阿奇霉素分散片人体相对生物利用度及药动学

目的:研究受试制剂阿奇霉素分散片与参比制剂人体相对生物利用度及药动学.方法:20名健康受试者自身交叉单剂量口服阿奇霉素分散片受试制剂和参比制剂各500 mg,定时取血,用微生物法测定血药浓度.结果:受试制剂阿奇霉素分散片与参比制剂的血药浓度-时间曲线基本一致,符合一级吸收二房室模型.受试制剂与参比制剂的主要药动学参数分别为:消除半衰期t1/2β:(36.1±7.8)h,(39.9±10.3)h;Tmx:(2.4±0.5)h,(2.4±0.5)h;Cmax:(413.0±72.5)μg·L-1,(404.0±69.5)μg·L-1.药动学参数经配对t检验,P＞0.05,差异均无显著性.两种制剂的药时曲线下面积AUC0→t平均值分别为:受试制剂分散片(9 806±1 308)μg·L-1·h-1,参比制剂(9 949±1 395)μg·L-1·h-1;受试制剂分散片的相对生物利用度为:(99.0±9.0)%.结论:统计学结果表明,受试制剂阿奇霉素分散片与参比制剂生物等效.     

非洛地平缓释片在健康人体内的药动学研究

目的:建立用于测定人血浆中非洛地平的LC-MS/MS法,研究非洛地平缓释片在健康人体内的药动学.方法:色谱条件:色谱柱为Agilent HC C18柱(150 mm ×4.6 mm,5μm),流动相为甲醇-0.05％甲酸溶液(83:17)和乙腈,线性梯度洗脱,流速为1 mL· min-1,柱温为35℃,进样量为20 μL;质谱条件:电喷雾正离子化,三重四极杆质谱多反应监测模式,非洛地平和内标西尼地平的选择性反应检测离子分别为m/z 384.0→338.1和m/z 493.0→375.1.20名中国成年健康男性受试者随机分为2组,采用自身双交叉试验设计,先单剂量空腹口服5 mg非洛地平缓释片受试制剂或参比制剂,并于不同时间点采集肘静脉血(0～72 h);随后进行多剂量试验,2组受试者连续8d服用受试制剂或参比制剂(5 mg,qd),于第8d服药后按单剂量试验中的采血方案在各时间点采集血样.对采集的所有血样进行血浆分离及处理,采用建立的LC-MS/MS法测定非洛地平血药浓度,用DAS2.0软件计算药动学参数.结果:分析方法学评价:非洛地平血药浓度在0.025～10 μg·L-1范围内线性关系良好,方法精密度、准确度和回收率均良好,且无明显基质效应.药动学评价:受试制剂单剂量和多剂量给药后的主要药动学参数Cmax分别为(1.29±0.49)和(1.26±0.48) mg·L-1以及AUC0-72 h分别为(21.2±5.0)和(20.1±7.9)mg·h·L-1,均与参比制剂无显著差异(P＞0.05);与单剂量给药相比,2种制剂经多剂量给药后的稳态Cmax、Tmax和AUC值均无显著性变化.结论:建立的LC-MS/MS法专属、灵敏、准确,可满足非洛地平缓释片的药动学研究要求;非洛地平缓释片多剂量给药,不会导致体内药物蓄积.     

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。     

液-质联用测定氯诺昔康国产与进口片剂的人体生物等效性

目的:建立液相色谱-串联质谱法(LC-MS/MS)的检测方法,评价受试与参比的氯诺昔康片在健康人体的生物等效性。方法:采用随机、开放、双周期交叉试验设计,20名中国男性健康受试者单剂量口服受试制剂和参比制剂8 mg后不同时间点的血浆样本经甲醇直接沉淀蛋白,应用LC-MS/MS法测定氯诺昔康的血药浓度,利用DAS 2.0软件计算药动学参数,并进行生物等效性评价。结果:受试制剂和参比制剂的药动学参数如下:Cmax分别为(782.0±275.1)μg·L-1和(823.4±256.1)μg·L-1,tmax分别为(2.8±1.4)h和(2.6±1.4)h,t1/2分别为(3.5±1.2)h和(3.3±0.8)h,AUC0-24 h分别为(4 545±1 714)μg.h.L-1和(4 516±2 054)μg·h.L-1,相对生物利用度为(103.8±15.0)%。结论:建立的分析方法灵敏、简便、准确,统计结果表明受试制剂和参比制剂生物等效。     

两种氯吡格雷片在健康人体内的生物等效性

目的研究两种氯吡格雷制剂药动学及在健康人体生物等效性。方法按双周期交叉试验设计,48例健康男性受试者单剂量口服氯吡格雷受试制剂和参比制剂75 mg后,采用液相质谱-串联质谱(LCMS/MS)的方法测定血浆中氯吡格雷的浓度,经DAS2.0软件统计,计算药动学参数及相对生物利用度,判定两制剂是否等效。结果受试制剂和参比制剂的主要药动学参数,氯吡格雷的t1/2分别为(3.31±2.34)和(4.02±2.98)h,ρmax分别为(2.15±5.27)和(1.66±2.91)μg·L-1,tmax分别为(0.79±0.36)和(0.90±0.47)h,AUC0-t(2.29±3.61)和(2.44±3.96)μg·h·L-1。以氯吡格雷成分计,相对生物利用度为(113.8±90.6)%。结论两种氯吡格雷制剂具有生物等效性。     

吉米沙星片在健康人体中的生物等效性

目的评价国产(受试制剂)及进口(参比制剂)吉米沙星片在中国健康人体内的生物等效性。方法 22名男性健康受试者采用随机交叉设计试验,用高效液相色谱-紫外检测(HPLC-UV)法测定单剂量口服吉米沙星片受试制剂和参比制剂各320 mg后吉米沙星的血药质量浓度。所得数据经WinNonlin4.2药动学计算程序处理计算主要药动学参数,并进行双单侧t检验确定是否生物等效。结果吉米沙星参比制剂与受试制剂主要药动学参数:tmax分别为(1.1±0.4)h和(1.0±0.5)h;ρmax分别为(2.39±0.58)mg·L-1及(2.54±0.76)mg·L-1;t1/2分别为(7.2±1.2)h及(7.5±1.6)h;AUC0-36 h分别为(12.88±2.29)mg·h·L-1和(13.07±2.83)mg·h·L-1;AUC0-∞分别为(13.57±2.32)mg·h·L-1和(13.82±2.87)mg·h·L-1;吉米沙星片受试制剂相对于参比制剂的生物利用度为(102.5±17.9)%,统计学结果表明受试制剂与参比制剂的tmax、ρmax、t1/2、AUC均无显著差异(P>0.05)。结论本文HPLC-UV法样品处理简便迅速,方法灵敏度高,可准确测定吉米沙星血药浓度。测定的国产吉米沙星片与进口品具有生物等效性。     

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。     

左炔诺孕酮片在健康人体内的生物等效性研究

目的 研究中国健康受试者单次口服左炔诺孕酮片的生物等效性.方法 将20名健康女性受试者随机分为2组,分别单剂量口服给予受试制剂或参比制剂各1.5 mg,洗脱1周后,交叉给药,用LC-MS/MS法测定血药浓度,计算两者的主要药动学参数和相对生物利用度.结果 口服受试制剂或参比制剂后,血浆中左炔诺孕酮的主要药动学参数:Tmax分别为1.79±0.17、1.83 ±0.16 h,Cmax分别为20.93±2.89、19.74 ±-3.13 ng·mL-1,以AUC0→∞计,受试制剂的相对生物利用度为102.2％±30.1％.结论 受试制剂与参比制剂在健康受试者体内具有生物等效性.     

拉米夫定片人体生物等效性评价

目的评价拉米夫定片在健康人体的生物等效性。方法健康志愿者22例,随机2×2交叉,单剂量口服受试和参比制剂拉米夫定片100mg,洗脱期为1周。采用LC．MS／MS法测定血药浓度,并用DAS药动学软件进行参数计算及评价2种制剂的生物等效性。结果单剂量口服受试和参比制剂后,血浆中拉米夫定的主要药动学参数：pmax分别为（881．44-236．8）和（985．0±292．4）μg·L-1,tmax分别为（O．989±0．323）和（1．0344-0．651）h,t1／2分别为（2．889±0．622）和（2．820±0．368）h,AUc-t分别为（3435±627．7）和（3504±506．7）μg·h·L-1,AUC0→∞分别为（3529±630．9）和（3592±519．4）μg·h·L-1,受试制剂与参比制剂的人体相对生物利用度（F）是（98．45±13．50）％。结论拉米夫定片受试制剂与参比制剂具有生物等效性。     

伊曲康唑胶囊的人体生物等效性研究

目的 研究两种伊曲康唑胶囊在健康人体的生物等效性.方法 18例健康受试者采用双周期交叉试验,单剂量口服200 mg受试制剂和200 mg参比制剂后,用HPLC法测定血清中伊曲康唑的浓度.计算主要药动学参数,并对两种制剂进行生物等效性评价.结果 受试制剂和参比制剂的主要药动学参数:t1/2分别为22.4±4.4、23.3±4.2 h;Cmax为318.50±106.97、328.15±98.20μg·L-1;Tmax为3.00±0.50、3.30±0.80 h;AUCo-t为4.700±1.766、5.191±1.456 mg·h·L-1;AUCo-∞为5.271±2.139、5.840±1.579 mg.h·L-1.受试制剂的相对生物利用度为89.3%±16.2%.结论 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.

     

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.     

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.     

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.     

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.     

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.