液-质联用法考察单硝酸异山梨酯片的人体生物等效性

目的：建立液-质联用法（LC-MS／MS）的检测方法，评价受试与参比的单硝酸异山梨酯片在健康人体的生物等效性。方法：健康志愿者20名，随机交叉试验设计，单剂量口服受试或参比制剂，给药剂量均为20mg，应用LC-MS／MS法测定各受试者给药后不同时间点的血药浓度，计算药动学参数，应用BAPP 2．0软件进行生物等效性评价。结果：受试与参比制剂的药动学参数如下，AUC0-24分别为（3．4±0．6）mg·h·L^-1、（3．3±0．7）mg·h·L^-1，AUC0-∞分别为（3．6±0．7）mg·h·L^-1、（3．5±0．7）mg·h·L^-1；tmax分别为（1．2±0．9）h、（1．0±0．6）h；Cmax分别为（464．9±108．2）μg·L^-1、（433．6±115．3）μg·L^-1；t1／2分别为（5．4±0．7）h、（5．5±0．9）h。单硝酸异山梨酯片的相对生物利用度为（106．0±16．0）％，主要药动学参数经统计学分析无显著性差异。结论：受试与参比制剂具有生物等效性。     

葛根素前体脂质体药动学和生物利用度研究

目的：建立高效液相色谱法测定血中葛根素的浓度，研究葛根素前体脂质体的药动学和生物利用度。方法：以愈风宁心片为对照品，3P37药动学软件处理数据，进行了药动学和生物利用度实验。结果：葛根素前体脂质体口服tmax，Cmax，CL（s），AUC分别为（2．18±0．27）h，（1．12±0．21）mg·L^-1，（10．1±2．2）L·h^-1，（7．8±1．7）mg·h·L^-1，愈风宁心片口服tmax，Cmax，CL（s），AUC分别为（1．52±0．35）h，（0．98±0．17）mg·L，（16．5±4．6）L·h^-1，（4．8±1．4）mg·h·L^-1。葛根素前体脂质体的相对生物利用度为145．6％。结论：葛根素前体脂质体血药浓度达峰时间相对滞后，达峰浓度提高，清除速率降低，葛根素前体脂质体生物利用度显著高于对照品。     

氟氯西林钠胶囊在健康人体的生物等效性

目的研究氟氯西林钠胶囊（青霉素类抗生素）的相对生物利用度并评价其生物等效性。方法用随机交叉给药方法，20名男性健康志愿者分别口服单剂量试验制剂和参比制剂的氟氯西林钠500nag；用高效液相色谱法测定血浆中浓度，计算2者的药代动力学参数及相对生物利用度。结果单次口服氟氯西林钠试验制剂和参比制剂500mg后的主要药代动力学参数：AUC01-10分别为（31．06±14．81），（33．13±15．97）nag·h·L^-1；AUC0-∞分别为（31．67±14．76），（33．79±16．01）mg·h·L^-1；Cmax分别为（13．61±9．06），（14．90±8．29）mg·L^-1；tmaz分别为（0．99±0．26），（0．85±0．32）h；t1/2分别为（1．79±0．50）和（1．84±0．33）h。受试制剂的相对生物利用度为（96．8±29．9）％。结论2种制剂具有生物等效性。     

氨咖黄敏胶囊中对乙酰氨基酚和咖啡因的人体药动学

目的研究氨咖黄敏胶囊中对乙酰氨基酚和咖啡因的人体药动学。方法本试验采用HPLC法测定了18名健康男性受试者口服氨咖黄敏胶囊后不同时刻血浆中对乙酰氨基酚和咖啡因的浓度，用31：97软件拟合房室模型并求出主要药动学参数。结果受试者口服含对乙酰氨基酚750mg和咖啡因45mg的氨咖黄敏胶囊制剂后，血浆中对乙酰氨基酚的tmax为（1．03±0．76）h，ρmax为（12．00±3．10）mg·L^-1，t1/2为（4．33±1．18）h，用梯形法计算AUC0→t为（52．51±16．81）mg·h·L^-1，AUC0→∞为（54．34±17．72）mg·h·L^-1；血浆中咖啡因的tmax为（0．89±0．50）h，ρmax为（1．290±0．379）mg·L^-1，t1/2为（5．37±2．15）h，用梯形法计算AUC0→t为（7．19±3．03）mg·h·L^-1，AUC0-∞。为（8．26±3．69）mg·h·L^-1。结论对乙酰氨基酚在人体内符合二房室模型，咖啡因在人体内符合一房室模型。     

灯盏花素分散片人体生物等效性研究

目的：以灯盏花素普通片为对照,研究灯盏花素分散片在健康人体内的相对生物利用度和生物等效性。方法：20名健康成年男性志愿者采用随机分组、自身交叉对照试验设计,用LC-MS法测定血浆中灯盏乙素苷元,线性范围为0.013~3.32μg.mL-1;平均回收率89.7%-100.5%,日内和日间精密度均小于12.0%。结果：灯盏花素分散片和普通片的主要药动学参数：tmax：（7.1±2.2）h和（6.6±1.9）h;Cmax：（0.87±0.37）mg.L-1和（1.0±0.44）mg.L-1;AUC（0-24h）：（4.68±1.53）mg·h·L^-1和（5.08±1.50）mg·h·L^-1;AUC（0-∞）：（4.78±1.55）mg·h·L^-1和（5.18±1.54）mg·h·L^-1.h;t1/2：（4.36±2.07）h和（4.09±1.35）h。以AUC（0-24h）计算的受试制剂的相对生物利用度为（93.1±16.9）%。结论：两种制剂的Cmax和AUC（0-24h）经方差分析和双单侧t检验其结果生物等效。     

枸橼酸他莫昔芬缓释片在健康人体的生物等效性

目的评价2种枸橼酸他莫昔芬制剂（抗肿瘤药）在健康人体的生物等效性。方法用双周期自身随机交叉试验设计。20名健康男性志愿者单剂量口服试验制剂或参比制剂，血浆样品用高效液相色谱-串联质谱测定，以内标法计算血药浓度。结果枸橼酸他莫昔芬受试制剂及参比制剂Cmax分别为（28．02±18．05），（44．43±13．53）μg·L^-1；tmax分别为（7．35±2．30），（4．30±0．92）h；t1/2（ke）分别为（130．25±49．49），（120．87±34．22）h；AUC0-tn分别为（3．14±1．09），（3．42±1．16）mg·h·L^-1；AUC0-∞分别为（3．44±1．20），（3．69±1．31）mg·h·L^-1；试验制剂枸橼酸他莫昔芬缓释片的相对生物利用度F0-tn、F0-∞分别为（92．79±16．97），（94．79±15．78）％。结论试验制剂和参比制剂具有生物等效性；但前者Cmax有所降低，tmax有所延长，表现出明显的缓释特征。     

普卢利沙星片在健康人体的药代动力学

目的评价国产盐酸普卢利沙星片（第4代喹诺酮类抗生素）在健康人体的药代动力学。方法10名健康志愿者单剂量和多剂量口服国产盐酸普卢利沙星片200mg，用液相色谱一串联质谱法测定血药浓度，用Winnonlin计算药代动力学参数。结果单剂量和多剂量给药后，Cmax 分别为（1．39±5．10），（1．67±0．23）mg·L^-1；tmax分别为（0．93±0．37），（1．07±0．43）h；tl／2ke分别为（6．74±1．09），（7．26±0．53）h；AUC0-x分别为（6．64±1．68），（11．82±1．32）mg·h·L^-1，多剂量AUC0-r为（8．68±0．79）mg·h·L^-1。结论每日2次，连续口服国产盐酸普卢利沙星片11次后，体内有一定蓄积。     

吲达帕胺缓释胶囊人体药动学和生物等效性试验

目的：研究吲达帕胺试验制剂（缓释胶囊）和参比制剂（片剂）的人体药动学和生物等效性。方法：20名健康志愿者按随机双周期交叉试验方案设计，分别口服受试制剂（吲达帕胺缓释胶囊）和参比制剂（吲达帕胺片）1．5mg，采用液相色谱串联质谱（LC／MS／MS）分析方法测定吲达帕胺的全血浓度。利用DAS程序计算其药动学参数和评价生物等效性。结果：吲达帕胺试验胶囊和参比片剂的主要药动学参数：Cmax分别为（38．2±14．6），（41．1±7．6）ug·L^-1；Tmax分别为（11．4±3．3），（8．0±3．0）h；t1/2kc分别为（19．7±2．3），（19．7±2．8）h；AUC0-96分别为（1252．8±404．3），（1267．5±278．8）ug·h·L^-1；AUC0-∞分别为（1308．0±424．6），（1319．4±292．4）ug·h·L^-1；受试制剂相对生物利用度为（97．5±14．5）％。结论：经方差分析及双单侧t检验结果显示，受试的吲达帕胺胶囊与参比的吲达帕胺片具有生物等效性。     

LC-MS/MS法测定克拉霉素血浓度及药动学

目的建立测定人血浆中克拉霉素的LC-MS／MS法，研究市售克拉霉素胶囊在人体的药动学特点。方法以罗红霉素为内标，取血浆样品0．3mL经蛋白沉淀后，以甲醇-水（1％甲酸溶液）-乙腈=（80：10：10）为流动相，用C18柱分离，采用电喷雾离子源，正离子方式检测，扫描方式为多反应检测（MRM）。结果克拉霉素线性范围为10～2500μg·L^-1，日内、日间RSD均〈3．5％。应用此法研究18名健康受试者单剂量口服250mg克拉霉素市售胶囊的药动学参数tmax、ρmax、t1/2、AUC0→t和AUC0→∞，其值分别为（1．95±0．71）h、（949±399）μg·L^-1、（4．79±0．84）h、（5600±1753）μg·h·L^-1、（5766±1776）μg·h·L^-1。结论该法用于人体药动学的研究具有专属、快速、灵敏等特点。     

阿奇霉素片在健康人体的相对生物利用度和药代动力学

目的研究阿奇霉素片（大环内酯类抗生素）在健康人体的相对生物利用度及药代动力学。方法19名健康受试者自身交叉单剂量口服阿奇霉素片受试制剂和参比药物各500mg后，用微生物法测定用药后不同时间血药浓度。结果2制剂的血药浓度-时间曲线基本一致，符合二房室模型，受试制剂和参比药物的药代动力学参数：t1/2β分别为（34．61±7．42），（31．16±5．28）h；tmax分别为（2．60±0．21），（2．55±0．16）h；Cmax分别为（557．15±129．57），（548．34±137．46）μg·L^-1；AUC0-tn分别为（8．45±2．29），（8．66±2．34）h·mg·L^-1；受试制剂的相对生物利用度为（99．35±19．77）％。结论受试制剂与参比药物生物等效。     

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.