头孢羟氨苄狗静注的药物动力学研究

用反相高效液相色谱法测定了头孢羟氨苄的血药浓度及药物动力学参数。狗静注本药后不同剂量药物动力学过程以二室模型 PHARMA 程序拟合。静注10mg/kg 的 t_(1/2(α))=0.24±0.32h;t_(1/2(β))=1.29±0.46h;AUC=46.46±9.58μg·ml~(-1)·h。     

亚硒酸钠在兔体内的药代动力学

给家兔单次iv或ig Na_2SeO_3 2.0mg/kg,iv血药-时曲线符合线性三室开放模型,药代动力学参数为t_(3/2)a 0.16±0.08d,t_(1/2)β9.93±2.52d,t_(1/2)π0.13±0.08 h,ig血药-时曲线符合二室开放模型,药代动力学参数t_(1/2)(Ka)2.69±0.56h,t_(1/2)a 0.96±0.45d,t_(1/2) β9.31±3.36 d。多次给硒时,每7d,14d igNa_2SeO_3 2.0mg/kg,每10d iv Na_2SeO_3 1.5mg/kg各组达到90％以上稳态血药水平的时间分别为35d,45d和30d。     

头孢羟氨苄胶囊的药代动力学及人体生物等效性研究

目的研究头孢羟氨苄胶囊的药代动力学和相对生物利用度并求证该制剂的生物等效性.方法24名男性健康志愿者按标准的2×2交叉试验方案随机交叉给药,分别口服单剂量石家庄制药的头孢羟氨苄胶囊(参比制剂)及上海三维制药的头孢羟氨苄胶囊(受试制剂),采用反相高效液相色谱法测定血清中药物浓度,计算两者药代动力学参数及相对生物利用度,并求证两制剂的生物等效性.结果口服头孢羟氨苄胶囊的参比制剂及受试制剂1000mg后的主要药代动力学参数tmax分别为1.81±0.55 h和1.69±0.32 h,Cmax分别为24.65±3.49 mg·L-1和26.72±3.54 mg.L-1,AUC(0-10)分别为93.89±11.99mg·h·L-1和100.20±12.8mg·h·L-1,AUC(0.inf)分别为99.45±13.36mg·h·L-1和105.99±13.83mg.L-1.h,t1/2Ka分别为1.62±0.15h和1.60±0.15 h,t1/2Ke分别为2.33±0.44 h和2.44±0.45h,Ke分别为0.31±0.06 h-1和0.29±0.05h-1.受试制剂对于参比制剂的平均相对生物利用度F-AUC(0-10)为106.98%±8.02%,F-AUC(0-inf)为106.88%±7.92%.两种胶囊剂的Cmax、AUC(0-10)、AUC(0-inf)经对数转换后3P97程序方差分析和双单侧t检验(α=0.05),结果表明两种制剂在给药周期及处方间均无显著性差异(P＞0.05),两制剂间生物等效.结论两种头孢羟氨苄胶囊制剂生物等效.     

国产氨噻肟头孢菌素家兔体内药代动力学研究

家兔肌肉和静脉注射20mg/kg国产氨噻肟头孢菌素药代动力学研究结果表明,两种给药途径的药代动力学均符合二室开放式模型,其数学表达式分别为C_1=58.5e~(-12.14t)+39.4e~(-2.48t)+19.1e~(-0.46t)(肌肉注射)和C_t=148.6e_(-5.28t)+30.6e~(-1.25t)(静脉注射)。家兔肌肉注射氨噻肟头孢菌素的消除半衰期(T(1/2)β)为1.51小时,表观分布容积(Vd)为1.77L,高峰血清浓度(C_(max))为35.3μg/ml,达峰时间(T_(max))为15分钟,24小时尿中回收率为67.39％;肌肉注射的生物利用度为91.6％,表明家兔肌注该药后被其机体吸收利用的程度较高;静脉注射的消除半衰期为0.55小时,表观分布容积为0.47L,24小时尿中回收率为61.45％。 家兔静脉注射氨噻肟头孢菌素与第一代头孢菌素噻吩头孢菌素、唑啉头孢菌素的药代动力学比较结果表明,氨噻肟头孢菌素的药代动力学性质同噻吩头孢菌素相似,具有半衰期短,室间转运速率快,体内分布、消除迅速,肾清除率高等特点;而与唑啉头孢菌素不同。 药代动力学的研究结果还表明,肌注和静注两种途径给药,均能得到高于临床常见致病菌的最低抑菌浓度(MIC)的数十倍到上百倍的血、尿药物浓度,可以有效地控制这些细菌所致的各种感染疾患。     

国产头孢哌酮药代动力学和药效学研究

文报告14例病人国产头孢哌酮的药代动力学与药效学研究结果。国产和进口头孢哌酮2g恒速静滴1h,血浓峰值分别为211μg/ml和252μg/ml。国产品V_n值为0.24L/kg,进口品为0.17L/kg(p<0.05),其余各项动力学参数无显著差异,药时曲线方程国产品为y=165.40e~(-2.3258t)+155.53e~(-0.2127t),进口品为y=145.93e~(-3.1223t)+230.99e~(-0.3199t)。国产品以双室模型模拟相关性为r=0.9669,败血症病人显效血浓为287±68μg/ml,呼吸道感染病人显放血浓为223±51μg/ml。产生毒副反应组与未产生毒副反应组血浓分别为295和178μg/ml(p<0.01)。     

单点采血反映口服CYP3A探针咪达唑仑的代谢清除率

目的:研究中国男性健康受试者口服咪达唑仑后其1＇-羟化代谢的药代动力学规律,并寻找适合的单个采血点血浆中1＇-羟化咪达唑仑/咪达唑仑的浓度比值来反映咪达唑仑的血浆清除率。方法:10名受试者禁食8小时后清晨空腹口服7.5mg咪达唑仑,利用非房室模型计算药代动力学参数。结果:咪达唑仑药代动力学参数C_(max)为(191±17)nmol/L,t_(max)为(1.01±0.14)h,t_(1/2)为(3.2±0.4)h,AUC_(0→∞)为(681±43)nmol·h·L~(-1),Cl_(oral)为(0.54±0.04)L/(h·kg),K_e为(0.2415±0.0021)h~(-1),K_α为(0.82±0.18)h~(-1)。1小时血浆中咪达唑仑与其代谢产物1＇-羟化咪达唑仑的比值与其清除率的相关性统计学上具有显著意义(r=0.7,P<0.05,n=10)。结论:可用口服咪达唑仑后1小时单个采血点的代谢产物1＇-羟化咪达唑仑与咪达唑仑浓度的比值来反映其血浆清除率,应用于CYP3A活性测定的人群试验。     

胸腺肽在家兔体内的药代动力学

目的研究家兔静注胸腺肽的药代动力学。方法用高效液相色谱法测定家兔血中胸腺肽浓度 ,3P87程序计算参数。结果与结论家兔静注胸腺肽后的药代动力学参数分别为 :Cmax=(30 .0 6± 9.2 7) μg/ml,t1/ 2 ( β) =(2 9.2 4± 2 3.78)min ,Ke =(0 .0 32 3± 0 .0 138)min-1,AUC0→∞ =(2 0 5 .6 3± 46 .48) μg·min/ml。     

罗哌卡因在手术病人的药代动力学

目的 对单剂量罗哌卡因硬膜外麻醉的手术病人进行药代动力学研究。方法 选择12例手术病人,硬膜外麻醉时,注入罗哌卡因150mg。血药浓度用反相高效液相色谱法测定。用3P97药代动力学计算程序拟合房室模型并计算药代动力学参数。结果 罗哌卡因的主要药代动力学参数:t_(max)为0.27±0.10h;C_(max)为1.86±0.40mg·L~(-1);t_(1/2 (α))为0.23±0.14h;t_(1/2 (β))为2.17±0.55 h;AUC为4.84±1.20 mg·h·L~(-1)。结论 罗哌卡因在手术病人中的代谢符合开放性二室模型。罗哌卡因在体内的消除不受疾病的影响。     

两种头孢羟氨苄胶囊的药代动力学与生物等效性研究

目的 :研究两种头孢羟氨苄胶囊在正常人体的药代动力学与生物等效性。方法 :22名健康志愿受试者随机交叉口服1000mg头孢羟氨苄胶囊和仙逢久胶囊后 ,采用高效液相色谱 (HPLC)法 ,以阿莫西林作内标 ,测定头孢羟氨苄(CFO)血浆药物浓度。结果 :两种胶囊剂均符合一级吸收开放性一室模型 ,主要药代动力学参数 :T1/2ke分别为 (1.40±0.15)h、(1.44±0.23)h ;Tmax分别为(2.3±0.5)h、(2.2±0.3)h ;Cmax分别为 (30.59±4.25) μg/ml、(30.57±4.24) μg/ml;AUC分别为 (99.31±14.50) μg/(ml·h)、(99.22±15.11h) μg/(ml·h)。结论 :两种胶囊剂生物利用度为(100.42±7.62) % ,具有生物等效性     

〔~3H〕-藏花素在大鼠体内吸收、分布及排泄的初步研究

用[~3H]-藏花素大鼠灌胃,血药半对数浓度-时间曲线用残数法处理,符合线性开放二室模型。中心室药浓度时间方程为:C=-2.7642e~(-0.5330t)+0.5328e~(-0.2592t)+2.1813e~(-0.0085t),主要动力学参数:t(1/2)ka=1.30hr,t(1/2)α=2.675r,t(1/2)β=81.53hr,t_(max)=4.54hr,v_1=630.81ml,TBCL=5.36ml/hr。除睾丸外各脏器放射性浓度高峰均出现在给药后 4～6 hr,与血浆中t_(max)一致。给药后96h各脏器中仍残留有一定量的放射性。大鼠灌胃后放射性主要由粪与尿中排出,给药96hr后粪及尿中分别排出全部放射性的68.22％和17.29％。     

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.