那格列奈片血浓度测定及相对生物利用度研究

目的:建立那格列奈血药浓度的HPLC-MS测定法,并用于人体生物等效性研究。方法:采用随机双交叉试验设计,20名健康受试者分别口服受试制剂和参比制剂60 mg,用HPLC-MS法测定血浆中的那格列奈浓度。结果:受试制剂和参比制剂的AUC_(0→10)分别为(8.47±1.01)和(8.19±0.99)mg·h·L~(-1);AUC_(0→∞)分别为(8.86±1.25)和(8.68±1.12)mg·h·L~(-1);C_(max)分别为(3.44±1.07)和(3.31±0.84)mg·L~(-1);t_(max)分别为(0.99±0.35)和(1.09±0.56)h;t_(1/2)分别为(1.78±0.39)和(1.83±0.41)h。受试制剂的相对生物利用度为(102.1±13.5)%。结论:两种那格列奈片具有生物等效性。     

羟苯磺酸钙颗粒剂在健康人体的药代动力学和生物等效性

目的研究羟苯磺酸钙(改善微循环、抗血栓药)颗粒剂和胶囊在健康人体的药代动力学及生物等效性。方法20名健康志愿者随机双交叉、单剂量口服受试制剂和参比制剂0.5 g,剂间间隔为1周,用高效液相色谱-紫外检测法测定血浆中羟苯磺酸钙浓度,用DAs ver 2.0药代动力学程序进行有关药代动力学参数、相对生物利用度计算,并评价2种制剂生物等效性。结果受试与参比制剂的药代动力学参数如下:t_(max)分别为(4.33±0.92)和(4.50±0.83)h,t_(1/2)分别为(4.05±1.37)和(4.06±1.53)h,C_(max)分别为(10.77±2.96)和(11.77±3.26)mg·L~(-1),AUC_(0-t)分别为(85.22±18.76)和(86.75±18.67)mg·h·L~(-1),AUC_(0-∞)分别为(88.69±21.14)和(89.71±19.88)mg.h·L~(-1),羟苯磺酸钙颗粒剂的相对生物利用度为(98.90±12.11)%。结论2种制剂具有生物等效性。     

格列美脲口腔崩解片人体药动学及相对生物利用度

目的:研究健康受试者口服格列美脲口腔崩解片的人体药动学及相对生物利用度。方法:18名健康志愿者随机交叉单剂量口服格列美脲受试片与对照片4mg,采用柱前衍生化 HPLC-紫外法测定其血药浓度。结果:受试片与对照片的主要药动学参数 t_(max) 分别为(3.00±0.73)和(3.25±0.85)h,C_(max)分别为(313.1±99.3)和(303.2±104.5)μg·L~(-1),t_(1/2Ke)分别为(7.337±2.190)和(8.239±2.631)h,AUC_(0-t)分别为(1767.2±598.3)和(1714.1±528.3)μg·h·L~(-1),AUC_(0-∞)分别为(1956.3±598.1)和(1945.4±682.0)μg·h·L~(-1)。受试片的相对生物利用度为100.1%±18.2%。结论:两种片剂具有生物等效性。     

双氯芬酸钠缓释片在健康人体的生物等效性与药代动力学

目的研究双氯芬酸钠(抗炎镇痛药)缓释片的相对生物利用度并评价其生物等效性。方法采用随机交叉试验设计,18名健康男性志愿者分别行单次和多次口服双氯芬酸钠缓释片受试与参比制剂,用高效液相色谱法测定血浆中双氯芬酸钠的血药浓度,计算药代动力学参数及相对生物利用度。结果单次口服2种双氯芬酸钠缓释片,受试制剂和参比制剂的主要药代动力学参数:t_(max)分别为(2.08±0.65)、(2.11±0.78)h,C_(max)分别为(472.14±184.86)、(471.59±159.94)μg·L~(-1),t_(1/2)分别为(8.36±1.60)、(8.76±1.82)h,MRT分别为(13.05±2.68)、(13.72±3.16)h,AUC_(0-t)分别为(4.52±2.27)、(4.59±2.12)mg·h·L~(-1),AUC_(0-∞)分别为(5.45±2.85)、(5.72±2.99)mg·h·L~(-1),受试制剂的平均相对生物利用度为(98.00±11.18)%。连续多次口服2种双氯芬酸钠缓释片,受试制剂和参比制剂给药4天后血药浓度达稳态,其主要药代动力学参数:t_(max)分别为(2.28±0.88)、(2.17±0.75)h,C_(ssmax)分别为(595.77±224.95)、(575.93±203.01)μg·L~(-1),C_(ssmin)分别为(84.50±46.71)、(84.34±53.62)μg·L~(-1),C_(ssav)分别为(257.64±134.41)、(261.09±129.89)μg·L~(-1),t_(1/2)分别为(9.68±2.82)、(9.56±2.63)h,MRT分别为(15.47±4.63)、(14.74±3.95)h,AUC_(ss)分别为(6.18±3.23)、(6.27±3.12)mg·h·L~(-1),DF分别为2.14±0.61、2.02±0.51,受试制剂的平均相对生物利用度为(98.25±5.82)%。结论受试制剂与参比制剂具有生物等效性。     

国产与进口盐酸米多君片在健康人体的生物等效性

目的考察国产与进口盐酸米多君片(抗低血压药)在健康人体的生物等效性。方法24名健康男性志愿受试者随机交叉先后单剂口服国产和进口盐酸米多君片5 mg后,用高效液相色谱法测定血浆中米多君和活性代谢产物去甘氨酸米多君的浓度,以DAS1.0程序计算药代动力学参数,进行生物等效性评价。结果口服国产与进口盐酸米多君片的主要药代动力学参数,米多君:AUC_(0-1)分别为(18.46±6.14)、(16.93±4.45)μg·h·L~(-1),AUC_(0-∞)分别为(21.15±7.95)、(18.93±5.14)μg·h·L~(-1),C_(max)分别为(23.51±9.24)、(20.61±7.20)μg·L~(-1),t_(max)分别为(0.49±0.14)、(0.46±0.15)h,t_(1/2)分别为(2.14±3.28)、(2.09±1.70)h。去甘氨酸米多君:AUC_(0-t)分别为(59.70±16.91)、(54.97±13.16)μg·h·L~(-1),AUC_(0-∞)分别为(64.60±17.94)、(58.76±13.72)μg·h·L~(-1),C_(max)分别为(12.31±3.22)、(11.79±3.54)μg·L~(-1),t_(max)分别为(1.31±0.69)、(1.10±0.56)h,t_(1/2)分别为(3.95±0.83)、(3.55土1.00)h。以进口盐酸米多君片为参比,国产盐酸米多君片中的米多君和去甘氨酸米多君的相对生物利用度分别为(110.44±25.45)%、(108.24±13.82)%。结论国产与进口盐酸米多君片在健康人体具有生物等效性。     

厄贝沙坦片在中国健康人体内的生物等效性研究北大核心CSCD

目的研究厄贝沙坦片在中国健康人体内的生物等效性。方法采用单中心、随机、开放、单剂量、两周期、2×2交叉试验设计,空腹试验和餐后试验中分别有32例受试者口服厄贝沙坦片受试制剂或参比制剂0.15 g。LC-MS/MS法测定给药后不同时间厄贝沙坦的血药浓度,并用Phoenix WinNonlin 7.0软件计算主要药代动力学参数,判定两制剂是否等效。结果空腹试验受试制剂和参比制剂厄贝沙坦的主要药代动力学参数:C_(max)分别为(2242.4±631.5),(2327.3±821.0)ng·mL^(-1),AUC_(0-t)分别为(9953.2±3339.6),(10218.5±2985.3)h·ng·mL^(-1),AUC_(0-∞)分别为(10201.7±3377.9),(10516.5±2995.6)h·ng·mL^(-1),T_(max)均为1.50 h;t_(1/2)分别为(12.3±5.8),(15.1±10.3)h。餐后试验受试制剂和参比制剂厄贝沙坦的主要药代动力学参数:C_(max)分别为(2691.8±663.7),(2598.8±877.1)ng·mL^(-1),AUC_(0-t)分别为(10129.8±3783.9),(9538.6±3151.8)h·ng·mL^(-1),AUC_(0-∞)分别为(10353.1±3792.3),(9720.1±3162.0)h·ng·mL^(-1),T_(max)均为1.50 h;t_(1/2)分别为(12.5±7.6),(10.3±5.2)h。受试制剂与参比制剂C_(max)、AUC_(0-t)、AUC_(0-∞)几何均值比的90%置信区间均完全落在80.00%~125.00%。结论2种厄贝沙坦片在中国健康志愿者体内具有生物等效性。     

辅酶Q_(10)胶囊的药动学与人体相对生物利用度

目的研究水溶性辅酶Q_(10)超分子包合物灌装的辅酶Q_(10)胶囊(受试制剂)与辅酶Q*10胶囊(参比制剂)的生物利用度和生物等效性。方法 18名健康男性受试者随机分成2组,分别服用含44 mg辅酶Q_(10)的受试制剂和参比制剂,用高效液相色谱法测定其血药浓度,并计算药动学参数。结果受试制剂与参比制剂的ρ_(max)分别为(3.06±0.41)和(1.16±0.24)mg·L~(-1),t_(max)分别为(6.0±0.0)和(6.0±0.0)h,AUC_(0-t)分别为(114.50±15.78)和(40.48±8.90)mg·h·L~(-1),AUC_(0-∞)分别为(131.19±19.42)和(48.09±8.83)mg·h·L~(-1)。结论水溶性辅酶Q_(10)超分子包合物灌装的辅酶Q_(10)胶囊人体的相对生物利用度为(288.7±35.4)%。受试制剂的生物利用度大于参比制剂,两制剂生物不等效。     

复方盐酸二甲双胍片在健康志愿者体内的药物动力学和生物等效性

目的:研究复方盐酸二甲双胍片在健康志愿者体内的药物动力学和生物等效性。方法:18名男性健康志愿者随机交叉单次口服复方盐酸二甲双胍片(含盐酸二甲双胍1000 mg,格列本脲5 mg,受试制剂)或联合服用盐酸二甲双胍片1 000 mg和格列本脲片5 mg(参比制剂)后,采用HPLC法分别测定盐酸二甲双胍和格列本脲的经时血药浓度,用3P97软件计算其药物动力学参数和相对生物利用度,评价两种制剂的生物等效性。结果:单次口服受试制剂和参比制剂后,盐酸二甲双胍主要药物动力学参数C_(max)分别为(1.60±0.55)μg·ml~(-1)和(1.46±0.46)μg·ml~(-1),t_(max)分别为(2.1±0.7)h和(2.5±0.8)h,t_(1/2)分别为(4.9±1.7)h和(4.3±1.6)h,AUC_(0→24)分别为(10.47±2.89)μg·ml~(-1)·h和(9.22±2.56)μg·ml~(-1)·h,AUC_(0→∞)分别为(10.95±3.13)μ·ml~(-1)·h和(9.53±2.73)μg·ml~(-1)·h,受试制剂的相对生物利用度F_(0→24)为114.8%±17.6%。格列本脲主要药物动力学参数C_(max)分别为(117.70±28.38)μg·L~(-1)和(106.92±33.76)μg·L~(-1),t_(max)分别为(4.1±2.7)h和(3.8±1.8) h,t_(1/2)分别为(7.6±4.1)h和(8.8±3.9)h,AUC_(0→30)分别为(899.97±296.76)μg·L~(-1)·h和(902.64±353.82)μg·L~(-1)·h,AUC_(0→∞)分别为(943.00±290.09)μg·L~(-1)·h和(989.82±399.90)μg·L~(-1)·h,受试制剂的相对生物利用度F_(0→30)为104.91%±28.31%。结论:两制剂两组分的AUC、C_(max)对数值,经F分析、双单侧t检验和(1-2α)%置信区间法统计分析。表明两种制剂具有生物等效性。     

氢溴酸加兰他敏口腔崩解片与普通片在健康人体的生物等效性

目的 研究中国健康志愿者单次口服氢溴酸加兰他敏(可逆性胆碱酯酶抑制剂)口腔崩解片的生物等效性.方法 20名健康志愿者随机分成2组,分别接受单次口服2种国产氢溴酸加兰他敏20 mg;采用液相色谱-串联质谱法测定给药后不同时间点血浆中的氢溴酸加兰他敏浓度,用DAS ver 2.1软件计算其药代动力学参数.结果 氢溴酸加兰他敏的受试制剂与参比制剂主要药代动力学参数:t_(max)分别为(1.06±0.81),(0.85±0.26)h;t_(1/2)分别为(8.39±1.60),(8.22±1.58)h;C_(max)分别为(39.69±8.17),(43.41±11.58)μg·L~(-1);AUC_(0-t)分别为(384.88±101.75),(407.53±101.12)μg·h·L~(-1);AUC_(0-∞)分别为(396.92±105.85),(420.10±103.73)μg·h·L~(-1).氢溴酸加兰他敏的相对生物利用度为(95.5±16.2)%.结论 2种制剂具有生物等效性.     

吗替麦考酚酯软胶囊及普通胶囊在健康人体的生物等效性

目的 评价男性健康志愿者单剂量口服吗替麦考酚酯(免疫抑制剂)软胶囊与普通胶囊在健康人体内的生物等效性.方法 用2制剂2周期随机交叉设计,20名男性健康志愿者单剂量口服受试软胶囊和参比胶囊,采用高效液相色谱-紫外检测法测定血浆中霉酚酸浓度变化并进行统计学分析,对2种制剂做出生物等效性评价.结果 吗替麦考酚酯受试软胶囊与参比胶囊的AUC_(0→t)分别为(69.95±14.13)和(66.95±19.05)μg·h·mL~(-1);AUC_(0-∞)分别为(85.18±20.51)和(77.39±23.78)μg·h·mL~(-1);C_(max)分别为(31.26±13.09)和(31.90±14.45)μg·mL~(-1);t_(max)分别为(0.88±0.36)和(0.78±0.29)h;t_(1/2)分别为(20.34±12.55)和(18.84±11.58)h.吗替麦考酚酯软胶囊相对生物利用度为(109.6±26.9)%.结论 受试软胶囊与参比胶囊具有生物等效性.     

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.     

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.     

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.     

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.