单剂量美他多辛注射液在健康人体的药代动力学

目的研究美他多辛注射液在健康人体的药代动力学。方法10名健康受试者随机分为3组,先后静滴美他多辛600,900,1200mg,点滴时间为3h;2次实验间隔1周,用高效液相色谱法测定血药浓度。结果主要药代动力学参数Cmax分别为(4.4±0.79),(8.35±1.64)和(11.61±2.33)mg·L-1;t1/2分别为(0.78±0.09),(0.83±0.10)和(0.81±0.12)h;AUC0-tn分别为(12.02±2.074),(22.89±4.79)和(35.02±7.07)mg·h·L-1;AUC0-∞分别为(13.14±2.06),(23.52±4.6)和(35.46±7.48)mg·h·L-1。约有10%~30%的美他多辛以原形物经肾脏排泄。对3组t1/2分别做t检验,结果显示无显著性差异(P>0.05)。结论不同给药剂量,其分布及消除过程基本一致。     

美罗培南在连续性肾脏替代治疗患者中的药代动力学

目的研究美罗培南(碳青霉烯类抗生素)在连续性肾脏替代治疗(CRRT)患者的药代动力学特点。方法10名CRRT患者在30 min内匀速静滴美罗培南1.0 g,给药后不同时间收集血样和置换液,用HPLC检测药物浓度,用3P97软件计算药代动力学参数。结果在静脉滴注美罗培南1.0 g后。血药浓度-时间数据以二室模型拟合最佳,t_(1/2α)为(0.25±0.06)h,t_(1/2β)为(6.96±2.17)h,C_(max)为(48.50±12.32)mg·L~(-1),Vc为(24.48±7.21)L,AUC为(203.20±48.61)mg·h·L(-1)。结论美罗培南在CRRT患者的主要药代动力学参数与健康者有较大的差异,临床应用时应适当减少剂量或延长给药间隔。     

中国健康志愿者单剂口服甲磺酸加替沙星片的药代动力学研究

目的研究中国健康成年志愿者单剂口服甲磺酸加替沙星片的药代动力学。方法按GCP指导原则设计试验方案,选择9名健康受试者分别依次单剂口服200、400、600mg三个剂量的甲磺酸加替沙星片后,应用HPLC测定血药浓度,采用3P97软件进行数据处理,求出药代动力学参数。结果受试者分别给药后,药-时曲线符合二房室模型,主要药代动力学参数Cmax分别为(2.028±0.362)mg/L、(3.749±0.446)mg/L、(4.876±0.569)mg/L;t1/2β分别为(7.489±0.806)h、(7.063±0.890)h、(7.735±0.8701)h;AUC0-t分别为(12.24±1.51)mg·h/L、(26.02±3.38)mg·h/L、(39.22±6.57)mg·h/L;原型药主要经肾排泄,48h尿药累积排泄率分别为(61.90±7.70)%、(60.90±5.70)%和(58.74±13.49)%。结论9名健康受试者分别口服给药后,药-时曲线符合二房室模型,甲磺酸加替沙星在200～600mg剂量范围内药物体内过程呈线性动力学特征而无饱和性,主要排泄途径为肾脏。     

注射用比伐卢定在中国健康受试者中的药代动力学

目的 研究注射用比伐卢定(抗凝药)在中国健康受试者中的药代动力学.方法 48名健康志愿者接受3种不同剂量的单次静脉推注以及序贯(推注后静滴维持剂量)注射用比伐卢定后,用液相色谱质谱-联用法测定其血药浓度,用WinNonlin 5.2.1进行药代动力学参数计算.结果 单次静脉推注0.50,0.75,1.05 mg·kg-1剂量组的主要药代动力学参数如下:C0分别为(4.90±4.56),(6.50±4.66),(6.81±4.13)mg·L-1;t1/2分别为(0.41±0.12),(0.48±0.17),(0.46±0.15)h;AUC0-t分别为(1.13±0.35),(1.97±0.36),(2.29±0.90)h·mg·L-1.序贯组t1/2为(0.94±0.26)h;AUC0-t为(18.03±6.25)h·mg·L-1.结论 中国健康受试者单次静脉推注比伐卢定0.50～1.05 mg·kg-1,药代动力学呈线性动力学特点,在本剂量范围内,能维持较为恒定的血药浓度.     

阿莫西林/克拉维酸钾片在健康人体的药代动力学与药效学

目的研究阿莫西林/克拉维酸钾片的药代动力学与药效学。方法健康男性志愿者单次口服阿莫西林/克拉维酸钾片625mg,用微生物法测定阿莫西林的血药浓度及尿药浓度。结果血药浓度-时间曲线符合二房室模型,阿莫西林的主要药代动力学参数Cmax为(7.69±0.74)mg·L-1,tmax为(1.39±0.53)h,t1/2β为(1.30±0.57)h,AUC0-∞为(19.95±1.76)mg·h·L-1,CL为(27.83±3.97)L·h-1,24h尿累积排泄百分率为(61.34±23.45)%。T>MIC为4.7~>8h,占给药间隔比例为39%~67%,对青霉素耐药肺炎链球菌株,T>MIC接近30%。结论对社区获得性呼吸道感染所常见敏感致病菌,阿莫西林/克拉维酸625mg,每日2次,有较好疗效。     

盐酸头孢他美酯的药代动力学研究

目的:观盐酸头孢他美酯的药代动力学特征.12名健康志愿受试者单次口服500 mg盐酸头孢他美酯片剂.方法:采用高效液相色谱法测定给药后不同时间的血浆中头孢他美浓度,用3P97程序拟合房室模型和计算药代动力学参数.结果:盐酸头孢他美酯口服后血浆中活性成分为头孢他美,血药浓度-时间曲线为二室模型,主要药代动力学参数tmax为2.3±0.5h,Cmax为4.43±1.33mg·L-1,T1/2β为2.31±0.42h,Vd/F为0.86±0.33L·kg-1,CL/F为16.75±4.43L·h-1,AUC为24.566±5.825 mg·h·L-1.结论:提示前体药物头孢他美酯的体内过程我国汉族人与西方人基本相似.     

注射用硫酸阿司米星单剂给药在健康人体的药代动力学

目的 研究注射用硫酸阿司米星(胺基糖苷类抗生素)在中国健康受试者单剂量给药的药代动力学.方法 采用随机、三交叉、拉丁方设计,12名受试者随机分为3组,先后静脉滴注3个剂量(150,200,250 mg)阿司米星.收集的血、尿样本,用柱前衍生化高效液相色谱-荧光法测定其血药浓度.结果 3个剂量组(150,200,250 nag)主要药代动力学参数:C_(max)分别为(11.27±2.65),(15.83±3.14),(21.97±3.67)mg·L~(-1);t_(1/2β)分别为(2.56±0.72),(2.97±1.30),(2.66±1.39)h;AUC_(0-t)分别为(30.92±8.49),(39.58±11.57),(47.31±11.59)mg·h·L~(-1);AUC_(0-∞)分别为(31.78±8.73),(40.50±11.56),(48.20±11.95)mg·h·L~(-1);V_c分别为(11.49±2.61),(10.69±1.52),(10.20±1.93)L;CL分别为(5.33±2.03),(5.49±1.51),(5.68±1.35)L·h-1.3种剂量12 h原型药物尿中累积排泄百分率分别为(78.75±7.00)%,(78.95±12.57)%,(79.94±10.28)%.结论 不同给药剂量的阿司米星主要药代动力学参数呈线性分布特性,药物主要通过肾脏排泄,3个剂量消除过程基本一致.     

依帕司他单剂量与多剂量给药的药代动力学研究

对10例健康志愿者按50mg单剂量和多剂量口服依帕司他(Epalrestat)后的药代动力学进行了研究.多剂量给药方案按q.8h共服药10次.应用高效液相色谱-紫外检测方法测定依帕司他血药浓度.血药浓度数据用3p87药代动力学软件处理,按两室模型拟合并求算药代动力学参数.单剂量给药后的药代动力学参数分别为:Tmax2.25±0.95h,Cmax4104.91±849.87mg.L-1,AUC13016.6±2865.4mg.h.L-1,T1/2b1.11±0.35h.多剂量给药达稳态后的药代动力学参数分别为:Tmax2.00±1.03h,Cssmin146.24±54.50mg.L-1,Cssmax4769.99±897.86mg.L-1,Cavg1789.03±416.04mg.L-1,AUC14689.5±3472.3mg.h.L-1,T1/2b1.21±0.26h.依帕司他在人体内的吸收速度和消除速度不随连续给药变化,按50mg,q.8h方案给药,药物在体内基本没有蓄积,性别对药代动力学参数没有影响.     

单次静滴头孢呋辛在肾功能不全患者的药代动力学

目的 研究肾功能不全患者单次静滴头孢呋辛(抗生素)的药代动力学.方法 20名肾功能不全受试者按照CKD分期分成2组:CKD 1-3期组与CKD4-5期组,分别静脉滴注头孢呋辛1 000 mg后,采用高效液相色谱法,测定不同时刻血浆中头孢呋辛的血药浓度,用DAS 2.0版软件计算主要药代动力学参数.同时,测定不同时间段的尿药浓度,计算尿药累积排泄率.结果 2组受试者静脉滴头孢呋辛1 000 mg后,血浆中头孢呋辛的Cmax分别为(65.06±31.20),(79.33±10.75)μg·mL-1;t1/2分别为(2.42±0.87),(8.58±4.14)h;AUC(0-t)分别为(154.70±81.10),(446.43±95.37)μg·h·mL-1;AUC(0-∞)分别为(162.10±92.64),(798.65±362.83)μg·h·mL-1;CLz分别为(7.68±3.19),(1.45±0.52)mL·min-1;Vz分别为(24.53±9.71),(15.42±3.91)L.12 h尿药累积排泄率分别为(39.08±7.86)%,(16.67±5.57)%.结论 肾功能不全受试者静脉滴注头孢呋辛后,CKD 4-5期患者较CKD 1-3期,t1/2明显延长,AUC(0-t)及AUC(0-∞)明显增加;而CLz、Vz及12 h尿药累积排泄率均明显降低.     

美罗培南在烧伤患者的药代动力学研究

目的考察美罗培南在烧伤患者的药代动力学。方法28例烧伤患者在30min内单剂匀速静脉滴注美罗培南500mg,给药后不同时间取血和收集尿样,HPLC测定浓度,根据浓度测定结果,用3P97软件拟合药动学模型,计算药动学参数。结果研究显示,在静脉滴注0.5g美罗培南后,血药浓度-时间数据以二室模型拟合最佳,美罗培南的t1/2α为(0.35±0.12)h,t1/2β为(2.10±0.71)h,AUC为(44.62±12.95)μg·h/ml,Vc为(10.6±3.93)L,CLs为(12.00±3.04)L/h,0～12h美罗培南的尿回收率为(58.06±16.83)%。结论美罗培南在烧伤患者的主要药动学参数t1/2β、AUC、CLs、Cmax与健康志愿者有较大的差异,在12h内有约60%的原型药物从肾中消除。     

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.     

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.     

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.