精氨洛芬片剂与颗粒剂在健康受试者体内的生物等效性

目的 研究精氨洛芬(非甾体抗炎药)片剂与颗粒剂在中国健康志愿者体内的生物等效性.方法 20名健康男性受试者分别随机交叉口服精氨洛芬片(试验制剂)及其颗粒(参比制剂)0.4 g,用HPLC-UV法测定给药后不同时间点的血浆布洛芬浓度;用DAS程序对试验数据进行统计处理,评价2种制剂的生物等效性.结果 试验制剂和参比制剂的药代动力学参数如下:Cmax分别为(50.60±9.12)、(50.53±8.58)nag·L-1,tmax分别为(0.51±0.20)、(0.34±0.11)h,AUC0～t分别为(118.63±21.42)、(115.75±20.23)mg·h·L-1,AUC0～∞分别为(121.18±22.18)、(118.55±21.83)mg·h·L-1.试验制剂与参比制剂AUC0-t之比和Cmax之比的90%可信区间分别为97.5%～107.6%和93.3%～107.2%.结论 试验制剂和参比制剂吸收程度等效(AUC0-t,AUC0-∞和Cmax均生物等效性);但吸收速度不等效(tmax不等效).     

苯磺酸氨氯地平片在健康人体的生物等效性

目的 研究苯磺酸氨氯地平片(抗高血压药)的相对生物利用度,并求证该制剂的生物等效性.方法 24名男性健康受试者随机交叉给药,先后口服单剂量试验制剂及参比制剂苯磺酸氨氯地平片剂5 mg,采用LC-MS/MS法测定血药浓度,计算2者的药代动力学参数及相对生物利用度,并评价2制剂的生物等效性.结果 口服试验制剂及参比制剂5 mg的主要药代动力学参数如下:t1/2分别为(47.15±17.28)、(43.22 ± 16.63)h;tmax分别为(5.81±2.09)、(6.38±2.33)h;Cmax分别为(4.77±1.28)、(4.37±1.14)ng·mL-1;AUC0-t分别为(176.39±57.95)、(182.55±58.36)ng·mL-1h;AUC0-t分别为(185.65±59.01)、(192.83±62.72)ng·mL-1h;试验制剂对于参比制剂的平均相对生物利用度F值:AUC0-t为(98.1±18.5)%,AUC0-∞为(98.6±20.0)%;tmax经非参数检验无显著性差异,试验制剂的平均生物利用度(AUC0-t、AUC0-∞)均大于98%,2种制剂的Cmax、AUC0-t和AUC0-∞双向单侧t检验和[1-2α]置信区间法的等效性分析均为合格,tmax经非参数秩和检验无显著性差异.结论 2种氨氯地平片剂为生物等效制剂.     

托拉塞米胶囊与片剂在健康人体内的药动学和生物等效性

目的研究托拉塞米试验制剂(胶囊)和参比制剂(片剂)的人体药动学和生物等效性.方法20名健康受试者随机交叉口服托拉塞米胶囊(试验制剂)和托拉塞米片(参比制剂),剂量均为10 mg.血样加入内标(呋塞米)经预处理后采用HPLC法测定.结果试验胶囊、参比片剂的主要药动学参数Cmax分别为(1160.1±188.0),(1 271.2±326.8)μg·L-1;Tmax分别为(1.1±0.4),(1.0±0.4)h;t1/2分别为(4.1±1.0),(4.0±1.0)h;AUC0-t分别为(3 662.3±782.2),(3 783.2±1390.1)μg·h·L-1.以AUC0→t计算的试验胶囊的相对生物利用度为(100.6±23.9)%.结论经方差分析及双单侧t检验结果显示,试验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.     

马来酸氯苯那敏片健康人体药动学和相对生物利用度

目的研究马来酸氯苯那敏片剂在健康人体内的相对生物利用度。方法采用HPLC法测定18名男性健康志愿者单剂量交叉口服马来酸氯苯那敏片参比制剂和被试制剂8mg后不同时间血浆药物浓度。用3P97药动学软件进行药动学参数计算及生物等效性评价。结果参比和被试制剂的药-时曲线均符合一房室模型,两制剂的主要药动学参数如下Cmax分别为(15.74±7.06)μg·L-1和(14.88±4.40)μg·L-1;tmax分别为(3.9±1.2)h和(4.5±0.8)h;t1/2ke分别为(15.54±3.76)h和(14.49±3.24)h;AUC0-t分别为(248.86±78.52)μg·h·L-1和(245.09±90.77)μg·h·L-1,AUC0-∞分别为(292.64±99.21)μg·h·L-1和(282.04±98.64)μg·h·L-1。与标准参比制剂相比,被试制剂的相对生物利用度F0-t为(104.1±36.1)%,F0-∞为(103.2±35.6)%。结论方差分析与双单侧t检验证明,两种制剂具有生物等效性。     

国产替米沙坦片健康人体生物等效性评价

目的:评价国产和进口替米沙坦片剂在健康人体的生物等效性.方法:采用高效液相色谱-荧光检测法测定18名健康志愿者单次、交叉口服替米沙坦片80 mg后血浆替米沙坦浓度.用3P97药动学软件进行药动学参数计算及生物等效性评价.结果:两种替米沙坦片的药-时曲线均符合二室模型,参比制剂、受试制剂的主要药动学参数为:Cmax分别为(931.0±367.7)μg·L-1和(894.2±421.7)μg·L-1;Tmax分别为(1.0±0.6)h和(1.4±0.8)h;T1/2β分别为(28.1±14.1)h和(27.0±10.8)h;AUC0-t分别为(4 085±2 313)μg·L-1·h和(3 920±2 199)μg·L-1·h;AUC0-∞分别为(4 751±2 742)μg·L-1·h和(4 352±2 569)μg·L-1·h.国产替米沙坦片的相对生物利用度F0-t为(97.5±15.6)%,F0-∞为(96.5±15.8)%.结论:方差分析和双单侧t检验证明两制剂具有生物等效性.     

加替沙星分散片的人体药动学及生物等效性研究

目的 研究加替沙星分散片的人体药动学和生物等效性.方法 健康志愿者20名,随机双交叉单剂量口服加替沙星分散片(试验制剂)和加替沙星片(参比制剂),剂量分别为400 mg,剂间间隔为1周.分别于服药后24 h内多点抽取静脉血;用高效液相色谱法(HPLC)测定血浆中加替沙星的浓度.用DAS药动学程序计算相对生物利用度并评价两种制剂生物等效性.AUC(0-24),UC(0-inf)和Cmax经方差分析和双单侧t检验,max进行秩和检验.结果 单剂量口服试验和参比制剂后血浆中的加替沙星的Cmax分别为(3.75±0.74)mg·L-1和(3.88±0.77)mg·L-1;Tmax分别为(0.81±0.31)h和(1.31±0.55)h;AUC(0-24)分别为(18.48±3.69)mg·h·L-1和(18.45±2.67)mg·h·L-1;AUC(0-inf)分别为(19.24±3.64)mg·h·L-1和(19.20±2.66)mg·h·L-1.AUC(0-24)、AUC(0-inf)和Cmax的90%可信区间分别为91.8%～107.2%、92.1%～107.2%和90.4%～103.0%.结论 试验与参比制剂的人体相对生物利用度为(101.01±19.26)%,两制剂具有生物学等效性.     

国产马来酸伊索拉啶片剂人体生物等效性研究

12名健康受试者随机交叉给药,分别口服单剂量国产马来酸伊索拉啶片剂及进口片剂8mg进行生物等效性的研究.采用高效液相紫外检测法测定血浆中马来酸伊索拉啶的浓度,经3p97中生物等效性程序计算处理, 被试制剂和标准参比制剂的: Tpeak分别为8.67±2.15h和9.00±2.34h, Cmax分别为300.09±20.21μg·L-1和302.48±21.91μg·L-1, T1/2Ke分别为127.18±16.83h和126.24±19.88h,经配对t-检验,两者的AUC0-t, Tpeak, Cmax ,T1/2Ke等主要药代动力学参数均无显著性差异(P>0.05).采用梯形法计算的两者的AUC0-t均值分别为37500.59±7605.32μg·h·L-1和38518.18±6934.74μg·h·L-1,经统计学分析,被试制剂和标准参比制剂具有生物等效性.被试制剂的相对生物利用度为97.3±5.9%.     

比较氨氯地平和阿托伐他汀复方片与单剂在健康人体的生物等效性

目的 评价氨氯地平/阿托伐他汀复方片剂与同剂量单剂的生物等效性.方法 66位健康男性志愿者随机交叉单次口服1片氨氯地平(5 mg)/阿托伐他汀(40 mg)复方片剂(受试制剂)和同时服用氨氯地平(5 mg)和阿托伐他汀(40mg)各1片(参比制剂);用GC-ECD法和LC-MS/MS法,分别测定药物血浆浓度,WinNonlin非房室模型计算药代动力学参数,SAS程序评价生物等效性.结果 受试制剂(复方)和参比制剂(单剂)的主要药代动力学参数,氨氯地平:tmax分别为6.0和6.0 h;t1/2分别为(39.2±7.6)和(39.7±9.9)h;Cmax分别为(3.0±0.9)和(3.0±0.5)ng·mL-1;AUC0-∞分别为(145.3±42.1)和(149.8±43.6)ng·h·mL-1;AUC0-t分别为(129.3±39.5)和(133.4±37.2)ng·h·mL-1.阿托伐他汀:tmax分别为1.0和0.5 h;t1/2分别为(6.7±1.8)和(6.9±1.8)h;Cmax分别为(18.8±9.8)和(20.2±11.7)ng·mL-1;AUC0-∞分别为(101.7±35.2)和(97.8±39.2)ng·h·mL-1;AuC0-t分别为(96.7±35.0)和(93.1±39.1)ng·h·mL-1.受试制剂和参比制剂AUC0-t、AUC0-∞和Cmax比值的90%置信区间:氨氯地平:93.3%～100.1%,93.8%～100.6%和95.8%～103.4%;阿托伐他汀:99.2%～111.0%,99.6%～110.6%和81.8%～107.2%.结论 2种制剂为生物等效制剂.     

国产与进口熊去氧胆酸胶囊在健康人体的生物等效性

目的 以进口熊去氧胆酸胶囊(抗胆石症药)为参比制剂,评价国产熊去氧胆酸胶囊的生物等效性.方法 21名男性健康受试者采用随机、自身交叉前后对照试验方案,用液相色谱-质谱联用法,以盐酸西替利嗪为内标,测定血浆中熊去氧胆酸的浓度,评价试验制剂的相对生物利用度.结果 单剂量口服熊去氧胆酸胶囊试验制剂和参比制剂各500 mg后的AUC0-24h分别为(18.9±7.0)和(19.0±5.5)mg·h·L-1;AUC0-∞分别为(22.6±11.8)和(20.9±5.9)mg·h·L-1;tmax分别为(2.4±0.4)和(2.3±0.6)h;Cmax分别为(9.2±5.0)和(8.2±4.0)mg·L-1.试验制剂的F0-24h为(104±38)%.对AUC0-24h、AUC0-∞、Cmax和tmax作方差分析、双单侧t检验及非参数法秩和检验,结果2组间无统计学差异.结论 试验制剂与参比制剂具有生物等效性.     

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.     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.