白花蛇舌草注射液中对香豆酸的药代动力学研究

目的:建立反相高效液相色谱法对白花蛇舌草中对香豆酸进行药代动力学研究。方法:血浆样品用甲醇沉淀蛋白,采用Diamonsil C18色谱柱(200 mm×4．6 mm,5μm),流动相为乙腈-1％醋酸(21:79,v／v),流速1．0 mL·min-1,检测波长为 322 nm,进样量为20 μL,内标为橙皮苷。结果:对香豆酸浓度在0．085-10．6μg·mL-1(r=0．9990)时与对香豆酸和橙皮苷峰面积比呈良好的线性关系,提取回收率和方法回收率分别为97．6％-110．0％和96．1％-100．5％,日内和日间的RSD均小于10％,大鼠腹腔注射白花蛇舌草注射液后,对香豆酸的药动学行为符合二室模型,Ka为(0．260±0．050)min-1,T1/2(Ka)为 (6．77±3．34)min,T1／2α为(33．83±8．52)min,T1／2β为(2．78±0．58)min,k21为(0．0676±0．0538)min-1,k10为(0．0489± 0.0154)min-1,k12为(0．0463±0．0354)min-1,AUC为(124．3±62．8)μg·min·mL-1,Tmax和Cmax实测值分别为(6．19± 0．99)min和(3．27±1．46)μg·mL-1。结论:该方法灵敏、准确,适合于对香豆酸的药代动力学研究。     

非诺贝特-羟丙基-β-环糊精包合物在大鼠体内的药动学及生物利用度研究

目的研究非诺贝特(FNB)-羟丙基-β-环糊精(HP-β-CD)包合物在大鼠体内的药动学及生物利用度。方法大鼠分别灌胃给予FNB原药及其HP-β-CD包合物,采用HPLC法测定给药后不同时间的血药浓度,并采用3P97药动学程序计算药动学参数。结果 FNB及其HP-β-CD包合物在大鼠体内的药动学过程符合开放一室房室模型。主要药动学参数tmax分别为(6.67±3.50)h和(3.17±2.62)h,Cmax分别为(6.31±3.04)μg·mL-1和(39.82±16.25)μg·mL-1,AUC0^t分别为(81.36±51.00)μg·h·mL-1和(462.74±196.68)μg·h·mL-1,AUC0t分别为(81.36±51.00)μg·h·mL-1和(462.74±196.68)μg·h·mL-1,AUC0^∞分别为(90.34±51.72)μg·h·mL-1和(483.90±260.92)μg·h·mL-1,2组间差异有显著统计学意义(P<0.01);FNB包合物的相对原药生物利用度为535.6%。结论 FNB与HP-β-CD形成包合物后,其在大鼠体内的吸收速度明显加快,生物利用度显著提高。     

尼群地平纳米片在犬体内的药动学与相对生物利用度

目的:建立反相高效液相色谱法(RP-HPLC)测定Beagle犬血浆中尼群地平的浓度,研究尼群地平纳米片在Beagle犬体内的药动学与相对生物利用度.方法:采用RP-HPLC测定12只Beagle犬口服受试药品及参比药品后的经时血药浓度,计算主要药动学参数及相对生物利用度.结果:受试药品与参比药品的主要药动学参数分别是:达峰时间(Tgeak)为(1.38±0.20)h和(1.87±0.22)h,峰浓度(Cmax)为(110.1±14.0)μg·L-1和(98.8±34.2)μg·L-1;曲线下面积(AUC)为(684.1±96.6)μg·L-1·h和(620.7±193.2)μg·L-1·h.结论:尼群地平纳米片吸收较为迅速,可快速发挥降压作用,其生物利用度也有所提高.     

马来酸氟吡汀缓释片在Beagle犬体内的药动学和生物等效性研究

目的:建立测定Beagle犬血浆中马来酸氟吡汀浓度的高效液相色谱-荧光检测方法,研究马来酸氟吡汀缓释片在Bea-gle犬体内单剂量和多剂量的药动学和生物等效性。方法:以替米沙坦为内标,血浆样品加二氯甲烷萃取,Diamonsil C18为色谱柱,0.005 mol·L-1磷酸氢二钠缓冲液(pH=6.7)-甲醇-乙腈(42∶14.5∶43.5)为流动相,流速为1.0 mL·min-1,进样量10μL,荧光检测波长λex=320 nm,λem=370 nm。采用随机双交叉自身对照试验设计,6只Beagle犬口服单剂量、多剂量马来酸氟吡汀缓释片参比制剂、受试制剂后测定血药浓度,计算药动学参数,评价两制剂的等效性。结果:马来酸氟吡汀的浓度在0.06～15.00μg·mL-1范围内线性关系良好(r=9984),准确度和精密度符合生物样品分析要求;单剂量给药后,参比制剂和受试制剂主要的药动学参数:t1/2分别为(6.97±3.71),(6.39±2.29)h;Cmax分别为(3.83±0.73),(3.81±1.13)μg·mL-1;Tmax分别为(3.17±0.42),(3.67±0.52)h;AUC0→48分别为(27.23±6.31),(27.17±9.33)μg.h.mL-1;AUC0→∞分别为(28.44±7.47),(28.04±9.37)μg.h.mL-1。多剂量给药后,参比制剂和受试制剂主要药动学参数:t1/2分别为(6.50±2.09),(7.94±1.70)h;Tmax分别为(2.08±0.80),(1.83±0.26)h;Csmsax分别为(4.89±0.76),(5.14±0.65)μg·mL-1,Csmsin分别为(0.23±0.19),(0.38±0.22)μg·mL-1;AUCss分别为(29.00±8.32),(30.58±4.33)μg.h.mL-1。结论:本测定方法可用于马来酸氟吡汀Beagle犬药动学研究,且两制剂在Beagle犬体内具有生物等效性。     

LC-MS/MS法测定Beagle犬血浆中妥洛特罗质量浓度及其在药动学研究中的应用

目的建立LC-MS/MS法测定Beagle犬血浆中妥洛特罗的质量浓度,研究Beagle犬给予妥洛特罗贴剂后的药动学特征。方法血浆经乙酸乙酯-二氯甲烷(体积比4∶1)提取。色谱柱为Agilent TC-C18柱,流动相为甲醇-体积分数1%甲酸溶液(体积比67∶33),流速为0.5 m L·min-1,进样量为30μL。质谱采用多反应监测模式(multiple reaction monitoring,MRM),电喷雾离子源,分析时间4.5 min。采用DAS 2.0软件以非房室模型计算药动学参数。结果妥洛特罗质量浓度在0.1~10μg·L-1内与峰面积呈良好的线性关系,定量下限为0.1μg·L-1。日内、日间精密度(RSD)均小于15%,准确度(RE)为-4.27%~-0.60%,方法回收率大于(82.0±6.35)%。健康Beagle犬给予妥洛特罗贴剂(规格为每贴2 mg)后主要药动学参数:tmax为(5.25±1.49)h,ρmax为(7.82±1.98)μg·L-1,t1/2为(5.59±2.37)h;采用梯形法计算,AUC0-t为(99.26±15.05)μg·h·L-1,AUC0-∞为(101.94±14.99)μg·h·L-1。结论该方法可用于妥洛特罗临床前药动学研究。     

高效液相色谱法测定板蓝根中丁香酸兔体内药物动力学

目的研究板蓝根抗内毒素活性成分丁香酸兔体内单剂量静脉注射动力学.方法分别经兔耳静脉注射给药后,在不同时间经耳缘静脉取血,用高效液相色谱法测定血浆药物浓度,绘制药-时曲线,拟合房室模型,计算药物动力学参数.结果静脉给药后,丁香酸在兔体内的药物动力学过程符合二室模型.其药动学参数为:α(0.11±0.14)min-1;β(0.04±0.01)min-1;Vc(373.8±119.2)mL;t1/2α(9.7±7.8)min;t1/2β(18.5±5.5)min;K21(0.08±0.16)min-1;K10(0.05±0.02)min-1;K12(0.008±0.013)min-1;AUC0～155min(6356.9±962.5)μg·min·mL-1;Cl(18.3±7.0)mL·min-1.结论本法简便、准确、灵敏度高、重现性好,可用于丁香酸体内动力学测定.     

盐酸莫西沙星氯化钠注射液在Beagle犬体内的药物动力学

建立了HPLC法测定Beagle犬血浆中的莫西沙星,研究Beagle犬静脉滴注盐酸莫西沙星氯化钠注射液后的体内药动学.采用C_(18)色谱柱,0.05 mol/L磷酸盐缓冲液(含0.01 mol/L四丁基硫酸氢铵,pH 3.8)-乙腈(85:15)为流动相,检测波长295nm.莫西沙星在0.1～25.6μg/ml浓度范围内线性关系良好.Beagle犬静脉滴注盐酸莫西沙星氯化钠注射液后药动学呈二室开放模型,c_(max)13.70μg/ml,AUC_(0-∞) 117.20μg·ml~(-1)·h,t_(1/2α) 5.326 h,t_(1/2β)7.82h.     

苦参素片、苦参素胶囊人体生物等效性研究

目的: 比较苦参素片剂与胶囊剂的生物等效性.方法: 20名男性健康志愿者,双交叉于试验当日晨空腹一次口服试验制剂苦参素片、参比制剂苦参素胶囊 600 mg,于药前和药后0.25,0.5,1.0,1.25,1.5,2.0,2.5,3.0,3.5,4.0,5.0,6.0,8.0 h取肘静脉血,高效液相色谱法测定主要成分氧化苦参碱血药浓度.氧化苦参碱血药浓度-时间数据经3P97处理,得药动学参数,参数进行方差分析、双单侧t检验和(1-2α)置信区间分析,并计算相对生物利用度评价两种制剂的生物等效性.结果: 苦参素片和苦参素胶囊氧化苦参碱主要药代动力学参数t1/2分别为(2.144±0.453)h 和(2.066±0.439)h,tmax 分别为(2.275±0.716)h和(2.175±0.654)h,Cmax 分别为(0.384±0.144)μg·ml-1 和(0.370±0.132)μg·ml-1,AUC0-8h分别为(1.098±0.278)μg·ml-1·h和(1.094±0.280)μg·ml-1·h,AUC0-∞分别为(1.216±0.292)μg·ml-1·h和(1.200±0.271)μg·ml-1·h.试验制剂苦参素片相对生物利用度F(以氧化苦参碱计)为100.403%±6.281%,两制剂具有生物等效性.结论: 苦参素片和苦参素胶囊为生物等效制剂.     

高蛋白饮食对犬体内左氧氟沙星药动学的影响研究

目的:研究高蛋白饮食对犬体内左氧氟沙星药动学的影响。方法:将6只犬随机均分为空腹组和高蛋白饮食组,高蛋白饮食组犬进食高蛋白饮食每只150g,2组犬分别灌服左氧氟沙星10mg/kg。采用高效液相色谱法检测给药后0.5、1、2、4、8、12、24、48h各组犬体内左氧氟沙星的血药浓度,2周后进行交叉实验,3p97软件计算药动学参数并进行比较。结果:2组犬体内左氧氟沙星的药动学过程均符合二室模型;空腹组和高蛋白饮食组犬体内左氧氟沙星的药动学参数分别为t1/2β:(11.07±8.46)、(21.65±4.65)h,tmax:(3.42±0.41)、(1.53±0.34)h,cmax:(2.71±0.60)、(2.22±0.22)μg/ml,AUC0-48h:(36.51±8.66)、(29.78±4.26)μg·h/ml;除tmax参数组间有显著性差异(P<0.01)外,其余参数均无显著性差异(P>0.05)。结论:高蛋白饮食可使左氧氟沙星tmax减小,促进其吸收。     

富马酸喹硫平在大鼠体内的药动学研究

目的:测定富马酸喹硫平在大鼠体内的血药浓度,并研究其药动学特征。方法:取6只大鼠灌胃给予富马酸喹硫平40mg/kg,与给药前和给药后5、15、30、45 min和1、1.5、2、4、6、8、12、24 h静脉采血0.5 ml,离心后取血浆,用乙腈沉淀蛋白后直接进样,以卡马西平为内标物,反相高效液相色谱法测定血药浓度,采用DAS2.0软件分析药动学参数。结果:富马酸喹硫平在大鼠体内的药动学特征呈二室模型,主要药动学参数t1/2α为(20.132±1.198)min、t1/2β为(62.883±11.120)min、tmax为(40.00±8.66)min、cmax为(2.21±0.066)μg/ml、AUC0-24 h为(687.453±12.026)mg·min/L、V1/F为(8.244±0.679)L/kg、K10为(0.183±0.028)min-1、K12为(1.764±0.161)min-1、K21为(0.189±0.018)min-1。结论:富马酸喹硫平在大鼠体内的分布和消除均比较快,且分布不广泛。     

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.