甲磺酸罗哌卡因注射液的狗药代动力学研究

目的研究狗静脉注射甲磺酸罗哌卡因注射液的药代动力学.方法采用高效液相色谱法测定狗交叉甲磺酸罗哌卡因注射液和参比制剂盐酸罗哌卡因注射液后的血药浓度,应用3P97程序计算主要药代动力学参数,估算其相对生物利用度,并进行等效性检验.结果甲磺酸罗哌卡因注射液的Ti/2、C0、AUCo～180分别为(33.03±2.12)min、(4.28±0.68)mg·L-1、(144.4±31.7)mg·min-1·L-1,盐酸罗哌卡因注射液的上述参数分别为(31.20±2.18)min、(4.57±0.73)mg·L-1、(154.6±33.4)mg·min-1·L-1.两制剂间的lnAUCo～180,lnAUCo～∞及lnCo经方差分析和双单侧t检验发现,具有生物等效性,甲磺酸罗派卡因注射液的相对生物利用度为(93.4±4.4)%.结论甲磺酸罗哌卡因注射液血药浓度时曲线均符合一级吸收的一房室模型,甲磺酸罗哌卡因注射液与盐酸罗哌卡因注射液间具有等效性.     

LC-MS/MS法测定手术患者中罗哌卡因注射液的血浓度及药动学

目的评价国产甲磺酸罗哌卡因注射液在手术患者中的药动学特点。方法采用LC-MS/MS法测定血浆中罗哌卡因的浓度,并用非房室模型计算药动学参数。结果16例下腹部或下肢手术患者单剂量给予135mg甲磺酸罗哌卡因(含罗哌卡因100mg)或112.5mg盐酸罗哌卡因注射液(含罗哌卡因100mg)的主要药动学参数分别是:甲磺酸罗哌卡因组AUC0→t为(7904.14±3699.28)μg·h·L-1;AUC0→∞为(8300.40±3891.91)μg·h·L-1;ρmax为(1701.25±198.60)μg·L-1;tmax为(0.41±0.29)h;t1/2为(6.50±1.39)h;MRT0→t为(5.23±1.07)h;MRT0→∞为(6.59±1.29)h;Ke为(0.11±0.02)h-1;V/F为(135.23±65.45)L;CL/F为(13.78±4.45)L·h-1。盐酸罗哌卡因组AUC0→t为(9559.03±3890.03)μg·h·L-1;AUC0→∞为(9936.23±3974.98)μg·h·L-1;ρmax为(1483.75±318.21)μg·L-1;tmax为(2.12±2.57)h;t1/2为(5.12±1.12)h;MRT0→t为(5.97±0.65)h;MRT0→∞为(7.00±1.09)h;Ke为(0.14±0.03)h-1;V/F为(90.50±48.24)L;CL/F为(12.06±6.00)L·h-1。结论在下腹部或下肢手术患者受试者中,单剂量注射甲磺酸罗哌卡因注射液或盐酸罗哌卡因注射液15mL后的主要药动学参数均无差异,而且耐受性和安全性良好,无不良事件发生。     

复合全麻下罗哌卡因硬膜外阻滞的药代动力学

目的：对罗哌卡因硬膜外阻滞复合全麻的手术病人进行药代动力学研究。方法：选择12例上腹部手术病人,硬膜外腔注入0.5%罗哌卡因,并行全麻诱导,于输入罗哌卡因后1、10、20、30、45、60、75、90、120、150、180min分别从左桡动脉采血,用高效液相色谱仪测定罗哌卡因血药浓度,用DAS2.0药动学统计软件拟合房室模型,并计算各项药代动力学参数。结果：术中、术后均未见与罗哌卡因有关的不良反应,罗哌卡因的主要药代动力学参数：tmax为10min;Cmax为0.713mg/L;t1/2α为122min;t1/2β为190min;AUC0→180为（72±10）μg·mL^-1·min^-1。结论：复合全麻下罗哌卡因硬膜外阻滞药物代谢符合二室模型,安全性良好,镇痛效果满意。     

罗哌卡因在犬坐骨神经阻滞时的药代动力学

目的探讨罗哌卡因在犬坐骨神经阻滞时的药代动力学特点。方法选取健康杂种犬12只,按取血样本分为动脉组和静脉组,每组6只。动脉组取动脉血,静脉组取静脉血。2组肌内注射3％戊巴比妥钠30mg／kg麻醉后,分别采用0．5％罗哌卡因10mg／kg行单次坐骨神经阻滞,于罗哌卡因给药前,给药后10、20、30、40、60、90、120、150、180、240、360、720min分别抽取股动、静脉血5ml,采用反相高效液相色谱法测定血浆罗哌卡因浓度。计算药代动力学[分布半衰期（t1／2α）、消除半衰期（t1/2β）、达峰时间（Tmax）、峰值浓度（Cmax）、曲线下面积（AUC）、一阶矩曲线下面积（AUMC）、平均吸收时间（MAT）、平均残余时间（MRT）]参数。结果2组罗哌卡因阻滞犬坐骨神经时的血药浓度-时间曲线符合二室模型,t1/2α、t1/2β,Tmax,Cmax、AUC0-720min、AUC0-∞、AUMC0-72min、AUMC0-∞、MAT、MRT0-720min,MRT0-∞比较差异均无统计学意义（均P〉0．05）。结论动静脉血对罗哌卡因阻滞犬坐骨神经时的药代动力学无影响。     

右美托咪定对肌间沟臂丛神经阻滞罗哌卡因血药浓度的影响

目的 研究盐酸右美托咪定对肌间沟臂丛神经阻滞罗哌卡因血药浓度的影响.方法 拟行肌间沟臂丛神经阻滞的上臂手术患者60例,性别不限,年龄18～59岁,体重46～ 80 kg,ASA分级Ⅰ或Ⅱ级,随机分为两组(n=30);对照组(C组),右美托咪定组(D组).C组神经阻滞用药为0.33％罗哌卡因30 ml,D组用药为右美托咪定100μg+0.33％罗哌卡因混合液30 ml.评价感觉和运动阻滞的效果,记录感觉阻滞和运动阻滞的起效时间和维持时间,于麻醉前(T0)、神经阻滞后1O min(T1)、30 min(手术开始、T2)、60 min(T3)、120min (T6)采静脉血通过高效液相色谱法测定罗哌卡因血药浓度.记录ECG、HR、SPO2、NIBP及恶心呕吐、呼吸抑制、心动过缓等并发症的发生情况.结果 D组T2、T3、T4罗哌卡因浓度分别(2.4±0.12)μ g/ml、(1.784±0.16)μ g/ml 、(1.552±0.12)μ g/ml均高于C组T2、T3、T4时点浓度(1.42±0.15)μg/ml 、(1.36±0.10)μg/ml、(1.02±0.08)μ g/ml(P＜0.05);C组4例使用芬太尼,1例更改麻醉方式;D组无一例使用芬太尼,无一例更改麻醉方式,4例心动过缓,两组均未见恶心呕吐、呼吸抑制等并发症.与C组比较,D组感觉阻滞、运动阻滞维持时间延长(P＜0.05),起效时间差异无显著性(P＞0.05).结论 右美托咪定可延长罗哌卡因在肌间沟臂丛阻滞的血药浓度,增强其阻滞效果.     

LC-MS/MS法测定浸润麻醉豚鼠血浆中罗哌卡因浓度

目的 建立测定豚鼠血浆中罗哌卡因浓度的液相三重四极杆串联质谱(LC-MS/MS)法,用以测定豚鼠局部浸润麻醉皮内注射后血浆中罗哌卡因浓度,并考察罗哌卡因药动学.方法 血浆样品用蛋白沉淀法进行预处理后HPLC-MS/MS法测定罗哌卡因含量.色谱系统:ZORBAX SB-C18 (3.0 mm×150 mm,3.5 μm ),甲醇-水 (80:20,内含5mmol·L-1 甲酸铵 )为流动相,流速0.4 mL·min -1,柱温25 ℃.通过电喷雾离子源(ESI)三重四极杆串联质谱,在正离子模式下以多重反应选择离子检测(MRM).色谱分析时间为4 min.药动学研究中豚鼠皮内浸润麻醉给药0.5%罗哌卡因注射液,按时测定血浆药物浓度.采用TOPFIT软件计算药动学参数.结果 罗哌卡因在6.58～6 580 ng·mL-1内线性良好 (r=0.999 1),方法的最低检测浓度为1 ng·mL-1,方法回收率在95.6%～96.6%之间,日内、日间精密度(RSD)均小于6%.豚鼠皮内注射0.5%罗哌卡因后,主要药动学参数:T1/2α (0.13±0.01) h,T1/ 2β (1.20±0.08) h,Cmax (4 960±13) ng·mL-1,AUC0→9 (11.3±1.6) mg·h·L-1,AUC0→∞ (13.1±2.3) mg·h· L-1,MRT(1.74±0.13) h.结论 建立的LC-MS/MS法快速、准确、灵敏,可用于罗哌卡因豚鼠浸润麻醉的药动学研究.     

舒芬太尼对罗哌卡因腰椎与硬膜下联合阻滞分娩镇痛的影响

目的观察舒芬太尼与罗哌卡因腰椎与硬膜下联合阻滞用于分娩镇痛的效果及安全性。方法选择美国麻醉医师协会（ASA）Ⅰ-Ⅱ级、单胎头位、足月初产妇60例,采取抽签法随机分为舒芬太尼组、芬太尼组、对照组各20例,舒芬太尼组蛛网膜下腔注入0．1％罗哌卡因2．5mg＋舒芬太尼4μg共2．5ml,硬膜外腔配置0．1％罗哌卡因＋舒芬太尼0．4μg／ml至50ml行患者自控镇痛（PCA）;芬太尼组蛛网膜下腔注入0．1％罗哌卡因2．5mg＋芬太尼20μg共2．5ml,硬膜外腔配置0．1％罗哌卡因＋芬太尼2μg／ml加生理盐水至50ml行PCA;对照组蛛网膜下腔注入0．1％罗哌卡因2．5mg,硬膜外腔配置0．1％罗哌卡因2．5ml硬膜外腔配置0．1％罗哌卡因生理盐水至5Tnl行PCA。观察并记录镇痛前后产妇生命体征变化、镇痛效果、Bromage评分、分娩方式、不良反应。结果镇痛前后3组的平均动脉压、心率差异有统计学意义（P〈0．05）;蛛网膜下腔注药后的显效时间,舒芬太尼组[（2．1±1．1）min]和芬太尼组[（2．5±0．7）]优于对照组[（5．5±1．6）min];舒芬太尼组蛛网膜下腔注药维持时间长于芬太尼组和对照组,差异有统计学意义（P〈0．05）,芬太尼组蛛网膜下腔注药维持时间长于对照组（P〈0．05）;舒芬太尼组和芬太尼组的罗哌卡因用药量均分别为（16．5±5．3）mg、（17．8±5．7）mg少于对照组（38．5±8．O）mg（P〈0．05）。结论舒芬太尼可增强罗哌卡因腰硬联合阻滞分娩镇痛的镇痛效应,安全可靠。     

罗哌卡因在手术病人的药代动力学

目的 对单剂量罗哌卡因硬膜外麻醉的手术病人进行药代动力学研究。方法 选择12例手术病人,硬膜外麻醉时,注入罗哌卡因150mg。血药浓度用反相高效液相色谱法测定。用3P97药代动力学计算程序拟合房室模型并计算药代动力学参数。结果 罗哌卡因的主要药代动力学参数:t_(max)为0.27±0.10h;C_(max)为1.86±0.40mg·L~(-1);t_(1/2 (α))为0.23±0.14h;t_(1/2 (β))为2.17±0.55 h;AUC为4.84±1.20 mg·h·L~(-1)。结论 罗哌卡因在手术病人中的代谢符合开放性二室模型。罗哌卡因在体内的消除不受疾病的影响。     

甲磺酸罗哌卡因的药代动力学特征分析

目的探讨甲磺酸罗哌卡因的药代动力学特征。方法首先对甲磺酸罗哌卡因进行色谱分析,然后选择肾功能衰竭患者10名与肾功能正常者10名,给予甲磺酸罗哌卡因镇痛麻醉后测定药代动力学情况。结果罗哌卡因在其浓度0.05~2.50 mg/L时呈良好的线性,最低检测浓度为0.025 mg/L。甲磺酸罗哌卡因的血浆中的平均回收率为104.1%,RSD为3.43%。药代动力学分析显示肾功能衰竭组与肾功能正常组的t1/2β、CL与T值对比差异明显(P<0.05)。结论甲磺酸罗哌卡因有很好的血药峰浓度,而肾功能衰竭可影响其在体内的消除,促进药物的体内蓄积,从而发挥更好的麻醉作用。     

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。     

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.