一步法在茶碱个体化给药中的意义

25例哮喘患者一步法得到茶碱的群体药动学参数Ke 0.087±0.022h~(-1),Vd 0.52±0.10L/kg,CL 44.98ml/(kg·h)当取一点稳态谷浓度作Bayes反馈可得到比较准确的个体药动学参数:12例老年COPD患者Ke 0.054±0.011h~(-1),CL 29±5ml/(kg·h)。18例哮喘患者Ke 0.087±0.030h~(-1),CL 45±15ml/(kg·h),两组患者反馈点实测血药浓度与预测血药浓度相关性均为r>0.99(P<0.01),由此可设计出合理的给药方案,并预报可信的血药浓度。     

健康志愿者及老年慢性阻塞性肺病患者丁胺卡那霉素的药物动力学研究

以荧光偏振免疫分析法(FPIA)测定了6例健康志愿者和4例老年慢性阻塞性肺病(COPD)患者静脉滴注丁胺卡那霉素(Amikacin,AM)7.5mg/kg 的药物动力学。血药浓度-时间曲线为二室开放模型。健康志愿者的平均T_(1/2)β=2.76±0.67h,AUC=68.5±7.2h·μg·ml~(-1);老年COPD 患者的T_(1/2)β=4.71±1.10h,AUC=94.91±25.6h·μg·ml~(-1)。提示该类病人体内AM 的药物动力学过程有所改变。     

表柔比星在肿瘤患者体内的药物动力学

目的;研究表柔比星(Epi)在肿瘤患者体内的药物动力学.方法:11例肿瘤患者单次iv 60mg/m~2Epi,用HPLC测定Epi血药浓度,数据用3P87药物动力学程序进行模型拟合并计算药物动力学参数.结果:Epi的药-时曲线符合三室模型,其主要药物动力学参数分别为:T_(1/2p)=(0.052±0.018)h,T_(1/2(?))=(1.25±1.18)h,T_(1/2p)=(31.1±13.7)h,Vc=(23.9±11.2)ml,AUC=(2009±429)ng·h/ml,CL=(50.1±12.1)ml/h.结论:Epi在肿瘤患者体内分布迅速,消除缓慢.     

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。     

卡铂对肿瘤患者的药物动力学与药效学

目的:研究国产卡铂(CBP)的临床药物动力学与药效学,方法:12例肿瘤病人iv gtt CBP 400mg,用反相HPLC法测定血清CBP浓度,并按残数法拟合药物动力学模型和参数.结果:12例肿瘤病人iv gtt CBP结束时的平均血药浓度(?).为55.10±13.00)mg/L,消除半衰期(T._(2?))为(143.09±49.36)min,清除率(CL)为(45.17±16.68)ml min.有效组和无效组的(?)分别为(61.03±9.28)和(52.14±12.77)mg/L,T_(?)分别为(191.27±26.92)和(119.00±35.31)min(P<0.01),CL分别为(31.42±6.79)和(52.04±15.97)ml/min(P<0.05).在2～10h内.有效组血清CBP浓度高于无效组(P<0.05).结论:肿瘤病人iv gtt CBP的血药浓度存在明显个体差异,且疗效与血药浓度和清除快慢有关.     

克拉霉素对茶碱在兔体内药动学的影响

目的研究克拉霉素对茶碱在新西兰兔体内药动学的影响.方法采用自身对照法,用HPLC测定合用克拉霉素后,茶碱不同时间间隔血药浓度,经3P97程序进行模型判别及参数计算.结果合用克拉霉素注射液后茶碱的t1/3β由(3.24±0.76)h延长至(4.90±1.16)h(P＜0.01);AUC由(75.02±22.41)mg·h·L-1增至(98.18±27.91)mg·h·L-1(P＜0.01);CL由(0.20±0.08)L·h-1下降至(0.13±0.04)L·h-1(P＜0.05).结论克拉霉素注射液与茶碱在兔体内合用可影响茶碱的t1/3β,AUC,CL.     

喹诺酮类药物对茶碱药代动力学的影响

目的探讨喹诺酮类药物对茶碱药代动力学是否存在显著影响,为临床合理用药提供参考。方法采用自身对照法,测定家兔iv 10mg.kg-1茶碱及每天1次灌服喹诺酮类药物,连续6d,再iv 10mg.kg-1茶碱后血浆中茶碱浓度,计算药动学参数。结果合用氟罗沙星前后茶碱在家兔体内按一室模型处理。合用前后茶碱的的药动学参数分别为,K:0.154±0.035h-1,0.151±0.044 h-1;T1/2:4.70±1.12 h,4.90±1.38 h;V:0.562±0.180 L.kg-1,0.556±0.166 L.kg-1;AUC0~10:93.70±32.87 mg.h.L-1,100.20±43.11 mg.h.L-1;AUC0~∞:147.87±68.08 mg.h.L-1,157.16±80.69 mg.h.L-1;CL:0.090±0.046 L.kg-1.h-1,0.091±0.052 L.kg-1.h-1;Cm ax:19.91±5.25 mg.L-1,20.12±5.24 mg.L-1。以上合参数均无显著性差异(P>0.05)。合用氟罗沙星后茶碱的血浆浓度有一定波动,但无统计学意义(P>0.05)。合用芦氟沙星前后茶碱在家兔体内呈一室模型。茶碱的药动学参数分别为,K:0.147±0.017 h-1,0.148±0.018 h-1;T1/2:4.76±0.54 h,4.74±0.56 h;V:0.581±0.089 L.kg-1,0.555±0.075 L.kg-1;AUC0~10:91.42±11.14 mg.h.L-1,94.97±10.20mg.h.L-1;AUC0~∞:119.48±14.96 mg.h.L-1,124.05±14.76 mg.h.L-1;CL:0.085±0.011 L.kg-1.h-1,0.082±0.010L.kg-1.h-1;Cmax:18.48±2.53 mg.L-1,19.16±2.34mg.L-1。合用芦氟沙星前后茶碱各参数均无显著性差异(P>0.05)。合用芦氟沙星后茶碱的血浆浓度有升高趋势,但无统计学意义(P>0.05)。合用培氟沙星前后茶碱在家兔体内呈一室模型。茶碱的药动学参数分别为,K:0.150±0.038 h-1,0.110±0.018 h-1,P<0.01;T1/2:4.95±1.67 h,6.69±2.01 h,P<0.01;V:0.584±0.149 L.kg-1,0.511±0.126 L.kg-1,P<0.05;AΜC0~10:97.71±40.09 mg.h.L-1,126.11±42.72 mg.h.L-1,P<0.01;AΜC0~∞:136.05±83.40 mg.h.L-1,202.10±99.81 mg.h.L-1,P<0.01;CL:0.091±0.038 L.kg-1.h-1,0.056±0.018 L.kg-1.h-1,P<0.01;Cmax:18.94±4.89 mg.L-1,21.82±5.40 mg.L-1,P<0.05。合用加替沙星前后茶碱在家兔体内按一室模型处理。合用前后茶碱的药动学参数分别为,K:0.147±0.035 h-1,0.127±0.026 h-1;T1/2:4.89±0.98 h,5.62±1.09h;V:0.541±0.162 L.kg-1,0.538±0.154 L.kg-1;AΜC0~10:97.81±29.87 mg.h.L-1,107.27±39.54mg.h.L-1;AΜC0~∞:153.32±65.64 mg.h.L-1,174.01±71.03 mg.h.L-1;CL:0.081±0.034 mg.h.L-1,0.074±0.033 L.kg-1.h-1;Cmax:20.51±5.12 mg.L-1,20.60±5.05 mg.L-1。合用加替沙星前后茶碱各参数除T1/2(P<0.05)外无显著差异。结论氟罗沙星、芦氟沙星对茶碱的血药浓度及药代动学参数没有显著影响;培氟沙星对茶碱的血药浓度及药代动学参数有显著影响;加替沙星对茶碱的血药浓度及除T1/2的药代动学参数没有显著影响。     

甲磺酸左氧氟沙星注射液的人体药物动力学

目的:测定国产甲磺酸左氧氟沙星注射液在人体的药物动力学.方法:12名健康受试者恒速iv gtt 200mg/0.5h,用HPLC法测定血清中和尿液中甲磺酸左氧氟沙星浓度.结果:经药物动力学计算程序拟合,符合二室模型.其初始血药浓度C_0为(3.54±0.24)mg/L,T_(1/2β)为(6.53±0.96)h,CL为(14.063±2.639)L/h,V/F为(38.529±3.913)L,AUC为(14.63±2.41)[(mg/L)·h].24h内累积尿药排泄率为(62.97±5.86)%.各项药物动力学参数与国外文献报道基本相符.结论:甲磺酸左氧氟沙星国产与进口产品的体内处置过程相同.     

分光光度法测定茶碱血药浓度和唾药浓度的研究

本文对6名健康人一次静脉注射氨茶碱注射液(剂量5mg/kg),用UV法测其血药浓度的经时变化。其一定模型药物动力学参数为:t_(1/2)8.4730±2.733h;K0.08907±0.02846h~(-1);Vd0.4380±0.1809L/kg;Cmax13.2257±5.6220μg/ml。其中4名受试者唾液与血浆中茶碱浓度比率为0.5340±0.1407;7名受试者全血与血浆中茶碱浓度比率为0.7234±0.08006     

加替沙星对老年慢性阻塞性肺病患者茶碱群体药代动力学的影响分析

目的探讨加替沙星对老年慢性阻塞性肺疾病患者茶碱群体药代动力学的影响。方法应用非线性混合效应模型(NONMEM)程序对所选16例老年慢性阻塞性肺疾病患者进行研究,分析前瞻性收集现口服茶碱缓释片、再联用加替沙星的16例老年慢性阻塞性肺疾病患者256份茶碱血药浓度样本。采用一级吸收一房室开放的模型进行实验患者的群体数据采集,估算所选患者的吸收速率常数(ka)、体内清除率(CL/F)、分布溶剂(V)及滞后时间(ALAG)的个体事件变异用指数模型,患者个体自身的变异数据采用加法模型进行计算。结果根据实验数据可知,单独服用茶碱缓释片与两种药物综合使用时,CL/F相比下降;了13.55%,其他数据无明显变化,两组数据对比差异具有统计学意义(P <0.05)。结论本研究针对老年慢性阻塞性肺疾病患者茶碱群体进行加替沙星结合治疗,可以有效提高药物在患者体内利用度,并保持药物在患者体内维持安全水平。     

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.