大鼠血浆中补阳还五汤及总苷元的阿魏酸药物动力学研究

目的:对补阳还五汤及总苷元在大鼠血浆中阿魏酸的含量进行测定,并研究其药物动力学。方法:采用反相高效液相色谱法,色谱柱:C_(18)柱(250 mm×4.6 mm,5μm),检测波长:322 nm,流动相:甲醇-水-冰醋酸(35:65:0.47),流速:1 ml·min~(-1),柱压:(2200±60)psi;温度:35℃。药物动力学参数采用3P87软件处理。结果:血浆样品中阿魏酸线性范围为1.01～5.05 ng(r=0.999 8),平均方法回收率为98.85%,RSD为1.3%。补阳还五汤中阿魏酸的t_(1/2α)为1.31 min;t_(1/2β)为58.9 min;CL为(2.83±0.12)ml·min~(-1)·kg~(-1);AUC为(531.6±67.9)μg·min·ml~(-1);总苷元中阿魏酸的t_(1/2α)为1.39 min;t_(1/2β)为52.3 min;CL为(3.43±0.22)ml·min~(-1)·kg~(-1);AUC为(593.3±45.7)μg·min·ml~(-1),两组药动学参数中B(μg·ml~(-1))、t_(1/2)β(min)和V_c(ml·kg~(-1))存在显著差异(P<0.05)。结论:补阳还五汤复方及总苷元中阿魏酸药物动力学为二室模型。中药复方成分组合对药物动力学参数有一定影响。     

异丙酚全麻下瑞芬太尼在手术患者的药代动力学

目的研究瑞芬太尼(麻醉药)复合异丙酚靶控输注静脉全麻的临床药代动力学。方法选择24例靶控输注异丙酚全麻手术患者,以不同速度0.50,0.75,1.00μg·(kg·min)-1输注瑞芬太尼,取桡动脉血浆,用高效液相色谱-紫外法检测瑞芬太尼浓度,用DAS计算药代动力学参数。结果瑞芬太尼符合二室模型,3组患者的t1/2α、t1/2β、V1、V、CL比较无显著性差异(P>0.05),AUC(0-∞)、V、t1/2β和CL的RSD分别为33.42%,67.38%,51.22%和68.10%。结论瑞芬太尼不同输注速率对药代动力学无明显影响,但应注意个体化给药。     

单次口服硫辛酸胶囊在中国健康志愿者体内的药物动力学研究

目的:研究硫辛酸胶囊在中国健康人体内的药物动力学。方法:22名健康志愿者单剂量口服硫辛酸胶囊200 mg,用HPLC-MS法测定硫辛酸血浓度,并拟合药动学参数。结果:主要的药动学参数Ka为(0.109±0.117)min~(-1),t_(1/2)为(24.42±9.51)min,t_(max)为(16.59±4.47)min,C_(max)为(1489.93±358.65)ng·ml~(-1),AUC_(0-1)为(59558.64±18456.17)ng·min·ml~(-1),MRT_(0-t)为(46.46±14.73)min,Vc/F为(129.09±59.59)L,Cls/F为(3646.83±1110.76)ml·min~(-1)。结论:健康志愿者口服硫辛酸胶囊后的体内过程呈线性动力学特征,符合一级消除过程。     

家兔静注蝮蛇抗栓酶的药物动力学

以家兔凝血时间的延长作为分级定量的药理指标,测定了蝮蛇抗栓酶 iv 给药的药动学参数和 ig给药的生物利用度。按二室开放模型拟合的结果如下:t_(1/2α)=1.12h;t_(1/2β)=3.8h;k_(12)=0.039h~(-1);k_(21)=0.56h~(-1);k_(10)=0.21h~(-1);CL=0.021kg/kg·h;V_c=0.098kg/kg;V_p=0.0069kg/kg;V_(ss)=0.105kg/kg;F=10.9%。     

体内药物累积法研究白血康的表观药物动力学

采用体内药物累积法测定小鼠 ip 白血康后的体内过程和药动学参数,白血康在小鼠体内的过程符合二室开放模型,模型方程为:体存率%=87.1711e~(-1.0952t) 138.1771e~(-0.0272t),t_(1/2)α=0.6328h,t_1/2β=25.48h,k_(21):0.6821h~(-1),k_(12)=0.3966h~(-1),k_(10)=0.0437h~(-1),Vc=3.55L/kg.     

HPLC-MS／MS法研究盐酸右美托咪定注射液的人体药物代谢动力学

目的:研究盐酸右美托咪定注射液在健康成年志愿者体内的药代动力学。方法:采用单次给药的开放、平行实验设计。将受试者随机分入3个剂量组,每组包含5名男性和5名女性,分别静脉注射盐酸右美托咪定0.5,1.0,1.5μg·kg~(-1),采用HPLC—MS/MS 法测定给药后不同时间的血药浓度,用 DAS Ver 2.0和 SPSS 进行药动学参数计算和统计分析。结果:健康受试者在10 min 内静脉注射不同剂量盐酸右美托咪定0.5,1.0,1.5μg·kg~(-1)后,盐酸右美托咪定的主要药代动力学参数 C_(max)(ng·L~(-1))分别为105.2±28.3,148.7±35.9,287.1±62.3;t_(1/2α)(min)分别为:3.2±0.7,5.5±3.2,4.0±0.6;t_(1/2β)(min)分别为:92.4±19.0,106.9±20.9,99.8±9.7。结果表明在上述剂量范同内 AUC_(0-360)、AUC_(0-∞)与给药剂量呈线性关系;t_(1/2β)、CL 和MRT 在上述不同剂量组间无显著性差异(P>0.05);t_(1/2α)和 V_d 在上述不同剂量组间差异有显著性(P<0.05),但与给药剂量无关。结论:在0.5～1.5μg·kg~(-1)的剂量范围内,盐酸右美托咪定注射液在健康成年志愿者体内呈线性动力学特征。     

盐酸阿芬太尼在手术病人中的药代动力学研究

本文进行了两组不同剂量的阿芬太尼在14例手术病人中药代动力学研究。7例一次性iv 80μg·kg~(-1)阿芬太尼,另7例一次性iv 40μg·kg~(-1)。用RIA方法测定0-8 h阿芬太尼的血浆浓度和0-48 h尿中的回收率。研究表明:阿芬太尼在两组病人体内的药代动力学过程均为3室模型。阿芬太尼的初级消除很快,给药后30 min内90％的原型药被消除。病人血浆浓度未发现2次上升现象。二者药-时曲线接近平行,说明阿芬太尼的代谢过程为1级消除。两组阿芬太尼的药代动力学数据经t检验无显著差异(P>0.05)。阿芬太尼的快、慢分布相和消除相的半衰期t_(1/2)π,t_(1/2)α和t_(1/2)β分别为0.71 min±s 0.37 min,11.66 min±s 3.46 min和86.12 min±s 19.15 min;平均总体和中心室的分布容积Vd、Vc分别为34.22L±s 8.27L和4.23L±s 1.72L;平均总体清除率Cl为0.29 L·min~(-1)±s 0.08L·min~(-1)。另外,k_(12)/k_(21)为1.5,k_(13)/k_(31)为3.5,k_(10)大于k_(31)。用药后48 h以内,40μg·kg~(-1)组和80μg·kg~(-1)组的病人尿中排出的原形阿芬太尼分别占总给药量的0.68％±s 0.72％和0.66％±s 0.54％。其肾清除率分别为0.0016 L·min~(-1)±s 0.0011 L·min~(-1)和0.0021 L·min~(-1)±s 0.0015 L·min~(-1)。     

地奥司明片在健康人体内的药物动力学

目的:建立测定人血浆中地奥司明苷元浓度的液相色谱-串连质谱检测法,并研究地奥司明片在健康人体内的药物动力学特征。方法:用LC/MS/MS法测定,色谱柱为CAPCELL PAK UG120柱,流动相为乙腈-0.1%甲酸溶液(80:20,v/v),流速0.6 ml·min~(-1),柱温为24℃,对12名健康志愿者口服地奥司明片后不同时间点的血药浓度进行测定,并用统计矩法计算药动学参数。结果:地奥司明片中地奥司明苷元在健康受试者体内的主要药动学参数t_(max)为(12.1±0.9)h,C_(max)为(8.88±2.69)ng·ml~(-1),t_(1/2)为(11.9±2.5)h,AUC_(0-48h)为(183±55)ng·h·ml~(-1),AUC_(0-∞)为(200±61)ng·h·ml~(-1)。结论:本方法具有良好的准确性、精密度和较高的灵敏度、简便快速,能满足地奥司明的血药浓度测定和药动学研究。     

复方纳米雄黄中砷在大鼠体内的药动学*

目的:研究复方纳米雄黄中砷在大鼠体内的药动学行为。方法:用氢化物发生-双道原子荧光光谱法测定血清中砷元素的浓度,并计算药动学参数。结果:低、中、高(35,70,140 mg·kg~(-1))三剂量组主要药动学参数分别为t_(1/2)Ka:0.34,0.30,0.29 h;t_(1/2)Ke:19.0,21.6,22.1 h;CL/F:7.1,6.5,6.0 mL·kg~(-1)·h~(-1);V_d/F:188.6,200.1,191.0 mL·kg~(-1);C_(max):180.9,334.4,693.1 ng·mL~(-1);AUC:5069,10650,23393 ng·mL~(-1)·h。除C_(max)和AUC外,其他药动学参数在3种剂量组间比较和雌雄性别之间比较,差异均无统计学意义(P>0.05),而C_(max)和AUC则与剂量呈正比。结论:复方纳米雄黄中砷在大鼠体内的药动学行为符合开放性血管外给药一室模型一级速率过程。     

米索前列醇片在健康人体内的药动学特征

目的建立人血浆中米索前列醇浓度的LC-MS/MS检测方法,研究米索前列醇片在健康志愿者体内的药动学特征。方法采用K-MS/MS C_(18)分析色谱柱(150 mm×4.6 mm,5μm);流动相为甲醇-水-1%氨水(55:45:0.075,V/V/V);流速为0.5 mL·min~(-1);柱温为室温。结果该测定方法的线性范围为10～3000 ng·L~(-1)(r=0.9964),最低检测浓度为10.0 ng·L~(-1)(按R_(S,N)≥3计),提取回收率为80%～90%,日内和日间RSD均<10%。药动学研究表明,米索前列醇片在体内代谢过程符合一室模型,主要药动学参数t_(1/2)、ρ_(max)、t_(max)、AUC_(0-360)分别为:(1.15±0.26)h,(1 209±973)ng·L~(-1),(32±13)min,(1 359±1 015)ng·h·L~(-1)。结论本法具有良好的准确性和较高的灵敏度,简便快速,适用于米索前列醇片血药浓度的测定和药动学研究。     

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.     

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.     

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.     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.