缬沙坦氨氯地平片在健康受试者中的生物等效性研究

目的 评价缬沙坦氨氯地平片受试制剂和参比制剂在健康受试者中的生物等效性。方法 试验为单中心、单剂量、随机、开放,其中空腹试验为三周期、三序列、三交叉设计,餐后试验为两周期、两序列、双交叉设计。空腹和餐后试验受试者每周期口服缬沙坦氨氯地平片(每片含缬沙坦80 mg和氨氯地平5 mg)1片。采用超高效液相色谱串联质谱法(UPLC-MS/MS)测定血浆中缬沙坦和氨氯地平的浓度,选择Phoenix WinNonlin 8.2,以非房室模型计算2种成分的主要药代动力学参数,并评价受试制剂和参比制剂的生物等效性。结果 空腹条件下,运用平均生物等效性(ABE)方法计算得到缬沙坦C_max、AUC_0-t和AUC_0-∞的个体内标准差(S_WR)均大于0.294,故采用参比制剂标度的平均生物等效性(RSABE)方法评价。结果显示,受试制剂中缬沙坦C_max、AUC_0-t、AUC_0-∞经对数转换后的几何均值比(GMR)的90%可信区间均在参比制剂的80.00%～...     

盐酸克林霉素胶囊随机开放两周期两交叉的人体生物等效性试验

目的 研究健康人群在空腹和餐后单剂量口服盐酸克林霉素胶囊受试制剂和参比制剂是否具有生物等效性(BE)。方法 采用随机、开放、单剂量、单中心、自身交叉设计,液相色谱串联质谱(LC-MS/MS)法测定健康受试者空腹(n=24)或餐后(n=24)给药后血浆中克林霉素的药物浓度,使用Phoenix WinNonlin软件(Certara USA Inc, 7.0)计算药动学参数,使用SAS 9.2软件进行生物等效性评价。结果 空腹生物等效性(BE)试验：24名健康受试者分别单次空腹服用克林霉素受试制剂和参比制剂0.15 g后,Cmax、AUC0-t及AUC0-∞的几何均值的比值分别为92.29%,95.32%和95.59%,90%CI分别为84.12%～101.27%,90.14%～100.79%和90.49%～100.98%,均落在等效区间80.00%～125.00%;餐后生物等效性(BE)试验：24名健康受试者分别高脂餐后服用受试制剂和参比制剂0.15 g后,Cmax、AUC0-t及AUC0-∞的几何均值的比值分别为95.79%,100.92%和101.65%,90%CI分别为87.75%...     

盐酸西替利嗪片人体生物等效性试验

目的 评价健康受试者空腹和餐后条件下单剂量服用盐酸西替利嗪片受试制剂和参比制剂是否具有生物等效性。方法 采用随机、开放、单剂量、自身交叉设计,液质联用（LC-MS/MS）法测定健康受试者空腹或餐后给药后血浆中西替利嗪的药物浓度,使用Phoenix Winnonlin 8.0软件计算药动学参数,使用SAS 9.4软件进行生物等效性评价。结果 空腹BE试验：24名健康受试者分别单次空腹服用受试制剂和参比制剂10 mg后,Cmax、AUC0-t、AUC0-∞几何均数的比值分别为100.18%、96.37%、96.00%,其90%置信区间分别为95.72% ~ 14.84%、92.37% ~ 100.55%、91.77% ~ 100.42%,均落在等效区间80.00% ~ 125.00%之间;餐后BE试验：22名健康受试者分别单次餐后服用受试制剂和参比制剂10 mg后,Cmax、AUC0-t、AUC0-∞几何均数的比值分别为103.98%、102.19%、101.58%,其90%置信区间分别为98.31% ~ 109.97%、98.33% ~ 106.20%、98.07% ~ 105.20%,均落在等效区间80.00% ~ 125.00%之间。结论 两种制剂对于空腹和餐后条件下的健康成年受试者具有生物等效性。     

阿普斯特片在健康受试者中的生物等效性研究

目的 评价阿普斯特片受试制剂和参比制剂在健康受试者中的生物等效性。方法 采用单中心、随机、开放、两制剂、两序列、两周期交叉设计。受试者空腹或餐后口服30 mg阿普斯特片受试制剂或参比制剂,清洗期为7 d。采用HPLCMS/MS法测定人血浆中阿普斯特,采用Phoenix WinNonlin软件(8.2版本)进行药动学参数的计算,根据每个受试者的个体血药浓度,采用非房室模型计算阿普斯特的药动学参数。结果 阿普斯特片空腹和餐后试验受试制剂和参比制剂的主要药动学参数峰浓度(C_max)、药时曲线下面积(AUC0-t)、AUC0-∞的几何均值比的90%置信区间均落在80.00%～125.00%等效区间。结论 阿普斯特片受试制剂和参比制剂在健康受试者空腹和餐后状态下具有生物等效性。     

头孢克肟颗粒在中国健康人体内的生物等效性研究北大核心CSCD

目的研究国产头孢克肟颗粒与参比制剂在中国健康人体内空腹和餐后状态下的生物等效性。方法采用随机、开放、单次给药,两制剂、两周期、自身交叉的平均生物等效性研究设计,空腹试验和餐后试验分别入组24例成年健康受试者。受试者按随机表分为2组,每周期分别口服受试制剂或参比制剂50 mg。用液相色谱-串联质谱(LC-MS/MS)法检测血浆中头孢克肟的浓度。结果空腹试验,受试制剂与参比制剂的C_(max)、AUC_(0-t)和AUC_(0-∞)几何均值比(90%置信区间,90%CI)分别为103.25%(98.47%~108.26%)、102.75%(98.18%~107.53%)和102.91%(98.33%~107.71%),完全落在80.00%~125.00%。餐后试验,受试制剂与参比制剂的C_(max)、AUC_(0-t)和AUC_(0-∞)的几何均值比(90%CI)分别为98.19%(91.57%~105.28%)、98.94%(92.87%~105.40%)和98.69%(92.77%~104.98%),完全落在80.00%~125.00%。结论在空腹及餐后状态下,中国健康成年受试者单次口服国产头孢克肟颗粒与参比制剂具有生物等效性。     

缬沙坦片在中国健康受试者体内的生物等效性研究

目的 在健康受试者中空腹及餐后情况下评价缬沙坦片的吸收速度和吸收程度，评价受试制剂和参比制剂是否具有生物等效性。方法 采用开放、单剂量、随机、3周期、部分重复交叉设计的生物等效性研究。每周期口服受试制剂或参比制剂40 mg。应用液相色谱-串联质谱（LC-MS/MS）方法测定血浆中缬沙坦浓度，使用WinNonlin^® 6.4软件，计算药动学参数，评价两种制剂的生物等效性。结果 空腹组受试制剂与参比制剂药时曲线下面积（AUC_0～t）和AUC_0～∞的几何均数比值分别为100.39%和100.35%，90%置信区间（90% CI）分别为91.91%～109.67%和92.11～109.32%，完全落入80.00%～125.00%内。达峰浓度（C_max）几何均值比值为97.61%，落在80.00%～125.00%内。餐后组受试制剂与参比制剂C_max、AUC_0～t和AUC_0～∞的几何均数比值分别为107.85%、105.03%和105.06%，90% CI分别为97.81%～118.92%、99.27%～111.12%和99.42%～111.02%，完全落入80.00%～125.00%内。结论 缬沙坦片受试制剂和参比制剂在空腹和餐后状态下均具有生物等效性。     

氢溴酸伏硫西汀片在中国健康受试者中生物等效性研究

摘要：目的:评价成都康弘药业集团股份有限公司生产的氢溴酸伏硫西汀片与参比制剂H.Lundbeck A/S公司生产的氢溴酸伏硫西汀片（心达悦?）在中国健康受试者中的生物等效性,为临床使用和一致性评价提供依据。方法:采用单中心、随机、开放、单次给药、两周期、两制剂、两交叉设计,将空腹给药和餐后给药的受试者均随机分成2组,每组受试者分别口服氢溴酸伏硫西汀片受试制剂和参比制剂10 mg,采血至服药240 h,采用HPLC-MS/MS法测定血浆中伏硫西汀的浓度。采用Phoenix WinNonlin （版本号：8.2）计算药动学参数,计算每个受试者的个体血药浓度,采用非房室模型（NCA）计算伏硫西汀的药动学参数,并对两种制剂进行生物等效性评价;在试验期间对受试者的临床观察指标进行相关的安全性评价。结果:受试者空腹口服受试制剂和参比制剂后,血浆伏硫西汀的主要药动学参数分别为：Cmax（3.935±1.061）和（4.003±0.915）ng·min-1;AUC0-t（308.23±107.51）和（305.74±115.16）ng·h·ml-1;AUC0-∞（373.42±180.60）和（372.22±207.42）ng·h·ml-1。受试者餐后口服受试制剂和参比制剂后,血浆伏硫西汀的主要药动学参数分别为：Cmax（3.862±0.985）和（3.771±0.619）ng·ml-1;AUC0-t（320.39±121.81）和（313.80±108.26）ng·h·ml-1;AUC0-∞（394.04±200.91）和（379.18±170.80）ng·h·ml-1。受试制剂与参比制剂的Cmax、AUC0-t、AUC0-∞经对数转换后几何均值比的90%置信区间均在80.00%～125.00%范围内,符合生物等效性要求。本试验中无严重或重度（常见不良反应事件评价标准CTCAE≥3级）不良事件发生。结论:氢溴酸伏硫西汀片受试制剂与参比制剂具有生物等效性,在健康受试者中安全、耐受。     

反相高效液相色谱法研究缬沙坦分散片人体生物等效性

目的研究缬沙坦分散片在人体内的相对生物利用度,与参比制剂(缬沙坦胶囊)进行比较,确定其是否具有生物等效性。方法20名健康受试者单剂量随机交叉口服受试制剂80mg和参比制剂80mg后,用HPLC-荧光法测定血浆中缬沙坦的浓度。以参比制剂为标准对照,用面积法估算受试制剂的相对生物利用度。结果缬沙坦分散片的Tmax=1.8±0.7h,Cmax=3142.02±931.93ng/(mL·h),AUC0-t=4267.25±1763.96ng/mL·h,方差分析结果表明,受试制剂和参比制剂间的AUC0-96、Cmax、Tmax没有显著性差异(P>0.05)。结论本法灵敏、简便、准确度和精密度高。受试制剂与参比制剂具有生物等效性,且受试制剂的达峰时间早于参比制剂,最大药物浓度大于参比制剂。     

双嘧达莫片在健康人体生物等效性研究

目的 研究健康受试者空腹和餐后条件下单剂量口服双嘧达莫片受试制剂和参比制剂的生物等效性。方法 用单剂量、随机、开放、自身交叉设计,用液相色谱串联质谱(LC-MS/MS)法测定给药后血浆中双嘧达莫的药物浓度,用Phoenix WinNonlin 8.0软件进行药代动力学参数计算,用SAS 9.4软件进行生物等效性评价。结果 空腹生物等效性试验：37例健康受试者空腹单次口服双嘧达莫受试制剂和参比制剂25 mg后,C_max、AUC_0-t及AUC_0-∞的几何均值的比值分别为107.44%,101.76%和101.91%,90%置信区间(CI)分别为98.11%～117.67%,94.59%～109.47%,94.99%～109.34%,均值均落在等效置信区间80.00%～125.00%;餐后生物有效性试验：38例健康受试者高脂餐后单次口服受试制剂和参比制剂25 mg后,C_max、AUC_0-t及AUC_0-∞的几何均值的比值分别为101.19%,102.41%和102...     

盐酸曲美他嗪片的生物等效性研究

目的:研究盐酸曲美他嗪片的人体生物利用度和生物等效性。方法:22名男性健康受试者,随机双交叉口服剂量为20mg的受试制剂和参比制剂,采用LC-MS法测定血浆中盐酸曲美他嗪的浓度,使用DAS2.1.1软件对各药代动力学参数进行计算,同时对其生物等效性进行统计分析。结果:22名健康受试者服用20mg盐酸曲美他嗪片受试制剂和参比制剂的Cmax分别为(42.64±17.00)ng/ml和(41.32±19.66)ng/ml,Tmax分别为(2.2±1.5)h和(2.7±1.7)h,AUC0-t分别为(418.1±177.4)ng·h/ml和(397.8±147.1)ng·h/ml,AUC0-∞分别为(428.5±181.1)ng·h/ml和(407.9±150.5)ng·h/ml,t1/2分别为(5.9±1.6)h和(5.6±1.3)h。受试制剂中曲美他嗪Cmax的90%置信区间为参比制剂的100.1%～111.1%,AUC0-t的90%置信区间为参比制剂的97.0%～111.9%,AUC0-∞的90%置信区间为参比制剂的96.9%～111.9%。以AUC0-t计算,受试制剂中曲美他嗪的相对生物利用度为(105.9±18.6)%。结论:两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.     

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.     

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.