枸橼酸莫沙必利口服液与片剂人体生物等效性评价

目的建立测定枸橼酸莫沙必利血浆浓度的高效液相色谱(HPLC)法,并对枸橼酸莫沙必利的口服液与片剂进行人体相对生物利用度和生物等效性研究.方法20名健康志愿者分别单剂量口服枸橼酸莫沙必利口服液或片剂10 mg,HPLC测定血药浓度,采用DAS 1.0程序进行药动学分析,并评价两制剂的生物等效性.结果单剂量口服10 mg枸橼酸莫沙必利口服液和片剂的药动学参数,AUC0→t分别为(170.2±40.7)μg·h·L-1和(176.6±69.4)μg·h·L-1,AUC0→∞分别为(182.2±43.7)μg·h·L-1和(193.2±73.3)μg·h·L-1;Cmax分别为(61.3±17.0)μg·L-1和(58.6±22.0)μg·L-1;tmax分别为(0.60±0.21)h和(0.8±0.4)h.分别以AUC→t与AUC0→∞计算其相对生物利用度分别为(105.8±36.0)%和(102.9±35.1)%.结论两种制剂具生物等效性.     

左羟丙哌嗪胶囊剂和口服溶液与片剂在健康人体内生物等效性

目的研究左羟丙哌嗪3种制剂的人体生物利用度。方法18名健康男性受试者采用三制剂三周期随机交叉试验设计,分别口服单剂量60mg左羟丙哌嗪胶囊(受试制剂A)、口服液(受试制剂B)和左羟丙哌嗪片剂(参比制剂R)。采用HPLC荧光检测法测定血清样品中的左羟丙哌嗪浓度。结果A、B与R的主要药动学参数分别为:tmax(51.11±31.74)、(41.67±19.70)和(54.44±20.14)min;ρmax(212.17±61.79)、(206.58±39.70)和(193.57±53.01)μg·L-1;AUC0→720(37113.66±10402.40)、(36579.53±8891.06)和(37184.75±9046.83)μg·min·L-1;AUC0→∞(38914.24±11416.86)、(38458.27±9407.49)和(38618.79±9463.20)μg·min·L-1;t1/2(166.73±53.64)、(177.66±88.24)和(155.09±33.46)min。相对生物利用度(100.21±13.11)%(A)和(99.24±10.05)%(B)。药动学参数经多因素方差分析显示周期间与制剂间差异均无统计学意义(P>0.05),双单侧t检验表明接受A与R和B与R生物等效的假设,经计算90%置信区间均在规定值内。结论A、B与R3种制剂生物等效。     

舒马普坦胶囊和片剂人体药物动力学及相对生物利用度研究

目的 研究国产舒马普坦胶囊、片剂在人体内的药物动力学及相对生物利用度。方法 采用随机、开放、3×3拉丁方设计,18名男性健康受试者分别单剂量口服试验制剂或参比制剂100 mg。采用HPLC-MS法测定给药后不同时间的血药浓度,采用双单侧t检验进行生物等效性判断。结果 进口参比制剂中舒马普坦的主要药物动力学参数Cmax为(41.68±18.38)μg·L-1;tmax为(2.08±0.65)h;AUC0→12为(152.14±61.63)μg·h·L-1;t1/2为(2.7±0.8)h。国产舒马普坦胶囊的主要药物动力学参数Cmax为(38.01±17.01)μg·L-1;tmax为(1.83±0.45)h;AUC0→12为(136.68±60.71)μg·h·L-1;t1/2为(2.7±1.0)h。国产舒马普坦片剂的主要药物动力学参数Cmax为(38.78±17.67)μg·L-1;tmax为(1.83±0.45)h;AUC0→12为(136.68±60.71)μg·h·L-1;t1/2为(2.7±1.0)h。国产胶囊剂和国产片剂对进口片剂的相对生物利用度分别为91.0％±14.8％和92.0％±11.6％。结论 经统计学分析,国产舒马普坦片剂和胶囊剂与进口制剂具有生物等效性,制剂间药物动力学参数无显著差异。     

氢溴酸加兰他敏口服液及片剂的人体生物等效性研究

目的:采用HPLC-RF检测法测定氢溴酸加兰他敏的血药浓度,研究其在人体内的药动学和生物等效性。方法:24例健康男性志愿者单剂量随机交叉口服5 mg加兰他敏口服液(受试制剂)和片剂(参比制剂)。血浆样品经碱化后用乙醚提取,采用反相HPLC-RF法测定血浆中加兰他敏浓度,检测波长:激发波长290 nm,发射波长320 nm。采用3P97药动学软件计算药动学参数和相对生物利用度,并对参数进行方差分析和双单侧t检验。结果:加兰他敏口服液和片剂的主要药动学参数:Cmax分别为(31．53±5．59)和(33．44±5．72)μg·L-1;Tmax分别为(1．66±0．79)和(1．51±0．72)h;t1/2分别为(7．06±2．16)和(6．64±2．30)h;AUC0～∞分别为(340．6±77．2)和(325．5±77．7)μg·h·L-1。氢溴酸加兰他敏口服液相对生物利用度为105．6％。结论:加兰他敏口服液和片剂生物等效。     

HPLC/MS研究国产盐酸班布特罗片及其代谢物特布他林人体生物等效性

目的　研究国产班布特罗片剂和进口片剂进行人体生物等效性研究。方法　 2 0名健康受试者随机交叉给药 ,用液相色谱 /质谱联用测定血浆中班布特罗其代谢物特布他林的浓度。结果　经数据处理 ,单次口服国产和进口班布特罗片剂后班布特罗的药代动力学参数 :AUC0 -t分别为 (5 2± 2 1) μg·h·L-1和 (5 1± 2 0 ) μg·h·L-1,Tmax分别为 (2 9± 0 9)h和 (2 6± 0 7)h ,Cmax分别为 (6 0± 2 6 ) μg·L-1和 (6 2± 2 9) μg·L-1。特布他林 :AUC0 -t分别为 (191± 30 ) μg·h·L-1和 (197± 37) μg·h·L-1,Tmax分别为 (4 2± 1 0 )h和 (4 2± 1 0 )h ,Cmax分别为 (10± 5 )μg·L-1和 (10± 4) μg·L-1。国产班布特罗片剂单次给药后的相对生物利用度为 10 2 %± 8% (班布特罗 ) ,10 0 %±12 % (特布他林 )。结论　经统计学证明两制剂有生物等效性     

高效液相色谱-串联质谱法测定人血浆中吲哒帕胺及其生物等效性研究

目的:研究用高效液相色谱-串联质谱(HPLC-MS)法进行试验制剂吲哒帕胺片剂与参比制剂市售吲哒帕胺片剂生物等效性研究。方法:男性健康志愿者20名,随机分为2组,分别交叉单剂服用受试制剂或参比制剂吲哒帕胺片剂2．5 mg,采用HPLC-MS法,选择正离子检测的大气压化学电离源(APCI源),以甲醇-1％甲酸水溶液(75:25,V／V)为流动相,测定吲哒帕胺血药浓度,计算药动学参数,评价2制剂的生物等效性。结果:受试制剂和参比制剂主要药动学参数tmax为(1．4±s 0．4)和(1．4±0．4)h, Cmax为(30±6)和(30±5)μg·L-1,t1／2为(14．7±2．1)和(14．3±2．5)h,AUC0-72为(539±103)和(534±95)μg·h·L-1,AUC0-∞为(570±105)和(565±98)μg·h·L-1。受试制剂吲哒帕胺片剂相对生物利用度(F)为(102±13)％。结论:该方法选择性强、灵敏度高、操作简便,适用于吲哒帕胺制剂的生物等效性评价及临床药动学研究。     

扎莱普隆胶囊的相对生物利用度研究

目的比较扎莱普隆胶囊和片剂在健康人体内的药代动力学过程,并对两制剂的生物等效性做出评价.方法20名健康男性志愿者采用交叉给药方案,分别单剂量口服10mg扎莱普隆胶囊和片剂,用高效液相色谱荧光检测法测定血浆中扎莱普隆浓度,进行生物等效性评价.结果实验表明扎莱普隆胶囊和片剂的tmax分别是1.04±0.35h和1.10±0.45h,Cmax分别是26.06±9.14μg·L-1和27.39±7.51μg·L-1,t1/2Ke分别是1.33±0.26h和1.34±0.22h,AUC0-8分别是83.39±37.35μg·h·L-1和87.44±35.25μg·h·L-1.相对生物利用度为94.40%±11.06%.结论结果显示两种制剂具有生物等效性.     

国产亚叶酸钙片、胶囊与进口亚叶酸钙片的人体相对生物利用度比较

目的 :研究 3种亚叶酸钙制剂 (国产片剂、胶囊和进口片剂 )在 12名健康志愿者体内的相对生物利用度。方法 :同体交叉试验后 ,测定血浆中亚叶酸钙浓度 ,计算主要药物动力学参数和相对生物利用度 ,并进行统计学分析。结果 :国产片、胶囊和进口片单剂量 75mg ,po后 ,Tmax 分别为 ( 2 .5±s0 .3)h ,( 2 .5± 0 .3)h和 ( 2 .4± 0 .3)h ;Cmax为 ( 654± 146) μg·L- 1,( 599± 132 ) μg·L- 1和 ( 640± 163)μg·L- 1;AUC0～∞ 为 ( 7811± 1481) μg·h·L- 1,( 70 91± 1397) μg·h·L- 1和 ( 7898± 1855) μg·h·L- 1;T12 为 ( 8.7± 0 .6)h ,( 8.6± 0 .4 )h和 ( 8.6±0 .5)h。国产片、胶囊相对生物利用度分别为 ( 10 1± 14) % ,( 93± 11) %。结论 :3种制剂生物等效。     

西酞普兰片剂的人体生物等效性研究

目的:研究国产氢澳酸西酞普兰片剂在健康人体内的药动学和与进口参比片剂比较的生物等效性。方法:24例健康男性志愿者单剂量随机交叉口服20 mg西酞普兰国产或进口片剂,血浆样品经碱化后用乙醚提取,再经酸化反提取处理。采用反相HPLC-RF法测定血浆中西酞普兰浓度,检测波长:激发波长240 nm,发射波长305 nm。采用3P97药动学程序计算药动学参数和相对生物利用度,并对参数进行方差分析和双单侧t检验。结果:西酞普兰受试片和参比片的主要药动学参数:Cmax分别为(26．99±4．68)和(27．27±4．16)μg·L-1;Tmax分别为(4．48±1．53)和(4．13±1．25)h;t1/2分别为(39．62±10．49)和(37．99±7．45)h;AUC0→∞分别为(1 459．4±480．9)和(1 388．4±1402．5)μg·h·L-1。国产片剂的相对生物利用度为(105．4±24．4)％,统计学结果表明两种片剂生物等效。结论:西酞普兰国产和进口片剂具有生物等效性。     

左羟丙哌嗪缓释片体外释放度测定

目的:建立左羟丙哌嗪缓释片体外释放度测定方法,并对其释放度影响因素及释药机制进行考察。方法:采用单因素考察方法,研究处方、工艺及释放方法学因素对左羟丙哌嗪缓释片释放度的影响。结果:左羟丙哌嗪在237nm波长有最大吸收,辅料对药物测定无干扰。左羟丙哌嗪在2.56-20.48 mg·L-1浓度范围内线性关系良好。羟丙甲基纤维素的种类、用量、黏度、片剂的比表面积以及不同释放条件对药物的释放特性有一定影响。结论:左羟丙哌嗪缓释片的释放表现为药物扩散和凝胶溶蚀的协同作用,许多因素可以影响药物释放行为。     

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.