2种洛伐他汀片人体药动学及生物等效性研究

目的:比较2种洛伐他汀片在健康人体内的药代动力学和生物利用度,评价2种制剂的生物等效性。方法:18名男性健康志愿者随机交叉分别单剂量口服山东罗欣药业股份有限公司研制的洛伐他汀片5片(20 mg·片~(-1))或北京万生药业有限责任公司生产的洛伐他汀片5片(20 mg·片~(-1)),采用 HPLC 测定血浆中药物浓度,通过方差分析和双向单侧 t 检验比较2种制剂的 AUC_(0→24)、C_(max)、T_(max)。结果:2种制剂的 T_(max)(h)分别为2.11±0.21和2.11±0.21,C_(max)(ng·mL~(-1))为93.73±17.42和92.67±13.98,t_(1/2)(h)分别为6.75±1.33和6.50±1.09,AUC_(0→24)(ng·mL~(-1)·h~(-1))分别为480.56±55.75和478.24±69.26,AUC_(0→∞)(ng·mL~(-1)·h~(-1))分别为555.33±69.98和543.04±76.25。结论:2种洛伐他汀片生物等效,受试制剂与参比制剂的相对生物利用度为(102.67±6.98)%。     

盐酸特拉唑嗪片人体药动学及生物等效性研究

目的:建立人血浆中特拉唑嗪药物浓度的 HPLC-UV 测定法,研究健康受试者口服盐酸特拉唑嗪受试制剂和参比制剂的生物等效性,并估算其药代动力学参数。方法:18名健康男性志愿受试者单剂量随机交叉口服2 mg 盐酸特拉唑嗪受试制剂或参比制剂,采用高效液相色谱法测定给药后不同时间血浆中特拉唑嗪的浓度,估算药动学参数,并作方差分析和双单侧 t检验。结果:受试者口服盐酸特拉唑嗪受试制剂和参比制剂后的 T_(max)分别为(1.08±0.19)h和(1.08±0.19)h,C_(max)分别为(320.49±44.82)ng·mL~(-1)和(316.03±45.40)ng·mL~(-1),t_(1/2)分别为(12.68±0.92)h和(12.97±1.33)h,AUC_(0→48)分别为(2648.00±316.85)ng·h·mL~(-1)和(2618.67±334.38)ng·h·mL~(-1),AUC_(0→∞)分别为(3002.46±322.25)ng·h·mL~(-1)和(2979.85±341.96)ng·h·mL~(-1)。结论:本方法操作简便,专属性强。盐酸特拉唑嗪受试制剂和参比制剂具有生物等效性。     

富马酸比索洛尔片在健康人体内的生物等效性评价

目的:建立人血浆中比索洛尔浓度的HPLC-MS测定方法,并评价国产与进口富马酸比索洛尔片的人体生物等效性。方法:18例男性健康受试者随机分成两组,分别交叉口服受试制剂和参比制剂各5mg,采用HPLC- MS法测定人血浆中比索洛尔的浓度。结果:血浆中比索洛尔的最低定量限为0.05 ng·mL~(-1),在0.05～120 ng·mL~(-1)范围内线性关系良好,批内及批间精密度RSD均小于8%。受试制剂与参比制剂的各主要药动学参数:T_(max)分别为(1.9±0.9)和(1.9±0.7)h,C_(max)分别为(20.3±3.3)和(20.6±3.3)ng·mL~(-1),t_(1/2)分别为(8.4±1.2)和(8.1±1.0)h,用梯形法计算AUC_(0～48h)分别为(244.0±38.5)和(249.5±41.0)ng·h·mL~(-1)。两种制剂的主要药动学参数C_(max)和AUC_(0～48h)经对数转换后进行方差分析及双单侧t检验,并计算90%置信区间,表明两种制剂生物等效,相对生物利用度为(98.4±10.6)%。结论:两种制剂生物等效。     

厄贝沙坦片在中国健康人体内的生物等效性研究北大核心CSCD

目的研究厄贝沙坦片在中国健康人体内的生物等效性。方法采用单中心、随机、开放、单剂量、两周期、2×2交叉试验设计,空腹试验和餐后试验中分别有32例受试者口服厄贝沙坦片受试制剂或参比制剂0.15 g。LC-MS/MS法测定给药后不同时间厄贝沙坦的血药浓度,并用Phoenix WinNonlin 7.0软件计算主要药代动力学参数,判定两制剂是否等效。结果空腹试验受试制剂和参比制剂厄贝沙坦的主要药代动力学参数:C_(max)分别为(2242.4±631.5),(2327.3±821.0)ng·mL^(-1),AUC_(0-t)分别为(9953.2±3339.6),(10218.5±2985.3)h·ng·mL^(-1),AUC_(0-∞)分别为(10201.7±3377.9),(10516.5±2995.6)h·ng·mL^(-1),T_(max)均为1.50 h;t_(1/2)分别为(12.3±5.8),(15.1±10.3)h。餐后试验受试制剂和参比制剂厄贝沙坦的主要药代动力学参数:C_(max)分别为(2691.8±663.7),(2598.8±877.1)ng·mL^(-1),AUC_(0-t)分别为(10129.8±3783.9),(9538.6±3151.8)h·ng·mL^(-1),AUC_(0-∞)分别为(10353.1±3792.3),(9720.1±3162.0)h·ng·mL^(-1),T_(max)均为1.50 h;t_(1/2)分别为(12.5±7.6),(10.3±5.2)h。受试制剂与参比制剂C_(max)、AUC_(0-t)、AUC_(0-∞)几何均值比的90%置信区间均完全落在80.00%~125.00%。结论2种厄贝沙坦片在中国健康志愿者体内具有生物等效性。     

2种恩替卡韦制剂的人体生物等效性研究

目的:研究2种恩替卡韦制剂的人体生物等效性。方法:20名健康男性志愿者随机交叉单剂量空腹口服恩替卡韦胶囊(受试制剂)与恩替卡韦片(参比制剂)0.5mg后,采用液-质联用法测定人血浆中药物浓度,并用DAS2.1.1软件计算药动学参数和生物利用度。结果:恩替卡韦受试制剂与参比制剂在人体内的主要药动学参数分别为:c_(max)(4.21±1.26)、(4.06±0.80)ng·mL~(-1),t_(max)(0.6±0.4)、(0.6±0.2)h,t_(1/2β)(29.97±4.24)、(36.36±9.14)h,AUC_(0～96h)(10.84±1.80)、(10.50±1.25)ng.h.mL~(-1),AUC_(0～∞)(11.69±1.88)、(11.82±1.54)ng.h.mL~(-1)。受试制剂相对于参比制剂的生物利用度为(103.7±16.6)%。AUC_(0～96h)的90%置信区间在等效范围内。结论:2种恩替卡韦制剂为生物等效制剂。     

2种格列齐特片在中国健康人体的生物等效性研究

目的研究2种格列齐特片在中国健康受试者的药动学和生物等效性。方法采用单中心、随机、自身交叉对照、双周期试验设计,24名健康志愿者(包括16名男性和8名女性)单剂量空腹给予80 mg(1片)格列齐特片受试制剂或参比制剂后,用高效液相色谱-串联质谱(HPLC-MS/MS)法测定血浆格列齐特浓度,计算药动学参数,进行生物等效性判定。结果格列齐特片受试制剂和参比制剂的主要药动学参数如下:tmax分别为(4.50±1.89)h和(4.21±1.61)h,Cmax分别为(5959.86±1251.32)ng·mL~(-1)和(6003.26±1357.84)ng·mL~(-1),AUC0~72分别为(100 251.84±42 195.63)ng·h·mL~(-1)和(102 778.12±46 622.56)ng·h·mL~(-1),AUC0~∞分别为(105 221.44±48 385.47)ng·h·mL~(-1)和(108 360.52±53 614.41)ng·h·mL~(-1),t1/2分别为(13.67±5.51)h和(14.05±6.16)h。受试制剂对参比制剂的相对生物利用度为(99.01±11.40)%。经对数转换后,受试制剂的Cmax、AUC0~72、AUC0~∞90%置信区间分别为95.11%~105.02%、86.33%~111.13%、86.89%~110.77%,均在参比制剂的80%~125%内。方差分析结果表明,受试制剂和参比制剂的主要药动学参数之间差异无统计学意义(P>0.05);tmax的配对Wilcoxon检验结果表明,2种药物的tmax差异无统计学意义(P>0.05);双单侧t检验结果表明,受试制剂与参比制剂为生物等效制剂。试验期间无任何不良事件发生。结论 2种格列齐特片具有生物等效性。     

洛芬葡锌那敏分散片与复方锌布颗粒在健康人体的生物等效性

目的 建立液相色谱-质谱联用法,比较洛芬葡锌那敏分散片和复方锌布颗粒(抗组胺药)的生物等效性.方法 用随机开放双周期自身交叉单剂量给药试验设计,清洗期为2周.20名健康受试者分别单次空腹口服洛芬葡锌那敏分散片(受试制剂)和复方锌布颗粒(参比制剂)(均相当于马来酸氯苯那敏4mg).以引达帕胺为内标,用ESI正离子选择性反应监测(SRM)模式测定马来酸氯苯那敏血药浓度,计算药代动力学参数及评价生物等效性.结果 以2种药物中的氯苯那敏为计,洛芬葡锌那敏分散片(受试制剂)和复方锌布颗粒(参比制剂)的C_(max)分别为(12.27±3.04),(13.47±3.52)ng·mL~(-1);t_(max)分别为(2.43±1.49),(2.10±1.07)h;AUC_(0-t)分别为(303.17±91.39),(315.58±76.78)ng·h·mL~(-1);AUC_(0-∞)分别为(355.19±120.30),(365.71±100.48)ng·h·mL~(-1);t_(1/2)分别为(24.86±5.83),(24.71±5.96)h.受试制剂相对参比制剂的生物利用度F为(99.80±41.20)%.结论 洛芬葡锌那敏分散片(受试制剂)和复方锌布颗粒(参比制剂)中马来酸氯苯那敏生物等效.     

石杉碱甲缓释片犬体内药动学研究

目的:测定石杉碱甲缓释片在杂种犬体内的药物动力学。方法:采用两制剂两周期交叉试验设计,6只杂种犬分别口服自制的石杉碱甲缓释片(2片,受试制剂)和市售石杉碱甲普通片(4片,参比制剂),各相当于石杉碱甲200μg。用HPLC法测定给药后不同时间血浆中的药物浓度,采用非隔室模型计算药动学参数。结果:受试制剂与参比制剂的t_(1/2)分别为(11.01±2.66)和(4.71±1.00)h;T_(max)分别为(9.33±1.63)和(3.00±0.92)h;C_(max)分别为(1.95±0.29)和(6.23±0.91)ng·mL~(-1),AUC_(0～t)分别为(28.29±2.03),(27.45±1.83)ng·h·mL~(-1)。受试制剂相对生物利用度为(103.06±3.72)%。结论:石杉碱甲缓释片呈现明显的缓释特征,在杂种犬体内吸收程度与参比制剂相当。     

盐酸维拉帕米迟释片及其普通片在健康人体的生物等效性

目的研究盐酸维拉帕米迟释片(抗心绞痛药)在健康人体内的药代动力学特征,并评价迟释片和普通片剂间的生物等效性。方法24名健康男性志愿受试者随机交叉单剂量口服盐酸维拉帕米迟释片(受试制剂)和普通片(参比制剂)各80 mg,采用高效液相色谱法按设计时间点采集血样进行分析测定,绘制血药浓度-时间曲线,计算相关的药代动力学参数。结果受试者口服受试制剂和参比制剂后,血浆中维拉帕米的主要药代动力学参数:t_(max)分别为(5.2±1.6)和(2.3±1.2)h;C_(max)分别为(39.0±21.0)和(36.1±13.7)ng·mL~(-1);t_(1/2)分别为(6.3±2.2)和(6.6±1.7)h;AUC_(0-t)分别为(223.6±109.9)和(210.3±92.7)ng·h·mL~(-1);AUC_(0-∞)分别为(239.8±113.2)和(225.1±95.7)ng·h·mL~(-1)。受试制剂的相对生物利用度为(113.5±42.9)%。结论盐酸维拉帕米迟释片和普通片剂之间体内生物作用等效。     

头孢克洛干混悬剂在健康志愿者体内的生物等效性

目的:评价头孢克洛干混悬剂在20名男性健康志愿者体内的生物等效性。方法:20名健康志愿者分两组,随机、交叉口服单剂量受试和参比制剂头孢克洛干混悬剂750 mg。采用高效液相色谱法测定血浆中头孢克洛浓度。用DAS软件进行药动学参数计算及生物等效性评价。结果:头孢克洛干混悬剂受试与参比制剂的t_(1/2)分别为(1.519±0.807)和(1.631±0.808)h;C_(max)分别为(5.858±1.614)和(5.850±1.715)μg·mL~(-1);T_(max)分别为(0.516±0.138)和(0.546±0.155)h;AUC_(0-6)分别为(7.184±1.919)和(7.133±1.758)μg·h·mL~(-1)。以AUC_(0～6)计算试验制剂的相对生物利用度为(101.4±15.3)%。结论:两种头孢克洛制剂生物等效。     

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.     

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.     

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.     

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.     

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.