国产与进口盐酸沙格雷酯片在健康人体的生物等效性

目的 研究国产与进口盐酸沙格雷酯片(抗血栓药)的相对生物利用度,评价2者的生物等效性.方法 采用双周期自身交叉试验设计,单剂量口服给药.24名健康男性受试者分别单剂量口服受试制剂和参比制剂,血浆样品采用高效液相色谱-串联质谱法检测.结果 受试制剂及参比制剂盐酸沙格雷酯片的主要药代动力学参数:Cmax分别为(710.25±305.79),(653.33±311.06)μg·L-1;tmax分别为(0.39±0.23),(0.38±0.19)h;t1/2分别为(0.72±0.10),(0.67±0.10)h;AUC0-tn分别为(473.80±216.83),(440.17±440.17)μg·h·L-1;AUC0-∞分别为(479.88±224.77),(443.79±144.70)μg·h·L-1;受试制剂盐酸沙格雷酯片的相对生物利用度F0-tn、F0-∞分别为(110.24±38.24)%,(110.64±39.07)%.结论 受试制剂和参比制剂具有生物等效性.     

阿立哌唑口腔崩解片在健康人体的生物利用度

目的研究阿立哌唑口腔崩解片(抗精神病药)的生物利用度。方法用随机自身交叉实验设计,24名男性健康受试者先后单剂量口服阿立哌唑口腔崩解片(试验制剂)及阿立哌唑片(参比制剂)20mg,用高效液相色谱-紫外检测法测定血浆中阿立哌唑浓度,用DAS1.0药代动力学程序处理血药浓度经时变化数据。结果单剂量口服试验制剂和参比制剂各20mg后的AUC0-t分别为(2520.6±2002.5),(2329.3±1771.0)μg·h·L-1;AUC0-∞分别为(2797.0±2096.7),(2742.9±1842.2)μg·h·L-1;Cmax分别为(62.3±37.8),(56.8±20.8)μg·L-1;tmax分别为(4.5±1.0),(4.4±0.9)h。2制剂比较均无显著性差异(P>0.05)。以阿立哌唑片为参比,口腔崩解片的相对生物利用度为(111.6±43.1)%。结论2种制剂具有生物等效性。     

复方对乙酰氨基酚片在健康人体的药代动力学和相对生物利用度

目的研究复方对乙酰氨基酚片(解热镇痛药)在健康人体的药代动力学和相对生物利用度。方法24名健康受试者单剂量随机交叉口服2种国产复方对乙酰氨基酚片(试验与参比制剂)2片,用高效液相色谱法测定对乙酰氨基酚、异丙安替比林和咖啡因的血药浓度,用DAS软件拟合计算药代动力学参数,评价2种制剂生物等效性。结果药代动力学参数如下。对乙酰氨基酚:tmax分别为(0.81±0.48),(0.78±0.30)h;Cmax分别为(9.29±2.23),(8.76±1.83)μg·mL-1;AUC0-24分别为(31.49±6.83),(31.64±7.77)μg·h·mL-1。异丙安替比林:tmax分别为(0.90±0.33),(0.88±0.30)h;Cmax分别为(6.99±1.79),(7.00±1.60)μg·mL-1;AUC0-24分别为(21.92±9.43),(19.51±5.22)μg·h·mL-1。复方中2种成分相对生物利用度分别为(102.3±22.4)%,(112.8±37.4)%。结论试验与参比制剂具有生物等效性。     

富马酸酮替芬颗粒与富马酸酮替芬片在健康人体的生物等效性

目的 研究富马酸酮替芬颗粒与富马酸酮替芬片(均为平喘药)的相对生物利用度,评价2者的生物等效性.方法 采用双周期自身交叉试验设计,单剂量口服给药.24例健康男性受试者分别单剂量口服受试制剂和参比制剂,血浆样品采用高效液相色谱串联质谱法检测.结果 受试制剂富马酸酮替芬颗粒及参比制剂富马酸酮替芬片的主要药代动力学参数:Cmax分别为(247.76±99.61),(229.24±96.44)ng·L-1;tmax分别为(2.38±0.97),(2.46±1.14)h;t1/2分别为(14.85±5.76),(14.69±7.91) h;AUC0-tn分别为(2641.07±1025.19),(2764.19±1231.50) ng·L-1·h;AUC0-∞分别为(3192.01±1272.20),(3431.11±1902.72) ng·L-1·h;受试制剂富马酸酮替芬颗粒的相对生物利用度F0-tn、F0-∞分别为(100.08±21.81)%,(102.75±30.33)%.结论 受试制剂和参比制剂具有生物等效性.     

氯沙坦钾胶囊及其片剂在健康人体的生物等效性研究

目的:研究氯沙坦钾胶囊及其片剂在健康人体内的药动学特征,并评价两种制剂间的生物等效性.方法:20名健康男性志愿受试者随机交叉单剂量口服试验制剂和参比制剂50 mg,清洗期1周,LC-MS/MS法测定血浆氯沙坦和代谢物氯沙坦羧酸(E-3174)浓度.药代参数的计算与统计分析使用DAS2.0软件.结果:口服试验制剂和参比制剂后,受试者的氯沙坦和E-3174主要药代动力学参数如下:氯沙坦Cmax分别为(183.83±91.30),(176.45±93.97) μg·L-1;AUC0-t分别为(333.18±105.00),( 323.75±101.92) μg·h·L1;AUC0-∞分别为(344.88±104.15),(341.32±106.13) μg·h·-1;t1/2分别为(1.84±0.52),(1.99±0.60)h;tmax分别为(0.70±0.22),(0.98±0.62)h.E-3174 Cmax分别为(344.85±114.33),(329.95±106.42) μg·L-1;AUC0-t分别为(2 445.09±608.97),(2 332.54±564.72) μg·h·L-1;AUC0-∞分别为(2 503.45±612.62),(2 390.92±567.03) μg·h·L-1;t1/2分别为(4.17±0.49),(4.13±0.66)h;tmax分别为(3.14±0.72),(3.39±0.96)h.试验制剂氯沙坦钾胶囊中氯沙坦和E-3174相对生物利用度分别为( 104.9±20.7)％和(105.2±12.1)％.结论:本试验采用的氯沙坦钾胶囊和氯沙坦钾片为生物等效制剂.     

格列喹酮片在健康人体生物等效性研究

目的:研究两种格列喹酮片在健康人体内的药动学特征,并评价两种制剂间的生物等效性。方法:18名健康男性志愿受试者随机交叉单剂量口服试验制剂和参比制剂60 mg,清洗期1周,采用HPLC法测定血清中格列喹酮浓度。结果:受试者口服试验制剂和参比制剂后,主要药代动力学参数如下:t1/2分别为(4.78±1.87),(4.19±1.57)h,tmax分别为(3.06±1.08),(3.28±1.49)h,Cmax分别为(0.87±0.35),(0.90±0.33)μg.mL-1,AUC0-t分别为(4.35±1.66),(4.62±1.23)μg.h.mL-1,AUC0-∞分别为(4.98±1.72),(5.19±1.42)μg.h.mL-1。试验制剂的相对生物利用度AUC0-t为(95.8±34.1)%,AUC0-∞为(97.7±29.4)%。结论:两种格列喹酮片为生物等效制剂。     

硫唑嘌呤片在健康人体的生物等效性

目的研究硫唑嘌呤片(免疫抑制剂)在健康人体的相对生物利用度并评价其生物等效性。方法20名健康志愿者自身交叉、单剂量口服硫唑嘌呤受试和参比制剂各100 mg后,用反相高效液相色谱法测定血浆中其代谢物6-巯基嘌呤浓度。应用DAS软件计算药代动力学参数和相对生物利用度。结果6-巯基嘌呤受试制剂和参比制剂的平均药物浓度-时间曲线均符合一室模型,主要药代动力学参数:t1/2分别为(1.30±0.25),(1.30±0.34)h;tmax分别为(1.25±0.16),(1.24±0.21)h;Cmax分别为(48.44±17.09),(52.32±24.37)μg.L-1;AUC0-t分别为(89.49±19.25),(91.90±25.31)μg.h.L-1;AUC0-∞分别为(96.11±19.74),(98.36±24.66)μg.h.L-1。与参比制剂比较,受试制剂的相对生物利用度F0-t为(99.62±15.29)%,F0-∞为(99.39±13.59)%。结论2种硫唑嘌呤制剂具有生物等效性。     

国产与进口吲达帕胺片在健康人体的生物等效性

目的 评价吲达帕胺(抗高血压药)在健康人体的相对生物利用度和生物等效性.方法 健康受试者22名,自身随机交叉试验方法,单剂量口服受试制剂及参比制剂2.5 mg,每次间隔1周清洗期.用液质联用方法测定血浆中的吲达帕胺浓度,计算药代动力学参数及相对生物利用度,并进行生物等效性评价.结果 单剂量口服受试制剂T与参比制剂R的Cmax分别为(29.30±9.64),(28.05±7.33)μg·L-1;tmax分别为(3.00±1.62),(2.80±1.12)h;t1/2分别为(15.80 ±3.48),(15.50±3.95)h;AUC0-tn分别为(562.75±186.25),(533.23±181.98)μg·L-1·h;AUC0-∞分别为(599.43±201.16),(566.76 ±194.32)μg·L-1·h.经统计学分析,组间无显著性差异(P>0.05).结论 国产吲达帕胺片与进口吲达帕胺片为生物等效制剂.     

二甲双胍格列吡嗪片人体生物等效性研究

目的:评价二甲双胍格列吡嗪片复方制剂与两种单方制剂盐酸二甲双胍片和格列吡嗪片的生物等效性。方法:采用双周期自身交叉试验设计,24名健康男性受试者分别单剂量口服二甲双胍格列吡嗪片和盐酸二甲双胍片加格列吡嗪片,并于给药前及给药后不同时间点采集肘静脉血。采用高效液相色谱-质谱方法分别测定血浆中二甲双胍和格列吡嗪的浓度。结果:受试制剂与参比制剂中二甲双胍的Cmax分别为(1 470.75±441.55)和(1 618.63±554.58)μg.L-1,tmax分别为(2.79±1.37)和(2.63±1.24)h,t1/2分别为(5.80±1.38)和(6.24±1.14)h;AUC0-tn分别为(9 699.83±2 619.73)和(10 180.88±2 559.62)μg.h.L-1,AUC0-∞分别为(10 095.41±2 681.73)和(10 616.67±2 616.83)μg.h.L-1,受试制剂的相对生物利用度F0-tn、F0-∞分别为(97.18±23.26)%和(96.83±22.43)%;格列吡嗪的Cmax分别为(251.25±61.94)和(240.13±52.43)μg.L-1,tmax分别为(3.35±1.22)和(3.38±1.35)h,t1/2分别为(4.85±1.39)和(5.08±1.76)h;AUC0-tn分别为(1 561.44±475.73)和(1 588.82±507.40)μg.h.L-1,AUC0-∞分别为(1 664.13±580.08)和(1 704.93±647.89)μg.h.L-1,受试制剂的相对生物利用度F0-tn、F0-∞分别为(100.73±19.66)%和(100.59±19.70)%。结论:受试制剂和参比制剂具有生物等效性。     

盐酸安非他酮缓释片人体生物等效性

目的:进行受试制剂盐酸安非他酮缓释片与市售参比制剂盐酸安非他酮缓释片的人体生物等效性研究。方法:20例健康男性志愿者采用自身交叉给药方案,分别口服单次给予和连续多次(18例)给予2种盐酸安非他酮缓释制剂,采用HPLC-MS/MS法测定其血药浓度,计算药动学参数,并判定2种制剂的生物等效性。结果:口服单次给予受试制剂和参比制剂安非他酮缓释片的主要药动学参数为Cmax分别为(174.0±55.5),(175.1±56.2)μg.L-1,tmax分别为(2.0±0.5),(2.0±0.6)h,t1/2分别为(11.1±5.0),(11.8±8.2)h,AUC0-72分别为(952.9±423.4),(901.6±372.5)μg.h.L-1,AUC0-∞分别为(968.2±441.0),(918.8±375.8)μg.h.L-1;以AUC0-72计,单次口服受试制剂的相对生物利用度为(106.0±24.3)%。口服连续多次给予的主要药动学参数为Cmax分别为(149.1±45.1),(149.2±38.4)μg.L-1,tmax分别为(2.1±0.9),(1.8±0.3)h,t1/2分别为(12.7±4.6),(1...     

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.