10.48)%。多剂量给药达稳态后,Csmsin为(0.13±0.05)μg.mL-1;Cmssax为(58.13±9.93)μg.mL-1;Cav为(7.14±1.00)μg.mL-1;t1/2α为(0.31±0.05)h;t1/2β为(1.09±0.11)h;AUCs0s-t为(57.15±8.01)μg.h.mL-1;尿药累积排泄率为(30.21±15.94)%。结论多剂量给药后,法罗培南在体内的分布和消除速度较单剂量给药有所加快。     

单次静滴头孢西酮钠在中国健康志愿者的药代动力学

目的 研究中国健康志愿者单次静脉滴注头孢西酮钠注射液(半合成头孢类抗生素)的药代动力学.方法 筛选20名健康志愿者,随机分为2组,分别单次静滴头孢西酮钠注射液0.5、1 g;用高效液相色谱-紫外检测法测定给药后不同时间点的血药浓度和尿药浓度,用DAS Ver1.0软件计算药代动力学参数.结果 血药浓度-时间曲线符合二房室模型,单次静脉滴注头孢西酮钠0.5、1 g后,t1/2β分别为(1.54±0.62)、(1.46±0.34)h;tmax分别为(0.75±0.00)、(0.75±0.00)h;Cmax分别为(54.99±11.14)、(118.17±31.66)μg·mL-1;AUC0-t分别为(97.90±21.33)、(200.93±40.13)μg·h·mL-1.24 h尿药累积排泄率分别为(66.78±15.39)%、(48.21±11.37)%.结论 本法专属性强、灵敏度高、操作简便,在人体内呈线性药代动力学过程.     

单剂量滴注注射用头孢替坦二钠在健康人体中的药动学及其安全性

目的:研究中国健康志愿者单剂量静脉滴注1.0,2.0,4.0g注射用头孢替坦二钠后的药动学行为,并评价药动学参数在剂量1.0～4.0g范围内的相关性。方法:12名健康志愿者,随机三交叉试验,分别单剂量静脉滴注注射用头孢替坦二钠1.0,2.0,4.0g;测定给药后24h内的血药浓度和尿药浓度,用DAS Ver 2.0软件计算药动学参数。结果:单剂量静脉滴注1.0,2.0,4.0g注射用头孢替坦二钠后,头孢替坦的消除半衰期大约为3～4h,血浆药物浓度(Cmax)随剂量增加呈线性增加(75.0±10.4～230.7±33.7μg·mL-1)。另外,曲线下面积(AUC)在1.0～4.0g剂量范围内也呈线性增加(AUC0-t:308.5±62.9～1 018.5±164.2μg.h·mL-1,AUC0-∞:314.4±63.2～1 031.7±172.5μg·h·mL-1)。24h尿药累积排泄率分别为65.6%±16.7%、44.4%±10.1%和49.1%±11.2%。结论:在剂量1.0～4.0g范围内头孢替坦呈线性药动学,Cmax、AUC的升高与剂量成正比。除2.0g剂量组t1/2性别间存在显著性差异,其他剂量组tmax、Cmax、t1/2、AUC0-t、CL、Vd、MRT0-t、尿排泄率性别间均无统计学差异。     

单次静滴头孢呋辛在肾功能不全患者的药代动力学

目的 研究肾功能不全患者单次静滴头孢呋辛(抗生素)的药代动力学.方法 20名肾功能不全受试者按照CKD分期分成2组:CKD 1-3期组与CKD4-5期组,分别静脉滴注头孢呋辛1 000 mg后,采用高效液相色谱法,测定不同时刻血浆中头孢呋辛的血药浓度,用DAS 2.0版软件计算主要药代动力学参数.同时,测定不同时间段的尿药浓度,计算尿药累积排泄率.结果 2组受试者静脉滴头孢呋辛1 000 mg后,血浆中头孢呋辛的Cmax分别为(65.06±31.20),(79.33±10.75)μg·mL-1;t1/2分别为(2.42±0.87),(8.58±4.14)h;AUC(0-t)分别为(154.70±81.10),(446.43±95.37)μg·h·mL-1;AUC(0-∞)分别为(162.10±92.64),(798.65±362.83)μg·h·mL-1;CLz分别为(7.68±3.19),(1.45±0.52)mL·min-1;Vz分别为(24.53±9.71),(15.42±3.91)L.12 h尿药累积排泄率分别为(39.08±7.86)%,(16.67±5.57)%.结论 肾功能不全受试者静脉滴注头孢呋辛后,CKD 4-5期患者较CKD 1-3期,t1/2明显延长,AUC(0-t)及AUC(0-∞)明显增加;而CLz、Vz及12 h尿药累积排泄率均明显降低.     

依卡倍特二钠颗粒在健康人体中的单次给药药代动力学研究

目的研究中国健康志愿者单剂量口服2.0、4.0g依卡倍特二钠颗粒后的药代动力学行为,并评价药代动力学参数在2.0～4.0g范围内剂量相关性。方法 10名健康志愿者,随机交叉试验,分别单剂量口服依卡倍特二钠颗粒2.0、4.0g;测定给药后36h内的血药浓度。结果单剂量口服2.0、4.0g依卡倍特二钠颗粒后,依卡倍特的t1/2分别为(11±5)h和(9±4)h,达峰浓度(Cmax)分别为(4 998±982)ng/mL和(11 699±4 143)ng/mL,AUC0～t分别为(43 863±10 341)ng.h-1.mL-1和(92 492±30 915)ng.h-1.mL-1,AUC0～∞分别为(48 611±15 029)ng.h-1.mL-1和(99 628±35 993)ng.h-1.mL-1。结论在2.0～4.0g剂量范围内依卡倍特呈线性药代动力学,Cmax、AUC的升高与剂量成正比。     

进口丙戊酸钠口服液与糖浆在健康人体的生物等效性

目的研究健康志愿者单剂量口服进口丙戊酸钠口服液(抗癫痫药)的药代动力学和生物等效性。方法采用开放、随机交叉给药方案,22名健康男性志愿者单剂量口服进口丙戊酸钠口服溶液与丙戊酸钠糖浆25mL(含丙戊酸钠1000mg),用HPLC-荧光检测法测定血清中丙戊酸钠浓度,计算其主要药代动力学参数。结果单剂量口服进口丙戊酸钠口服溶液和糖浆的主要药代动力学参数:AUC0～tn分别为(1850.7±424.2)和(1838.9±382.4)μg.h.mL-1;AUC0～∞分别为(1934.3±491.9)和(1923.0±432.0)μg.h.mL-1;Cmax分别为(115.2±14.8)和(110.0±12.1)μg.mL-1;tmax分别为(0.88±0.79)和(0.99±0.54)h;t1/2分别为(13.85±3.53)和(14.10±3.63)h;F为(100.82±10.57)%。结论2种制剂具有生物等效性。     

连续口服盐酸噻氯匹定片在健康人体的药代动力学

目的研究连续口服盐酸噻氯匹定片(抗血栓药)在健康人体的药代动力学。方法12名男性健康志愿者连续口服噻氯匹定片,每次250mg,每日2次。第11日按照预定时间点采血,用LC-MS-MS方法测定血浆稳态血药浓度,并求算其药代动力学参数。结果t1/2为(115±13.8)h,AUC0-21d为(24.48±10.02)μg.h.mL-1,tmax为(1.8±0.6)h,Cmax为(1303±428)ng.mL-1,Cmin为(235±107)ng.mL-1,Cav为(541±194)ng.mL-1,AUCss为(6.49±2.32)μg.h.mL-1,CLss为(48.1±33.7)L.h-1。结论连续口服盐酸噻氯匹定,吸收迅速,消除半衰期较单剂量大大延长;个体变异小。     

烟酸缓释片在健康人体的生物等效性

目的 研究烟酸缓释片(广谱凋血脂药)在健康人体的药代动力学,并评价其生物等效性.方法 30名男性健康志愿者随机交叉单剂量口服试验制剂或参比制剂1.5 g,用高效液相色谱-串联质谱法测定血浆中烟酸浓度.结果 单剂量口服烟酸试验制剂或参比制剂1.5 g,药代动力学参数如下:AUC0-t分别为(20.05±16.29),(21.61±18.06)μg·h·mL-1;AUC0-∞分别为(20.81±16.30),(22.81±18.47)μg·h·mL-1;Cmax分别为(8.72±6.81),(9.57±8.22)μg·mL-1;tmax分别为(4.41±1.34),(4.31±1.29)h;t1/2分别为(4.00±4.90),(2.91±3.39)h,烟酸缓释片的相对生物利用度为(96.6±30.9)%.结论 受试制剂与参比制剂生物等效.     

国产与进口齐多夫定胶囊在健康人体的药代动力学和生物等效性

目的研究国产与进口齐多夫定胶囊(抗艾滋病药)在健康志愿者体内的药代动力学和生物等效性。方法20名健康男性受试者随机交叉单剂量口服国产与进口齐多夫定胶囊300mg,用高效液相色谱法测定给药后不同时间的血浆浓度,计算主要药代动力学参数。结果国产与进口齐多夫定胶囊主要药代动力学参数:t1/2分别为(1.72±0.42),(1.53±0.27)h;tmax分别为(0.86±0.42),(0.88±0.30)h;Cmax分别为(1.60±0.61),(1.60±0.55)μg.mL-1;AUC0～8分别为(2.06±0.37),(2.08±0.34)μg.h.mL-1;AUC0-∞分别为(2.11±0.37),(2.12±0.34)μg.h.mL-1。国产齐多夫定胶囊相对生物利用度F为(99.02±5.02)%。结论2制剂具有生物等效性。     

氯沙坦及其代谢物在维吾尔族和汉族健康志愿者的药代动力学

目的 研究维吾尔族和汉族健康受试者单剂量口服氯沙坦钾片(抗高血压药)的药代动力学特征.方法 20名健康受试者(其中维吾尔族10名,汉族10名,男女各半),单剂量口服氯沙坦钾片50 mg;用高效液相色谱-荧光法测定氯沙坦及其代谢物E-3174血药浓度,用DAS软件进行数据处理、SPSS 13.0软件进行统计学分析.结果 维吾尔族受试者单剂量口服氯沙坦钾片50 mg后氯沙坦和代谢物E-3174的主要药代动力学参数分别为:Cmax(344±153),(477±166)μg·mL-1;tmax(1.0±0.3),(2.6±0.5)h;t1/2(1.0±0.4),(2.9±0.8)h;AUG0-24h(598±216),(2243±518)μg·h·mL-1;AUC0-∞(632±242),(2429±552)μg.h·mL-1.汉族受试者单剂量口服氯沙坦钾片50 mg后氯沙坦和代谢物E-3174的主要药代动力学参数分别为:Cmax(351±168),(242±60)ng·mL-1;tmax(1.4±1.1),(3.6±1.7)h;t1/2(0.8±0.4),(4.7±1.1)h;AUC0-24h(497±172),(1853±194)ng·h·mL-1;AUC0-∞(523±184),(1960±182)ng·h·mL-1.结论 氯沙坦的代谢物E-3174的药代动力学参数t1/2、Vd、Cmax在维吾尔族和汉族健康受试者间的差异有显著性意义(P＜0.05),不同性别间药代动力学参数的差异无显著性意义(P＞0.05),所有药代动力学参数在同一民族和不同民族的个体间差异都很大,临床治疗中应实行个体化给药方案.     

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.