万古霉素在危重患者体内的药代动力学研究

目的 研究万古霉素在危重患者体内的药代动力学特点.方法 入选8例肝肾功能正常的危重病患者,给予万古霉素0.5g溶解100 ml 0.9％氯化钠溶液中静脉滴注1h后多次留取血液标本和尿液标本,利用高效液相色谱分析得到万古霉素的血、尿药代动力学参数.结果 在危重病患者体内万古霉素仍符合二室模型,血样回归方程:A =5315.3p+ 1176.4(r =0.9998,A为峰面积,为万古霉素浓度),尿样回归方程:A= 10 368p -7150.3.血浆药代参数药物浓度-时间曲线下面积(AUC)( 162.72±84.23)μg(h·ml);二室模型分布相的半衰期(t1/2α)(0.49±0.30)h,二室模型消除相的半衰期(t1/2β)(7.08±4.01)h,总清除率(Cl)(63.09±31.09) ml/min,一次给药后的最大血药浓度(Cmax)(44.46 ±28.60) μg/ml,tmax(1.0±0)h,表观分布容积(0.28±0.15) L/kg,尿液药代参数tmax(3.50±3.16)h,Cmax(74 889.86±83 277.71) μg/h,t1/2β( 10.47±9.61)h,AUC[ (31 5464.1±284 428.3)μg/(h·ml)].结论 对于危重病患者,给予0.5g万古霉素,AUC约为健康人的2倍;t1/2β也长于健康人.这可能与危重患者组织灌注不足,药物从循环向组织扩散减慢,体温异常而使药物代谢的酶活性降低等有关.同时对于重症患者因万古霉素谷浓度易高于正常而应更关注万古霉素的不良反应.     

ICU老年患者液体出入量对万古霉素药代动力学的影响

目的 研究液体出入量对ICU老年患者万古霉素药代动力学的影响.方法 完全随机选择8例ICU中应用万古霉素的老年患者,记录其每日液体出入量,并采集患者血液,利用高效液相色谱法测定万古霉素的血药浓度,计算药代动力学参数,对万古霉素药代动力学参数与患者每日出入量之间的关系给予统计学分析.结果 ICU老年患者年龄(71 ±11)岁,急性生理学与慢性健康状况评分系统Ⅱ(APACHEⅡ)评分(17.13±3.13)分,液体净出入量(375±123)ml,分布半衰期(t1/2α)(0.45±0.27)h,清除半衰期(t1/2β)(6.86±3.42)h,浓度时间曲线下面积(AUC)(137.9±19.9) mg/(h·L),峰值浓度(Cmax)(36.14±10.30) mg/L,清除率(61.56±29.11) ml/min,表观分布容积(0.28±0.14)L/kg.ICU老年患者与正常老年人相比,表观分布容积差别有统计学意义(P＜0.01).ICU老年患者APACHEⅡ评分与液体净出入量和万古霉素t1/2β均呈正相关(r=0.811,P=0.015;r =0.035,P=0.035);液体出入量与血AUC呈负相关,与血t1/2β呈负相关(r=- 0.786,P=0.021).结论 当ICU患者的出入量平衡增加时,其万古霉素的杀菌效果可能会降低,难以达到预期疗效.     

甾体激素的紫外光谱褶合变换可视化指纹谱鉴别研究

目的:考察注射用复方氨苄西林钠的药代动力学特征。方法:HPLC法检测注射家兔后不同时间血浆的氨苄西林与丙磺舒药代动力学参数。结果:以氨苄西林钠计,注射用复方氨苄西林钠300 mg/kg组能够显著的增加氨苄西林半衰期,由(23±10)min增至(31±15) min,AUC由(8．5±0．9)mg/(h·mL)增至(6．2±0．8) mg/(h·mL),注射用复方氨苄西林钠120 mg/kg组氨苄西林AUC由(2．8±0．9)mg/(h·mL)增至(5．7±1．0)mg/(h·mL),注射用复方氨苄西林钠50 mg/kg组氨苄西林AUC由(0．7±0．2)mg/(h·mL)增至(1．5±0．3)mg/(h·mL)(P＜0．05或P＜0．01)。结论:注射用复方氨苄西林钠具有增强注射用氨苄西林钠活性的作用。     

静脉注射盐酸关附甲素的人体药代动力学研究

目的:关附甲素(Guanfu Base A-GFA)是从中药关白附的根块中提取分离得到的具有抗心律失常活性的单体药物.为研究单次静脉注射盐酸GFA人体内药代动力学.方法:健康男性10名,年龄:22岁～24岁(平均22.7±0.7岁);体重:50kg～70kg(平均60.6±4.5kg).单一剂量盐酸GFA 4mg·kg-1,恒速静推5min.静脉用药前及静注完毕即刻(0),5,10,20,30,60,90,150,240,360,540,720min取血.采用气相色谱法测定关附甲素血药浓度.绘制药物浓度-时间曲线图.用3P87药代动力学程序拟合药-时曲线,推导出其动力学模型;并求出相应的药代动力学参数.结果与结论:静脉应用关附甲素的药代动力学类型以三室模型解释为宜.药代动力学参数:中心室分布容积(Vc),17.5±2.8L;血药浓度-时间曲线下面积(AUC0-t)980.6±163.9mg·L-1·min;药物总清除率(CL)0.2±0.1L·min-1;分布半衰期(T1/2pi)2.6±1.2min;分布半衰期(T1/2α)18.1±20.4min;消除半衰期(T1/2β)480.4±134.4min.     

多烯紫杉醇在乳腺癌患者体内的药代动力学研究

目的研究多烯紫杉醇在乳腺癌患者体内的药代动力学。方法 10例乳腺癌患者采用多烯紫杉醇75 mg·m~(-2)静脉滴注1 h化疗,在化疗后不同时间采集血液标本,用HPLC法测定多烯紫杉醇血药浓度,用DAS 3.0软件计算药代动力学参数。结果多烯紫杉醇的血浆药物峰浓度Cmax均值为(3.345±1.05)mg·L~(-1),血药浓度-时间曲线下面积AUC0~12 h均值为(3.247±0.91)mg·h·L~(-1),消除半衰期t1/2均值为(9.602±3.72)h,清除率CL均值为(18.718±3.84)L/(h·m)-2。药动学参数在患者个体间存在较大差异。结论多烯紫杉醇在乳腺癌患者体内的药代动力学存在较大个体差异,提示在临床用药时需要监测多烯紫杉醇的血药浓度,进行个体化给药。     

艾普拉唑肠溶片在中国健康人体中药代动力学及绝对生物利用度研究

目的 采用液相色谱串联质谱(UPLC-MS/MS)分析方法研究艾普拉唑肠溶片在中国健康人体中的吸收特性. 方法 采用随机交叉自身对照试验设计,16名健康受试者随机等分成4组,先后口服艾普拉唑肠溶片或静脉注射艾普拉唑钠,采用UPLC-MS/MS测定血浆药物浓度.利用WinNonlin(V6.1)软件标准非房室模型方法进行药代动力学参数的计算. 结果 注射用艾普拉唑钠(10mg)的主要药代动力学参数:最大血药浓度(Cmax)为(834.3±101.2)ng/mL,消除半衰期(t1/2)为(3.4±0.9)h,表观分布容积(Vz)为(14.0±2.2)L, 0到t时间药时曲线下面积(AUC0_t)为(3520.9±915.3)ng·h/mL,血浆清除率(CL)为(3.0±0.9)L/h.艾普拉唑肠溶片(10mg)的主要药代动力学参数:Cmax为(347.9±176.3)ng/mL,t1/2为(3.5±0.8)h,Vz为(29.1±12.2)L,AUC0_t为(1970.2±834.7)ng·h/mL,CL为(5.9±2.5)L/h.与静脉给药相比,口服艾普拉唑肠溶片的绝对生物利用度为(55.2±13.9)%. 结论 艾普拉唑肠溶片生物利用度良好,适于开发.     

注射用法罗培南钠在健康人体的耐受性及其连续给药的药代动力学

目的 确定注射用法罗培南钠(碳青霉烯类抗生素)最大耐受剂量及其连续给药的药代动力学研究.方法 58名健康受试者分别单次静滴注射用法罗培南钠100、200、300、450、600、800 mg及连续静滴给药每次200、300mg,每日3、2次,连续滴注7天.用HPLC法测定连续静滴注射用法罗培南钠200 mg组受试者血浆及尿中法罗培南的浓度.结果 单次450 mg组和连续200、300 mg组,各1人血清ALT、AST升高外;其余受试者无任何不良反应发生.连续多剂量静滴法罗培南钠200 mg后,其药代动力学参数:tmax为(1.00±0.00)h;Cmax为(15.80±3.96)μg·mL-1;t1/2为(1.07±0.27)h;CL/F为(0.15±0.03)L·kg·h-1;Vd/F为(0.23±0.07)L·kg-1;Cav为(2.81±2.96)μg·mL-1;DF为(6.55±5.47);AUC0-t为(24.00±6.23)μg·h·mL-1;AUC0-∞为(23.70±6.27)μg·h·mL-1.其12 h累积尿药排泄率为40.49%.结论 其最大耐受剂量为800 mg;推荐Ⅱ期临床剂量为每次200mg,每日3次.     

CYP2D6抑制剂对艾瑞昔布大鼠体内药代动力学的影响

目的考察CYP2D6抑制剂帕罗西汀对艾瑞昔布在大鼠体内药代动力学的影响。方法选用甲苯磺丁脲为内标,色谱柱为Diamonsil C18柱(150 mm×4.6 mm,5μm),流动相为甲醇-水-甲酸(85∶15∶0.1,V/V/V),等度洗脱,流速为1.0 mL/min,柱温为30℃。将40只健康雄性SD大鼠随机分为实验组和对照组,各20只,实验组大鼠灌胃帕罗西汀溶液2 mg/kg,对照组大鼠灌胃等量1‰羧甲基纤维素溶液,1次/日,连续给予7 d。两组大鼠均于第8天灌胃艾瑞昔布灌胃液(20 mg/kg),并按时取血,测定血药浓度,采用DAS 2.1.1软件拟合药-时曲线(AUC),并计算药代动力学参数,采用SPSS 13.0统计学软件分析。结果实验组的0-∞药时曲线下面积(AUC0-∞)为(1730.4±606.5)mg/(h·L)明显高于对照组的(1331.3±592.6)mg/(h·L)(P<0.05);实验组的峰浓度(Cmax)为(192.1±70.8)mg/L,明显高于对照组的(162.2±53.0)mg/L(P<0.05);实验组的清除率(CL)为(0.01±0.01)L/(kg·h),明显优于对照组的(0.02±0.01)L/(kg·h)(P<0.05)。结论CYP2D6抑制剂帕罗西汀预处理的大鼠,其体内艾瑞昔布的暴露量增大,清除率减小。CYP2D6抑制剂减慢了艾瑞昔布在大鼠体内的代谢,推断CYP2D6参与了艾瑞昔布的代谢。     

阿斯咪唑混悬剂的人体药代动力学

目的比较国产、进口阿斯咪唑混悬剂在健康中国人体的药代动力学。方法用放射免疫法测定血浆阿斯咪唑 去甲阿斯咪唑含量 ,按交叉设计法对国产和进口阿斯咪唑混悬剂进行健康中国人体的药代动力学的比较,并求相对生物利用度。结果经3P87软件处理 ,阿斯咪唑的药代动力学呈二室模型。主要药代动力学参数 :国产剂 :Vd=6.88±1.36L;αT1/2=4.24±4.06h;βT1/2=170.31±73.80h;CL=0.067±0.023ng/ml;Tpeak=1.00±0.53h;Cmax=1.25±0.17ng/ml;AUC=162.97±48.57ng/ml·h-1。进口片 :Vd=6.40±3.07L;αT1/2=1.31±0.91h;βT1/2=156.02±120.74h;CL=0.079±0.045ng/ml;Tpeak=1.00±0.53h;Cmax=1.08±0.19ng/ml;AUC=173.46±114.66ng/ml·h-1。结论国产、进口阿斯咪唑混悬剂在中国人体的药代动力学参数均未发现明显差异。     

超氧化物歧化酶在小鼠体内的药代动力学

本文研究了~(125)Ⅰ-超氧化物歧化酶(~(125)Ⅰ-SOD)1次皮下注射后在小鼠体内的药代动力学。血中药物浓度——时间曲线近似一级吸收一室开放模型。皮下注射~(125) -SOD~5·~5MBq/Kg(325,000u/Kg)后的药代动力学参数为吸收半衰期(t_1/_2Ka)0.25h;消除相半衰期(t_1/_2β)15h;表观分布容积(Vd)30.01ml/Kg;体内清除率(CL)1.3835ml/Kg.h-1;血药浓度一时间曲线下面积(AUC)4748.45u/ml.h。 SOD在体内的分布以肾脏最多,尤其是肾皮质;心脑分布最少,说明SOD不易通过血脑屏障进入中枢神经系统。SOD为广泛存在于有机体内的一种金属酶。自猪血红细胞内提取的SOD具有明显的抗炎及放射防护作用。关于SOD的药代动力学国内尚未见报道。我们进行了SOD在小鼠体内的吸收、分布及排泄的实验研究,并提出初步数学模型及有关药代动力学参数,提供临床设计给药方案参考。     

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.     

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.     

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.