6种抗癌药对奥丹西酮在原发性肺癌患者体内药物动力学的影响

目的 研究6种抗癌剂对奥丹西酮药动学的影响。方法 奥丹西酮的药动学在21例分别应用甲氨蝶呤、5－氟尿嘧啶、环已亚硝脲、环磷酰胺和长春新碱、顺氯氨铂的原发性肺癌患中进行观察，化疗前和化疗同时服用奥丹西酮，其血浆浓度采用反相高效液相色谱法测定。数据处理采用PKBP－N1程序。结果 奥丹西酮吸收快，并符合二房室模型，除单／大剂量冲击疗法，持续应用抗癌药物均使其药动学参数发生明显变化，T1／2β延长约1h,T1/2α发生不规则变化，Cmax和AUC也明显升高，但Tmax和T1／2ka长期用药将发生体内蓄积。结论 临床应用奥丹西酮防治化疗所致胃肠道反应时，应据患条件和化疗方案调整给药。     

奥丹西酮在原发性肝癌患者的药物动力学

目的观察奥丹西酮在原发性肝癌患者体内的药物动力学特性。方法8名接受顺铂 5 -氟尿嘧啶化疗的原发性肝癌患者单次和多次口服16mg 奥丹西酮后 ,应用反相高效液相色谱法测定血浆药物浓度 ,并用PKBP -N1程序在计算机上拟合。结果奥丹西酮表现为二房室模型,其单剂量和多剂量口服主要药动学参数分别为 :T1/2β 为4.3±0.5h和5.7±0.7h(P<0.01),Cmax 为42.6±3.8μg/L和49.2±2.3μg/L(P<0.05),Tmax 为1.8±0.2h和1.8±0.1h,AUC0～∞为643.2±84.7μg/h·L和833.4±96.7μg/L·h(P<0.01)。结论原发性肝癌患者多次口服奥丹西酮后与单次口服相比 ,体内有蓄积现象 ,消除能力下降 ,生物利用度升高     

奥丹西酮在原发性肝癌患者的药物动力学

目的 观察奥丹西酮在原发性肝癌患体内的药物动力学特性。方法 8名接受顺铂＋5－氟尿嘧啶化疗的原发性肝癌患单次和多次口服16mg奥丹西酮后，应用反相高效液相色谱法测定血浆药物浓度，并用PKBP－N1程序在计算机上拟合。结果 奥丹西酮表现为二房室模型，其单剂量和多剂量口服主要药动学参数分别为：T1／2β为4.3±0.5h和5.7±0.7h(P<0.01),Cmax为42．6±3.8μg/L和49．2±2.3μg/L(P<0.05),Tmax为1．8±0.2h和1.8±0.1h,AUC0-∞为643．2±84.7μg/h·L和833．4±96.7μg/L·h(P<0.01)。结论 原发性肝癌患多次口服奥丹西酮后与单次口服相比，体内有蓄积现象，消除能力下降，生物利用度升高。     

奥丹西酮片在8例老年肺癌患者中的药物动力学

目的：观察奥丹西酮在老年人体内的药物动力学特性。方法：８名接受顺铂化疗的老年原发性肺癌患者单次和多次口服奥丹西酮后，用高效液相色谱法测定血浆药物浓度，用ＰＫＢＰ－Ｎ１药动学程序拟合计算。结果：奥丹西酮口服后在老年人体内表现为二房室模型。单剂量和多剂量给药时主要药动学参数为：Ｔ１／２β为４．５±０．５ｈ和５．９±０．７ｈ，Ｃｍａｘ为２０．３±１．８μｇ·Ｌ－１和２４．７±２．２μｇＬ－１，Ｔｍａｘ为１．９±０．２ｈ和１．８±０．１ｈ，ＡＵＣ０～２４为３１６±４０μｇ·ｈ·Ｌ－１和４０７±４５μｇ·ｈ·Ｌ－１，积蓄因子为１．３。结论：老年患者多次口服奥丹西酮后与单次口服相比，体内消除能力明显下降     

坎地沙坦西酯片人体药动学和与必洛斯片的生物等效性及坎地沙坦吸收机制的研究

目的研究评价坎地沙坦西酯片人体药动学和与必洛斯片的生物等效性研究。方法药动学研究选取20例中国健康男性受试者口服8mg坎地沙坦西酯片;生物等效性研究选择20例受试者,随机编号分成两组,交叉给药;建立Caco-2细胞模型,考察其生物等效性。结果坎地沙坦西酯片Cmax约为93ng/mL,Tmax为3~5h,T1/2为9h,药动学个体差异较大;坎地沙坦西酯片与必洛斯片的药动学参数无显著差异,试验制剂与参比制剂等效。结论本次试验研究中坎地沙坦西酯片的药动学特征,坎地沙坦西酯片与必洛斯片的生物等效性与国外文献报道基本一致。     

甘草提取物对胺碘酮在大鼠体内药动学的影响

目的研究甘草对胺碘酮在大鼠体内药动学的影响。方法 14只实验大鼠随机分为对照组与实验组,分别予0.9%氯化钠溶液和甘草提取物（0.5g·kg^-1,qd×7d）后,胺碘酮灌胃给药按时间点连续采样,采用HPLC法测定血药浓度。计算并比较主要药动学参数。结果对照组和实验组的胺碘酮主要药动学参数ρmax、tmax、t1/2、AUC0→24h2、AUC0→∞、CL/F和MRT差异均无统计学意义（P〉0.05）。结论甘草连续给药7d后不影响胺碘酮在大鼠体内的药动学特征。     

预测在儿童白血病患者治疗中依托泊苷的血药浓度

目的采用一个简单的、实用的方法评价临床个体患儿体内CYP3A酶活性;预测儿童白血病患者体内依托泊苷血药浓度、药动学参数。方法采用HPLC测定药物浓度,一点法计算药物消除半衰期,尿样法测定体内CYP3A酶活性。结果儿童白血病患儿体内依托泊苷药物浓度与CYP3A酶活性相关性较差,而其t1/2与个体在化疗前CYP3A酶活性变化的相关性较好。结论依托泊苷t1/2与儿童白血病患儿体内CYP3A酶活性有一定的相关性。     

注射用头孢噻肟钠/舒巴坦钠在犬体内的药物动力学研究

目的考察注射用头孢噻肟钠、注射用舒巴坦钠、注射用头孢噻肟钠/舒巴坦钠在犬体内的药动学特征,比较复方制剂与单方制剂的药动学差异。方法本实验采用6只健康Beagle犬,分为三组,进行3×3拉丁方实验,间隔一周后于股静脉注射,交叉给药。采用RP-HPLC测定犬血浆中头孢噻肟与舒巴坦浓度;采用3P87程序对血药浓度-时间曲线进行室模型拟合;采用SPSS软件对药动学参数进行统计处理。结果头孢噻肟与舒巴坦在犬体内的处置都符合二室模型。复方制剂与单方制剂中头孢噻肟和舒巴坦的药动学参数α、β、AUC0-∞、AUC0-t、t1/2α、t1/2β、CL和Vc经方差分析和配对t检验,均无显著性差异(α=0.05)。结论头孢噻肟钠与舒巴坦钠组成复方制剂后,其各自的药动学特征未发生改变,两组分无药动学的相互作用。     

黄芪注射液对格列喹酮在糖尿病大鼠体内药动学的影响

目的:研究黄芪注射液对格列喹酮在糖尿病大鼠体内的药动学的影响。方法:将10只糖尿病大鼠随机分为2组,A组作为对照组单独灌胃给予120 mg.kg-1的格列喹酮混悬水溶液;B组作为实验组给予黄芪注射液(8 mL.kg-1)5 min后,灌胃给予格列喹酮混悬水溶液(120 mg.kg-1)。于给药后不同时间点采集血样,采用HPLC-荧光检测器测定格列喹酮的血药浓度,绘制药时曲线,用DAS 2.0计算药动参数,并对主要药动学参数进行统计学分析。结果:格列喹酮单用或与黄芪注射液合用后,其在糖尿病大鼠体内的药动学过程均符合二室模型,但合用后格列喹酮Cl/F较单用时显著性减小(P<0.01),Cmax、t1/2β和AUC较单用时显著性增大(P<0.01)。结论:黄芪注射液可降低格列喹酮经肝药酶CYP2C9的代谢,从而提高了格列喹酮的生物利用度,提示糖尿病患者在两药合用时应降低格列喹酮的用药剂量。     

CYP3A5和MDR1基因多态性对中国肝移植患者他克莫司药动学的影响

目的探讨细胞色素P450酶3A5（CYP3A5）基因和多药耐药基因（MDR1）C1236T、G2677T／A、C3435T多态性对肝移植患者口服他克莫司（TAC）后体内药动学参数的影响。方法采集28例肝移植患者手术后第1周和第3周血标本,采用LC—MS／MS法检测TAC血药浓度,计算主要药动学参数。采用聚合酶链反应结合基因测序分析28例肝移植患者CYP3A5＊3和MDR1主要基因型。结果携带MDR1 3435T基因型的肝移植患者口服TAC后,药动学参数AUC0→1和ρmax明显高于3435CC型患者,而CYP3A5＊3、MDR1 C1236T和G2677T／A基因多态性对TAC的药动学参数无明显影响。结论携带MDR1 3435T基因型肝移植患者比3435CC型患者需要较高剂量才能达到目标浓度。     

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.