西布曲明片在健康人体中的药代动力学与相对生物利用度

目的研究国产盐酸西布曲明片（减肥药）在健康人体的药代动力学，并评价2种制剂的生物等效性。方法用双交叉试验设计，20名健康志愿者口服国产西布曲明片剂和参比胶囊15mg，服药后0～72h内，按规定时间取血。用高效液相色谱-质谱法测定血浆中西布曲明主要代谢物N-双脱甲基西布曲明的浓度。计算主要药代动力学参数，判断其生物等效性。结果单次口服国产西布曲明片和参比胶囊后的主要药代动力学参数：AUC0-∞分别为（146．44±36．19），（155．08±46．22）h·ng·mL^-1；AUC0-71分别为（130．32±32．75），（139．41±43．50）h·ng·mL^-1；tmax分别为（3．08±1．36），（3．18±1．15）h；Cmax分别为（6．38±2．07），（6．92±2．48）ng·mL^-1；t1／2分另0为（23．15±4．68），（22．17±3．70）h；西布曲明片剂的相对生物利用度F0-n为（96．24±16．74）％。结论国产西布曲明片剂与参比胶囊具有生物等效性。     

高效液相色谱法测定人血浆中他林洛尔浓度

目的：建立测定人血浆中他林洛尔浓度的高效液相色谱一紫外检测法。方法：采用依利特Hypersil—BDSC18色谱柱（4．6mm×200mm，5μm），乙腈-10mmol·L^-1甲酸胺（20：80）为流动相，流速为1mL·min^-1，紫外检测波长为248nm。结果：他林洛尔浓度在2．1～535ng·mL^-1范围内，线性良好（r=0．9983），最低检测限1．0ng·mL^-1（S／N〉3），绝对回收率大于62．4％，符合生物样品分析要求。将建立的方法用于12名受试者单剂量口服（100mg）他林洛尔片后不同时间血药浓度的测定。受试者口服他林洛尔片后，达峰时间Tmax为（2．4±1．0）h，峰浓度Cmax为（375±131）ng·mL^-1，半衰期T1/2为（7．6±3．3）h，AUC0-48为（2586±1266）ng·h·mL^-1，AUC0-∞为（2764±1409）ng·h·mL^-1。结论：本方法快速、经济、准确、灵敏，重现性好，可用于他林洛尔血药浓度监测和药代动力学研究。     

胺碘酮与地尔硫(艹卓)控制快速心房颤动心室率的疗效观察

目的探讨胺碘酮与地尔硫[艹卓]对快速心房颤动（房颤）心室率控制的疗效和安全性。方法64例房颤患者随机分为胺碘酮组和地尔硫[艹卓]组。胺碘酮组33例，接受负荷量150mg静注后，以0．5～1．0mg／min维持静脉滴注，并据心率变化调节胺碘酮用量；地尔硫[艹卓]组用0．25mg／kg静注后，无效者120min重复应用同剂量地尔硫[艹卓]。每隔5min及每次用药前、后记录心率、血压及临床表现。结果胺碘酮组与地尔硫[艹卓]组控制心室率有效率分别为84．8％和90．3％；平均起效时间分别为（15．1±7．7）min和（8．7±4．1）min。胺碘酮组发生心动过缓2例，对心功能无影响，不良反应发生率6．1％；地尔硫[艹卓]组心动过缓3例，心功能恶化5例，不良反应发生率25．8％，二者比较，差异有统计学意义（P〈0．05）。结论胺碘酮控制心室率与地尔硫[艹卓]相比，同样有效。地尔硫[艹卓]起效迅速；但胺碘酮不良反应少，更加安全。     

高效液相色谱-荧光检测法测定萘哌地尔血药浓度及其在健康人体的药代动力学研究

目的建立测定人血清中萘哌地尔（抗高血药）的高效液相色谱-荧光检测法，研究萘哌地尔片剂在健康人体的药代动力学。方法10名健康男性志愿者单次口服萘哌地尔片剂50mg，用高效液相色谱-荧光检测法测定血清中萘哌地尔浓度，用3P87计算其主要药代动力学参数。结果在0．5～100ng·mL^-1内线性良好，日内差≤7．83％，日间差≤9．08％，回收率为98．04％～99．22％；Cmax为（97．65±16．91）ng·mL^-1；tmax为（0．53±0．13）h；t1／tKe为（3．42±0．80）h；AUC0-16为（123．64±31．98）ng·h·mL^-1。结论本方法灵敏、准确，可用于人体药代动力学研究。     

进口与国产齐多夫定胶囊在健康人体的生物等效性

目的研究国产与进口齐多夫定胶囊（抗病毒药）在健康志愿者体内的药代动力学及生物等效性。方法18例健康志愿者单剂量随机交叉口服试验药和对照药齐多夫定胶囊各200mg，用反相高效液相色谱法测定血药浓度，计算其药代动力学参数，评价2制剂的生物等效性。结果试验与参比制剂的主要药代动力学参数Cmax分别为（1．41±0．34），（1．25±0．36）μg·mL^-1；tmax分别为（0．4±0．2），（0．5±0．2）h；t1／2分别为（1．2±0．15），（1．73±0．39）h；AUC0-t分别为（1．64±0．32），（1．66±0．24）μg·h·mL^-1；AUC0-∞分别为（1．69±0．33），（1．72±0．24）μg·h·mL^-1。上述参数经统计学分析无明显差异。结论2种制剂具有生物等效性。     

阿司达莫缓释片在健康人体的药代动力学和相对生物利用度

目的研究阿司达莫缓释片（抗血栓药）在健康人体的药代动力学。方法18例健康男性志愿者随机交叉口服受试制剂（阿司达莫缓释片）或参比制剂（含双嘧达莫片200mg与阿司匹林肠溶片25mg），用高效液相色谱一紫外法测定血浆中双嘧达莫与水杨酸浓度，经DAS软件计算相对生物利用度，并进行生物等效性评价。结果①单剂量受试与参比双嘧达莫：tmax分别为（3．89±0．47），（1．69±0．42）h；Cmax分别为（1．27±0．33），（2．17±0．75）μg·mL^-1；t1／2分别为（8．40±1．92），（4．78±1．13）h；AUC0-t分别为（7．89±2．70），（8．36±3．41）μg·h·mL^-1；AUC0-∞分别为（8．99±3．12），（8．56±3．50）μg·h·mL^-1。受试与参比水杨酸：tmax分别为（2．11±0．53），（4．78±0．81）h；Cmax分别为（0．97±0．47），（0．95±0．48）μg·mL^-1；t1／2分别为（4．22±0．68），（5．46±1．09）h；AUC0-t分别为（4．06±1．65），（3．98±1．73）μg·h·mL^-1；AUC0-t分别为（4．06±1．65），（3．98±1．73）μg·h·mL^-1；AUC0-∞分别为（4．13±1．65），（4．15±1．79）μg·h·mL^-1。②多剂量受试与参比双嘧达莫：tmax分别为（3．94±0．80），（1．90±0．58）h；Cssmax分别为（1．23±0．38），（1．31±0．32）μg·mL^-1；AUCss分别为（7．48±2．72），（7．73±2．62）μ·h·mL^-1。单次给药后，生物利用度双嘧达莫为（97．2±16．7）％、水杨酸为（103．1±9．8）％；多次给药后，双嘧达莫的生物利用度为（96．7±13．4）％。结论2制剂在体内生物作用等效。     

盐酸纳曲酮片在健康人体的药代动力学和相对生物利用度

目的研究进口与国产盐酸钠曲酮（解毒药）在健康人体的生物等效性。方法20名健康志愿者交叉口服受试制剂或参比制剂50mg。用HPLC-MS测定其血药浓度，计算主要药代动力学参数及相对生物利用度，判断其是否有生物等效性。结果在0．10-41．08ng·mL^-1，线性关系良好，最低定量限为0．10ng·mL^-1。受试制剂和参比制剂的药代动力学参数：t1/2分别为（3．59±0．49），（3．76±0．48）h；tmax分别为（1．0±0．4），（1．0±0．5）h；Cmax分别为（16．30±8．31），（15．83±7．17）ng·mL^-1。以AUC0-16计算受试片剂的相对生物利用度为（102．2±13．9）％。2制剂的主要药代动力学参数无显著性差异。结论2种制剂具有生物等效性。     

氟罗沙星胶囊在健康人体的药代动力学和生物等效性

目的研究氟罗沙星胶囊（第3代喹诺酮类抗生素）的药代动力学并评价2种国产制剂的生物等效性。方法用随机分组自身对照方法，20例健康男性志愿者单次口服氟罗沙星参比和受试制剂200mg后，用高效液相色谱一紫外法测定血浆中氟罗沙星浓度，用3P97软件进行药代动力学参数的计算及生物等效性评价。结果2种氟罗沙星胶囊在健康志愿者体内的药一时曲线均符合一室开放模型，参比与受试制剂的主要药代动力学参数：Cmax分别为（2．90±0．55），（2．94±0．53）μg·mL^-1；tmax分别为（1．09±0．44），（1．09±0．38）h；t1/2分别为（12．64±1．71），（13．14±1．78）h；AUC0-t分别为（29．86±3．40），（32．81±4．54）μg·h·mL^-1；AUC0-∞分别为（32．54±3．90），（35．70±5．53）μg·h·mL^-1。受试制剂的相对生物利用度为（110．1±11．4）％。结论氟罗沙星的受试制剂和参比制剂在健康人体有生物等效性。     

盐酸二甲双胍肠溶胶囊人体药动学及生物等效性

采用双周期随机交叉给药法，比较T20名健康男性志愿者单剂量口服盐酸二甲双胍肠溶胶囊500mg后的药物动力学，并与参比制剂进行生物等效性评价。采用LC—MS／MS法测定血浆药物浓度，结果表明，受试制剂和参比制剂的主要药物动力学参数为：Cmax为（533．0±203．2）和（549．5±210．6）ng／ml，tmax为（3．6±1．5）h和（3．5±1．7）h，AUC0→24h为（3330．5±1027．3）和（3468．4±1139．1）h·ng·ml^-1，AUC0→∞（3405．7±1046．7）和（3553．2±1155．7）h·ng·ml^-1。受试制剂的相对生物利用度为（97．8±12．2）％，表明两种制剂生物等效。     

卵磷脂络合碘片的人体药动学研究

目的：研究健康受试者单剂量口服卯磷脂络合碘片的人体药动学。方法：18名健康受试者分别口服单剂量4．5mg卵磷脂络合碘片，以催化光度法测定血药浓度，用Das2．0软件计算药动学参数。结果：口服卵磷脂络合碘片4．5mg后，主要药动学参数分别为：Cmax（34．6±12．7）ng·mL^-1，Tmmax（1．2±0．3）h，t1/2（5．8±3．2）h，AUC0-48（171．9±49．4）ng·mL^-1，AUC0-∞（194．4±60．2）ng·mL^-1，MRT0-48（6．1±1．2）h，MRT0-∞（8．5±3．7）h．。结论：建立的催化光度法测定仪器简单，灵敏度高。可用于药动学参数的测定。     

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.