静脉、腹腔给予羟喜树碱冻干粉针和脂质体在小鼠血液中的分布

目的 研究羟喜树碱(HCPT)冻干粉针及脂质体通过小鼠腹腔及静脉给药其血液中的分布.方法 昆明种小鼠108只随机分成4组:2组腹腔给予冻干粉针及脂质体；另2组静脉给药.给药后15,60,120 min取血,测定羟喜树碱浓度.结果 腹腔给药后在15,60 min的血药浓度,羟基喜树碱脂质体较注射用羟基喜树碱明显减少；而120 min较注射用羟基喜树碱明显增加(P＜0.05).静脉给药后在60,120 min的药物浓度,较15 min时2组均明显减少(P＜0.05)；而120 min时的药物浓度,脂质体较注射剂明显增加(P＜0.05).结论 静脉、腹腔给予冻干粉针及脂质体HCPT,药物在血液中迅速分布,很快被消除,符合其药动学特征.     

羟基喜树碱脂质体的制备及质量评价研究

目的:制备羟基喜树碱(HCPT)脂质体,并对其质量进行评价.方法:采用薄膜分散-高压乳匀法制备羟基喜树碱脂质体;用激光粒度分析仪测定其Zeta电位、粒径大小;考察其在0.9%NaCl溶液、水、5%葡萄糖溶液中8 h的稳定性;用凝胶柱层析法考察包封率;采用薄膜透析法考察体外释药性质.结果:羟基喜树碱脂质体Zeta电位为(-33.1±1.3) mV,平均粒径(182.5±5.6) nm,8 h内在水、5%葡萄糖溶液中稳定性良好;包封率(91.2±1.2)%;体外释药曲线符合Higuchi方程Q=1.291 6t1/2 0.309 8,r=0.980 3.结论:本试验制备的羟基喜树碱脂质体稳定性好,大小均匀, 包封率高,并具有延缓药物释放的性质.     

9-硝基喜树碱内酯型与羧酸盐型在大鼠体内的药动学与肾排泄研究

目的:比较静脉注射9-硝基喜树碱内酯型与羧酸盐型溶液后大鼠体内药动学和肾排泄情况。方法:采用HPLC法同时测定大鼠血浆中9-硝基喜树碱内酯型浓度与总(内酯型+羧酸盐型)浓度以及尿液中9-硝基喜树碱的总浓度。按4mg.kg-1剂量给大鼠静脉注射9-硝基喜树碱内酯型与羧酸盐型溶液,绘制药-时曲线,并采用DAS 2.0软件拟合药动学参数。按同剂量给大鼠静脉注射9-硝基喜树碱内酯型与羧酸盐型溶液,并在各时间段收集尿液,测定尿液中9-硝基喜树碱原形药物累积排泄量。结果:根据AUC计算,9-硝基喜树碱内酯型与羧酸盐型溶液给药以后内酯型的比例分别为(46.7±8.0)%和(8.8±2.5)%,两者的MRT分别为(21.6±2.1)min与(12.7±5.1)min,Vz分别为(0.91±0.16)L.kg-1与(0.56±0.13)L.kg-1,t1/2分别为(17.2±2.4)min与(13.3±3.9)min,差异均有显著性,但总量的AUC并无明显差别。9-硝基喜树碱羧酸盐型及内酯型给药后累积尿液排泄百分率为(30.3±6.4)%和(8.9±0.8)%。结论:9-硝基喜树碱内酯型与羧酸盐型的体内药动学过程存在显著差异,羧酸盐型给药后的肾排泄量远高于内酯型。     

纳米羟喜树碱注射用灭菌粉末在家兔体内的药动学研究

目的考察纳米羟喜树碱注射用灭菌粉末经静脉注射给药后在家兔体内的药动学特征。方法建立测定家兔血浆中羟喜树碱含量的高效液相色谱法，标准曲线的回归分析采用加权最小二乘法；采用3p97药动学计算软件模拟房室模型并计算纳米羟喜树碱注射用灭菌粉末在家兔体内的药动学参数。结果纳米羟喜树碱注射用灭菌粉末在家兔体内的代谢符合1/C2权重的三室模型。相同剂量下普通羟喜树碱在家兔体内的半衰期较纳米制剂短。结论纳米羟喜树碱注射用灭菌粉末的药动学特性与普通羟喜树碱制剂的特性有明显区别。     

RP-HPLC法测定注射用羟喜树碱脂质体含量

目的建立测定注射用羟喜树碱脂质体含量的方法。方法采用反相高效液相色谱法。色谱系统为ODS柱,以甲醇-水(60∶40)为流动相,检测波长为266 nm。结果本品在5.886~10.930μg.ml-1范围内呈线性关系,回归方程为:A=6.438×104C-2.184×104,r=0.9998。回收率为98.9%,RSD%为0.38(n=9)。结论本法可测定注射用羟喜树碱脂质体中羟喜树碱的含量,方法快速、简便、准确。     

肺靶向羟基喜树碱脂质体的制备及其在小鼠体内的组织分布研究

目的： 研究羟基喜树碱脂质体的制备方法并考察其肺靶向及在小鼠体内的分布。方法： 采用薄膜分散－冻融法制备,添加D-甘露糖和十八胺修饰可得到肺靶向羟基喜树碱脂质体;用HPLC法测定给药后小鼠体内不同组织中的药物浓度。结果： 制得的脂质体平均粒径大于2 μm,表面电荷为+21.5 mV,包封率大于65%,稳定性好,符合要求。羟基喜树碱脂质体和注射液经小鼠尾静脉给药后,脂质体主要被肺摄取,在肺部停留的时间较普通注射剂显著延长,其相对摄取率r_e为60.72,脂质体组的肺靶向效率t_e为17.57。结论： 本实验制得羟基喜树碱脂质体具有较高包封率及稳定性,在小鼠肺部浓度高、滞留时间长,能达到肺靶向目的。     

羟喜树碱脂质体中药物对磷脂稳定性的影响

目的:通过对磷脂水解产物溶血磷脂(LPC)的测定,对比空白脂质体与含药脂质体中溶血磷脂含量变化,系统研究了羟喜树碱脂质体中药物对脂质体稳定性的影响.方法:通过高温加速试验的方法,对HCPT脂质体中LPC含量的变化进行比较性研究,并采用HPLC-ELSD法对其含量进行准确测定.结果:经加速试验后发现,含药脂质体中LPC的百分含量较空白脂质体增加10%,两者存在显著性差异(P＜0.05).结论:HCPT脂质体中药物对磷脂水解过程有明显的催化作用,建议在此类药物的研发中应高度关注.     

卡巴拉汀脂质体的制备及其大鼠鼻腔给药的药代动力学

制备卡巴拉汀脂质体,研究其在大鼠鼻腔给药的药代动力学。采用硫酸铵梯度法制备包载卡巴拉汀的脂质体,考察粒径、zeta电位和包封率,测定脂质体在磷酸盐缓冲液中的释放;大鼠鼻腔给予卡巴拉汀脂质体,以安替比林为内标,采用高效液相色谱-串联质谱法(HPLC/MS)测定血浆中卡巴拉汀的浓度,运用DAS 2.0软件拟合药代动力学参数。经筛选制备的脂质体包封率为(33.41±6.58)%,平均粒径在154～236 nm,zeta电位(-10.47±2.41)mV。脂质体的体外释放符合一级动力学方程。大鼠鼻腔给药后,Cmax,Tmax和AUC0-∞分别为(1.50±0.15)mg.L-1,15 min和(89.06±8.30)mg.L-1.min。卡巴拉汀制备成脂质体经大鼠鼻腔给药后,吸收迅速,血药浓度可以达到一定水平。     

高效液相色谱法测定灯盏乙素血药浓度及其脂质体大鼠药代动力学的评价

目的研究灯盏乙素脂质体及水剂在大鼠体内的血药浓度,考察大鼠灌胃给药后体内药代动力学参数。方法通过大鼠灌胃灯盏乙素水溶液和脂质体后,用高效液相色谱法测定不同时间点的血浆药物浓度,用DAS2.0软件对血药浓度数据拟合分析,比较药动学参数。结果灯盏乙素水剂和脂质体大鼠灌胃给药后,Cmax分别是(15.35±1.37)μg/mL和(22.04±1.67)μg/mL,AUC0-∞分别为(50.03±13.45)μg/(h·mL)和(80.96±15.26)μg/(h·mL),灯盏乙素包衣脂质体大鼠口服给药后药动学呈双室模型特征,与灯盏乙素水剂相比,其脂质体的灌胃AUC0-∞显著提高(P<0.01)。结论本高效液相色谱法对大鼠血浆灯盏乙素测定,稳定性、灵敏度及专属性强,灯盏乙素脂质体可显著提高灯盏乙素的生物利用度。     

双氯芬酸钠脂质体凝胶的制备及家兔体内药动学研究

目的研究双氯芬酸钠脂质体以及脂质体凝胶的制备方法,考察双氯芬酸钠脂质体凝胶肌注后在家兔体内的血药浓度经时过程.方法家兔肌注双氯芬酸钠溶液、凝胶、脂质体及脂质体凝胶后,采用高效液相色谱法检测血中药物浓度.结果4种制剂主要药动学参数Cmax分别为(12.8±4.0),(5.3±2.2),(5.5±1.9),(4.6±1.9)mg·L-1;tmax分别为(0.17±0.08),(1.3±0.3),(0.6±0.4),(2.0±0.8)h;t1/2分别为(0.52±0.18),(0.9±0.6),(1.0±0.5),(1.6±0.8)h; MRT分别为(0.79±0.26),(2.1±0.6),(1.9±0.8),(3.0±0.8)h;AUC0-∞分别为(9.0±2.2),(11.0±3.3),(10.7±4.0),(12.6±3.7)mg·h·L-1.结论与其他3种制剂相比,双氯芬酸钠脂质体凝胶肌注后tmax推迟,Cmax降低,MRT、t1/2延长,AUC增加,表明该制剂可延长药物在家兔体内的存留时间,具有一定的缓释作用并可提高生物利用度.     

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.