人血浆中磷酸苯丙哌林的测定及其缓释制剂在人体内的生物等效性研究

目的 建立快速测定人血浆中磷酸苯丙哌林浓度的方法,并用于评价磷酸苯丙哌林缓释制剂的生物等效性.方法 24名健康志愿者分别单剂量空腹口服40mg磷酸苯丙哌林缓释片和缓释胶囊,给药后于不同时间收集血浆样品,采用液液萃取的方法进行生物样品前处理,采用LC-MS/MS法测定磷酸苯丙哌林在血浆中的浓度.用DAS ver2.1.1药动学软件进行数据处理并进行等效性分析.结果 磷酸苯丙哌林浓度的线性范围为0.25～500 ng·mL-1(r=0.9997).最低定量限为0.25ng·mL-1,最低定量限的RSD=8.78%;磷酸苯丙哌林及内标的萃取回收率均大于75%.日内、日间RSD均小于11%,高、中、低浓度血浆样品的平均方法回收率分别为100.41%、100.81%、105.96%.磷酸苯丙哌林缓释胶囊和缓释片的药动学参数:Tmax为4.21±0.55、4.19±0.51 h;Cmax为82.12±14.27、78.43±10.44ng·mL-1;AUC0-72为2113.45±770.19、2076.89±818.25μg·h·L-1.结论 所建方法灵敏、准确、专属性强,适用于磷酸苯丙哌林血药浓度的测定及其药动学的研究;受试制剂与参比制剂具有生物等效性.     

苯丙哌林缓释胶囊人体生物等效性研究

目的评价两种磷酸苯丙哌林制剂的人体生物等效性。方法将18名志愿受试者随机分成2组,分别单剂量交叉1：7服两种制剂,用高效液相色谱法测定血中磷酸苯丙哌林的药物质量浓度,用3P97软件计算药代动力学参数和等效性分析。结果两种制剂的达峰时间（Tmax）分别为（4．28±0．96）h和（4．66±1．28）h,峰浓度（Cmax）分别为（92．85±26．03）ng／mL和（96．93±28．43）ng／mL,0～48h药时曲线下面积（AUC0-48）分别为（2403．06±690．47）ng／mL·h和（2445．50±591．03）ng／mL·h,相对生物利用度为（100．9±26．8）％。结论西南药业股份有限公司研制的磷酸苯丙哌林缓释胶囊与湖北中佳药业有限公司生产的磷酸苯丙哌林缓释片具有生物等效性。     

磷酸苯丙哌林缓释片制备工艺研究

目的：制备磷酸苯丙哌林缓释片。方法：以HPMC、丙烯酸树脂作辅料，使其形成基本骨架，采用湿颗粒法制备磷酸苯丙哌林缓释片。结果：缓释片在2，4，8h的释放度分别为30%-60%，55%-80%和80%以上。结论：磷酸苯丙哌林缓释片在酸性溶液中具有显的缓释作用。     

磷酸苯丙哌林缓释胶囊的制备

目的制备磷酸苯丙哌林缓释胶囊。方法以苏丽丝、聚山梨酯20为包衣材料制备缓释胶囊。结果缓释胶囊在2，4，8h时的体外释放度分别为20％～40％，40％～70％及75％以上。结论磷酸苯丙哌林缓释胶囊处方合理、工艺可行。     

磷酸苯丙哌林人体药代动力学及其制剂的相对生物利用度研究

本文首次报道了测定苯丙哌林血浆浓度的高效液相色谱法及该药在人体内的药代动力学行为.绘制了10名健康男性受试者服用磷酸苯丙哌林两种制剂60 mg(以苯丙哌林计)后的血浆浓度-时间曲线,用TopFit 2.0软件进行房室模型拟合,结果表明苯丙哌林体内药动学过程符合二室模型.磷酸苯丙哌林分散片和胶囊的Tmax分别为1.76 ± 0.29 h和1.80 ± 0.41 h, Cmax分别为479.4 ± 171.5和456.4 ± 173.9 μg· L- 1;AUC0-t为4309.4 ± 1549.9和4119.5 ± 2018.8 μg· L-1· h.统计检验表明,10名受试者服用两种制剂后的药代动力学参数无显著性差异,具有生物等效性.     

磷酸卡维地洛缓释微丸的制备及其在比格犬体内的药动学

目的:评价自制磷酸卡维地洛缓释微丸在Beagle犬中的等效性。方法:〗流化床包衣法制备磷酸卡维地洛缓释微丸;试验采用两周期交叉试验设计,将6条Beagle犬,雌雄各半,分为两组,分服试验制剂磷酸卡维地洛或参比制剂磷酸卡维地洛;采用HPLC-FD法比较给药后原研和自研制剂在Beagle犬体内不同时间点的血药浓度。计算药动学参数并根据试验制剂和参比制剂AUC计算相对生物利用度。同时对主要药动学参数进行方差分析、双单侧t检验和[1-2α]置信区间分析,评价试验制剂和参比制剂的生物等效性。结果:磷酸卡维地洛在1~300 ng·mL^-1范围内线性关系良好(r=0.999 3),定量下限为1ng·mL^-1。提取回收率均高于50%,日内、日间RSD均小于12%,专属性良好,在本实验涉及的条件下样品稳定。磷酸卡维地洛缓释微丸试验制剂和参比制剂主要药动学参数t_1/2、t_max、C_max、AUC_0-t、AUC_0-∞无明显差异,与参比制剂相比较试验制剂相对生物利用度为(96.8±8.7)%。结论:自研制剂与原研制剂在Beagle犬体内生物等效。     

盐酸阿比朵尔缓释微丸在犬体内的药动学

目的评价自制盐酸阿比朵尔(arbidol hydrochloride,AH)缓释微丸在犬体内的药动学.方法6只犬分别单剂量服用自制盐酸阿比朵尔缓释胶囊和市售阿比朵尔普通胶囊,剂量均为200 mg.1周后2组交叉用药.采用HPLC法,以磷酸苯丙哌林为内标测定犬绐药后不同时间的血药浓度,用以估算药动学参数和相对生物利用度.结果AH速释胶囊和缓释微丸的峰质量浓度(Cmax)分别为(1289.2±356.7)μg·L-1和(602.3±179.0)/μtg·L-1,达峰时(tmax)分别为(1.62±0.32)h和(4.6±1.3)h.缓释微丸相对于速释胶囊生物利用度为116.0%,两者制剂吸收程度等效.结论AH缓释微丸具有明显的缓释特征.     

洛伐他汀缓释片的体外释放度和生物利用度

目的:考察洛伐他汀缓释片的体内外性质,评价其缓释性能.方法:测定制剂的体外释放度,考察不同因素的影响;测定制剂在比格犬体内的血药浓度,以洛伐他汀胶囊为参比制剂,计算相对生物利用度等药动学参数.结果:制剂在pH 7.0的十二烷基硫酸钠溶液中可持续释药24 h,释放规律符合零级动力学和Higuchi方程,不同的压片压力、转篮转速对药物释放有明显影响.缓释片的相对生物利用度为(111.5±16.9)%.结论:缓释片与参比制剂在吸收程度方面具有生物等效性,在吸收速度方面差异有显著性,具有良好的缓释性能.     

国产与进口替莫唑胺胶囊在Beagle犬体内的生物等效性研究

目的:研究国产与进口替莫唑胺胶囊在Beagle犬体内的药动学及生物等效性。方法:6只Beagle犬随机交叉单剂量口服进口替莫唑胺胶囊(参比制剂)和国产替莫唑胺胶囊(受试制剂),采用HPLC法测定犬血浆中替莫唑胺的浓度,Bapp 3.0软件计算其主要药动学数据,并进行两种制剂的等效性评价。结果:参比制剂与受试制剂的Cmax分别为(11.35±1.35)和(11.70±2.77)μg·m L-1;Tmax分别为(0.97±0.56)和(1.08±0.49)h;t1/2β分别为(1.44±0.37)和(1.43±0.24)h;AUC0~t分别为(27.34±2.30)和(28.34±7.47)μg·h·m L-1,AUC0~∞分别为(29.85±4.49)和(30.85±8.46)μg·h·m L-1。受试制剂对参比制剂的相对生物利用度为(106.1±36.1)%。结论:本实验结果表明,两种替莫唑胺胶囊在Beagle犬体内具有生物等效性。     

右旋兰索拉唑缓释胶囊在Beagle犬体内的药动学及生物等效性

目的研究右旋兰索拉唑缓释胶囊在Beagle犬体内的药动学特征及生物等效性。方法采用LC-MS/MS法测定10只Beagle犬单次和多次口服右旋兰索拉唑缓释胶囊受试制剂和参比制剂后的血药质量浓度,计算药动学参数。结果单次口服受试制剂和参比制剂后,血浆中右旋兰索拉唑的t1/2分别为(1.2±1.0)和(1.0±0.7)h,tmax分别为(2.3±1.0)和(2.6±1.1)h,ρmax分别为(2.388 6±0.639 1)和(2.348 5±0.728 6)mg·L-1,AUC0-t分别为(5.601 4±1.627 4)和(5.602 3±1.865 7)mg·h·L-1,AUC0-∞分别为(5.653 6±1.630 9)和(5.657 5±1.878 6)mg·h·L-1。以AUC0-t计算,受试制剂中右旋兰索拉唑的相对生物利用度为(101.6±8.9)%。多次口服给药后的主要药动学参数与单次口服基本一致。结论右旋兰索拉唑的药动学参数在Beagle犬体内个体差异较大,右旋兰索拉唑缓释胶囊的两种制剂生物等效。     

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.