依托泊苷隐形前体脂质体的构建及家兔体内药动学研究

构建依托泊苷隐形前体脂质体，并考察其在家兔体内的药动学。采用薄膜分散法构建窄白隐形脂质体；硫酸铵梯度法包封依托泊苷；结合真空冷冻干燥技术构建依托泊苷隐形前体脂质体。采用凝胶色谱法测定脂质体包封率；透射电镜观察脂质体的形态；电泳光散射技术测定Zeta电位与粒径分布；以市售依托泊苷注射液和普通脂质体为参比制剂，评价其在家兔体内药动学特点。脂质体平均包封率为83．92％±3．65％，粒径为（124．5±26．9）nm，Zeta电位为（-39．50±1．04）mV，家兔单剂量静脉注射1．5mg／kg依托泊苷制剂后呈二室模型特征，依托泊苷隐形前体脂质体的T1/2β为（19．26±3．16）h，AUC为（26．04±3．53）μg／h／mL；注射液的T1/2β为（0．94±0．21）h，AUC为（0．98±0．26）μg／h／mL；普通脂质体的T1/2β为（7．99±1．36）h,AUC为（11．65±1．70）μg/mL。构建的隐形前体脂质体包封率高，且延长了依托泊苷在血液中的循环时间。     

多西紫杉醇脂质体家兔体内药动学

目的:研究多西紫杉醇脂质体在家兔体内的药动学。方法:18只家兔随机分为3组,分别在耳缘静脉单剂量(7.5mg·kg-1)注射多西紫杉醇普通脂质体、长循环脂质体和市售注射液,用高效液相色谱法测定各时间点血药浓度。结果:血药浓度-时间数据均符合二房室模型;t1/2α分别为(0.31±0.11),(0.32±0.06),(0.17±0.04)h;t1/2β分别为(11.2±1.3),(10.5±1.1),(8.5±1.0)h;Vd分别为(8.6±1.1),(6.3±0.6),(13.7±3.6)L;AUC0→24分别为(22.8±3.6),(29.3±6.0),(13.4±2.4)mg.h.L-1;AUC0→∞分别为(28.7±5.0),(37.0±9.1),(15.1±2.8)mg.h.L-1;CL分别为(0.54±0.08),(0.42±0.07),(1.10±0.18)L.h-1。2种脂质体与注射液相比,t1/2α,t1/2β,Vd,CL,AUC0→24及AUC0→∞均有显著性或极显著性差异;脂质体之间Vd和CL差异有显著性。结论:与普通注射液相比,家兔静注两种脂质体后,均具有较长的消除半衰期,更大的药-时曲线下面积,较低的总体消除率和较小的表观分布容积,说明脂质体制剂具有长效和缓释的特点;经PEG修饰的长循环脂质体较之普通脂质体,在能够维持较长的体内循环时间的同时,能够更好地浓集于靶组织,减少药物对其他组织的不良反应并增加疗效。     

多西他赛亚微乳注射液在犬体内的药动学

目的研究多西他赛(DTX)亚微乳注射液在比格犬体内的药动学,比较亚微乳注射液与普通注射液犬体内药动学差异。方法采用单剂量双周期自身交叉设计,Beagle犬前肢分别静脉滴注(20 mg.m-2)DTX亚微乳注射液和DTX注射液(泰素帝),分别于0、0.33、0.67、1、1.5、2、2.5、3、4、6、8、12、24 h采血,血浆中DTX采用液相色谱-质谱联用(LC-MS)法测定。结果相同剂量的DTX亚微乳或普通注射液的AUC0-24分别为(476.80±96.18)和(451.94±43.91)μg.h.L-1,Cmax分别为(510.06±168.58)和(466.71±73.14)μg.L-1,t1/2分别为(5.76±4.24)和(4.40±0.51)h,2种制剂的各药动学参数无显著性差异(P>0.05)。结论多西他赛制成亚微乳制剂后,两者具有相似的体内药动学行为。亚微乳制剂DTX的药-时曲线下面积和峰浓度有所增加,消除半衰期延长可能与制剂形式不同有关。     

BAPTA-AM脂质体注射液在大鼠和Beagle犬体内的药动学比较

目的：比较研究BAPTA-AM脂质体注射液在大鼠和Beagle犬体内的药动学过程。方法：通过LC-MS/MS方法测定大鼠、Beagle犬血浆中BAPTA-AM的浓度,采用非房室模型计算BAPTA-AM注射液在大鼠、Beagle犬体内的药动学参数。结果：大鼠尾静脉注射1.5、3.0、6.0mg/kgBAPTA-AM脂质体注射液后,体内消除半衰期分别为（255±140）、（290±260）、（376±257）min,AUC0-∞分别为（831±251）、（1467±528）、（3650±1664）μg.L^-1.min;Beagle犬静脉注射0.5、1.0、2.0mg/kgBAPTA-AM脂质体注射液后,体内3个剂量的消除半衰期分别为（362±305）、（347±278）、（432±292）min,AUC0-∞分别为（400±118）、（569±139）、（1185±640）μg.L-1.min。结论：静脉注射给药后,BAPTA-AM脂质体注射液在大鼠和Beagle犬体内代谢较快,分布较广,在两种动物内的药动学过程无统计学差异。     

羟喜树碱注射液在小鼠体内的药动学研究

目的:研究羟喜树碱(HCPT)注射液在小鼠体内的药动学特征。方法:70只小鼠随机分成两组,每组35只。两组小鼠分别尾静脉注射和腹腔注射HCPT注射液(6 mg/kg)后,于不同时间点进行眼眶静脉丛取血,建立测定小鼠血浆中HCPT浓度的RP-HPLC荧光检测法,分别测定两种给药途径下小鼠血浆中的药物浓度,并用DAS药动学程序对血药浓度进行处理。结果:HCPT可与血浆中的其他成分较好地分离。小鼠尾静脉注射和腹腔注射HCPT的药动学规律可用一室模型来描述,达峰时间(tmax)分别为(0.080±0.023)和(0.170±0.051)h,峰浓度(cmax)分别为(1.849±0.263)和(0.975±0.317)μg/mL,半衰期(t1/2)分别为(0.265±0.072)和(0.892±0.135)h,AUC0→4分别为(0.902±0.102)和(0.432±0.054)mg.h.L-1,平均滞留时间(MRT)分别为(0.423±0.056)和(0.400±0.062)h。腹腔注射的绝对生物利用度为47.9%。结论:HCPT腹腔注射的药动学规律与静脉注射有所不同,前者血药浓度较低,对全身的副作用小于静脉注射。     

甲磺酸罗哌卡因注射液病人体内药代动力学研究

目的：研究甲磺酸罗哌卡因注射液病人体内的药代动力学过程及药动学参数的性别差异。方法：单剂量硬膜外给药15 mL,采用HPLC测定血浆中罗哌卡因的浓度。用DAS软件计算其药代动力学参数。结果：单剂量使用甲磺酸罗哌卡因注射液后男性和女性的消除半衰期t1/2β分别为（4.050±2.548）、（2.088±0.135）h;吸收半衰期t1/2ka分别为（0.085±0.045）、（0.107±0.069）h;达峰时间分别为（0.333±0.118）、（0.417±0.167）h;峰浓度分别为（1.066±0.135）、（1.113±0.317）mg/L;吸收程度（AUC0-tn,统计矩法）分别为（2.856±0.321）、（2.369±0.386）mg.L^-1.h;MRT0-tn分别为（2.070±0.113）、（2.022±0.089）h。结论：本试验建立了甲磺酸罗哌卡因注射液血药浓度的固相萃取-HPLC测定方法,提供了单剂量使用的药动学参数,试验结果表明各药动学参数性别间差异无统计学意义。     

地西泮亚微乳注射液大鼠体内药动学

目的:研究地西泮亚微乳注射液在大鼠体内药动学特征.方法:大鼠股静脉注射地西泮亚微乳注射液(4 mg·kg-1),采用HPLC法测定不同时间点大鼠血浆中的药物浓度,并用3P87药动学程序对血药浓度进行处理.结果:地西泮可与血浆中的其他成分较好地分离,在0.05～5 mg·L-1的血药浓度范围内呈良好的线性关系.地西泮亚微乳注射液和地西泮注射液2种制剂大鼠静脉给药后体内药动学符合三室模型,主要药动学参数t1/2β,AUC0～∞,MRT和Vc分别为:(10.97±1.89)和(5.72±1.24)h,(6.10±1.25)和(6.24±1.80)mg·L-1·h,(15.67±1.48)和(9.98±1.31)h,(0.34±0.03)和(0.10±0.01)L·kg-1;2种制剂的t1/2β,MRT和Vc均存在统计学差异(P＜0.01).结论:地西泮亚微乳注射液可在一定程度上延长药物体内循环时间.     

大鼠静脉注射康莱特注射液的药动学研究

目的:研究康莱特注射液在正常大鼠体内的药动学。方法:采用甘油三酯试剂盒检测康莱特注射液经尾iv后大鼠血清中外源性甘油三酯的浓度变化,外源性甘油三酯浓度为测定血样中甘油三酯扣除本底后的浓度,采用3P97药代软件计算药动学参数。Cmax为实测值,AUC计算采用梯形法。结果:康莱特注射液10、5mL/kg剂量的主要药动学参数:Cmax分别为(8.532±1.031)、(5.418±0.764)mmol/L,AUC0-t分别为(13.248±3.692)、(5.339±1.219)mmol/L·h,Vc分别为(1.030±0.131)、(0.756±0.150)L2/(kg·mol),CLs分别为(0.838±0.319)、(0.975±0.330)L2/(kg·mol·h),t1/2α分别为(0.481±0.168)、(0.322±0.109)h,t1/2β分别为(1.452±0.776)、(1.384±0.404)h。结论:康莱特注射液经尾iv给药后在大鼠体内的药动学过程经拟合为二室模型。     

溴吡斯的明口腔崩解片和普通片在兔体内的生物等效性

目的:研究新西兰大耳白兔口服溴吡斯的明口腔崩解片和普通糖衣片后的药动学。方法:12只新西兰大耳白兔随机分为2组,分别口服给予溴吡斯的明口腔崩解片和市售普通片(60mg),反相离子对色谱法测定血浆药物浓度,用DAS2.1.1药动学软件计算药动学参数。结果:口腔崩解片和普通片均符合一室开放模型,Cmax分别为(1.81±0.09)mg.L-1和(1.71±0.03)mg.L-1;tmax分别为(2.25±0.27)h和(2.67±0.26)h;t1/2分别为(3.0±0.8)h和(3.27±0.18)h;AUC0-24分别为(15.8±0.5)mg.h.L-1和(14.85±0.17)mg.h.L-1;AUC0-∞分别为(16.1±0.6)mg.h.L-1和(15.14±0.19)mg.h.L-1;口腔崩解片相对生物利用度F0-24为106.19%,F0-∞为106.07%;经方差分析、双单侧t检验和非参数检验,两制剂在兔体内无显著性差异。结论:两种制剂生物等效。     

生脉注射液与参麦注射液在健康人体的药代动力学

目的 比较研究健康志愿者单次静脉滴注生脉注射液(益气养阴中药)和参麦注射液(治疗心脏病的急救中药)的药代动力学.方法 16名健康受试者分成2组,交叉试验,分别单次静滴相同剂量生脉注射液和参麦注射液;用液相色谱-质谱仪检测法测定给药后不同时间点的血药浓度,用DAS 2.0软件计算药代动力学参数.结果 两者的血药浓度-时间曲线均符合二房室模型,健康受试者单次静滴生脉注射液和参麦注射液后主要的药代动力学参数如下.Rg1:Cmax分别为(0.89±0.52),(0.81±0.53)mg·L-1;t1/2分别为(2.01±0.82),(1.78±0.98)h;AUC0-144分别为(1.15±0.44),(1.24±0.84)mg·h·L-1.Re:Cmax分别为(0.26±0.15),(0.27±0.19)mg·L-1;t1/2分别为(0.59±0.34),(0.60±0.44)h;AUC0-144分别为(0.26±0.13),(0.33±0.25)mg·h·L-1.Rb1:Cmax分别为(10.57±8.92),(16.54±11.70)mg·L-1;t1/2分别为(47.98±7.26),(47.17±8.75)h;AUC0-144分别为(346.67±267.89),(525.45±387.32)mg·h·L-1.结论 单次静滴相同剂量的生脉注射液和参麦注射液其药代动力学参数无显著性差异.     

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.