普卢利沙星片在健康人体的药代动力学

目的评价国产盐酸普卢利沙星片（第4代喹诺酮类抗生素）在健康人体的药代动力学。方法10名健康志愿者单剂量和多剂量口服国产盐酸普卢利沙星片200mg，用液相色谱一串联质谱法测定血药浓度，用Winnonlin计算药代动力学参数。结果单剂量和多剂量给药后，Cmax 分别为（1．39±5．10），（1．67±0．23）mg·L^-1；tmax分别为（0．93±0．37），（1．07±0．43）h；tl／2ke分别为（6．74±1．09），（7．26±0．53）h；AUC0-x分别为（6．64±1．68），（11．82±1．32）mg·h·L^-1，多剂量AUC0-r为（8．68±0．79）mg·h·L^-1。结论每日2次，连续口服国产盐酸普卢利沙星片11次后，体内有一定蓄积。     

高效液相色谱法测定甲磺酸帕珠沙星氯化钠注射液的含量及有关物质

目的：建立高效液相色谱（HPLC）法测定甲磺酸帕珠沙星氯化钠注射液中有关物质的方法。方法：采用HPLC，色谱柱为ZORBAXSB-C18（4．6mm×250mm，5μm），流动相为磷酸盐缓冲液（含40mmol·L^-1磷酸二氢钾溶液，7．5mmol·L^-1辛烷磺酸钠）-乙腈-甲醇（67：23：10），用磷酸调节pH至4．1，检测波长243nm／1，流速1．0mL·min^-1，柱温为35℃。结果：甲磺酸帕珠沙星氯化钠注射液中的甲磺酸帕珠沙星峰的理论塔板数大于5000，且与杂质的分离度高。结论：本方法的专属性强，准确性高，适合于分析该产品的有关物质。     

甲磺酸帕珠沙星氯化钠注射液在健康人体内的药物动力学

30名健康志愿者（男女各半）随机分为3组,分别单剂量静脉滴注低、中、高剂量（150、300、600mg,以帕珠沙星计）甲磺酸帕珠沙星氯化钠注射液,用HPLC法测定血药浓度。3个剂量组药动学参数cmax分别为（5.46±1.11）、（9.43±2.15）和（18.30±4.69）μg/ml,t1/2Z分别为（1.83±0.38）、（1.75±0.18）和（1.94±0.16）h,AUC0-12h分别为（8.64±1.10）、（16.93±1.73）和（40.92±9.74）μg·ml-1·h,VZ分别为（45.13±8.95）、（44.93±7.08）和（42.23±8.41）L,CLZ分别为（17.21±2.13）、（17.72±1.94）和（15.14±3.14）L/h。结果表明,帕珠沙星在150～600mg剂量范围内cmax和AUC与给药剂量呈正相关。高剂量组中男性受试者的cmax比女性低,其它药动学参数在男女性别间均无显著性差异。     

甲磺酸帕珠沙星注射液单次给药在人体内的药物动力学研究

目的建立测定甲磺酸帕珠沙星血浆药物浓度的HPLC-UV检测法,研究国产甲磺酸帕珠沙星氯化钠注射液在人体内的药物动力学。方法12名健康志愿受试者单次静滴甲磺酸帕珠沙星氯化钠注射液500 mg,以盐酸芦氟沙星为内标,测定血浆中帕珠沙星的浓度,用DAS 1.0软件处理经时血药浓度数据,计算主要药物动力学参数。结果单次静滴甲磺酸帕珠沙星氯化钠注射液500 mg后,于给药后0.50 h达到峰浓度9.83±2.52 mg.L-1,AUC0-t为18.99±4.15 mg.h.L-1,T1/2β为2.67±0.31 h,Cl/F和V/F分别为23.73±3.81 L.h-1和1.16±0.31 L.kg-1。结论单次静滴甲磺酸帕珠沙星氯化钠注射液的体内过程符合二室开放模型;除AUC外,男、女受试者的其余药动学参数比较,差异无统计学意义。     

头孢哌酮／舒巴坦（1：1）在健康成年与老年人的药代动力学

目的研究（1：1）头孢哌酮（第3代头孢类抗生素）／舒巴坦（13内酰胺酶抑制剂）在成年与老年的药代动力学。方法44名健康受试者（成年：男12人，女12人；老年：男20人）每次静脉给予头孢哌酮和舒巴坦各lg，每日2次，连续给药3天，第4天首次给药后，采集不同时间的血样，分离血清，用HPLC方法分别测定头孢哌酮和舒巴坦的血药浓度。结果舒巴坦：稳态时，成年男性、女性和老年人的CL分别为（30．64±5．2），（29．34±4．3），（13．74±4．9）L·h^-1；K分别为（49．74±21．2），（58．84±23．1），（28．74±15．7）L;t1／2分别（1．24±0．5），（1．4±0．4），（1．44±0．4）h；Cmax分别（27．94±4．8），（26．54±4．3），（54．74±19．9）mg·L^-1；AUC分别（33．74±6．74），（34．74±4．64），（81．84±28．4）mg·h·L^-1。头孢哌酮：稳态时，成年男性、女性和老年人的CL分别为（5．74±1．2），（4．84±1．3），（4．24±1．2）L·h^-1；K分别为（11．7±2．7），（11．74±4．6），（12．84±3．8）；t1／2分另0为（1．54±0．5），（1．74±0．4），（2．24±0．6）h；Cmax分别为（89．44±10．7），（110．84±24．7），（102．04±15．3）mg·L^-1；AUC分别（182．34±49．6），（224．74±60．7），（256．34±72．0）mg·h·L^-1。结论成年人和老年人的药代动力学中，舒巴坦存在明显差异；而头孢哌酮的差异不明显；两性间的药代动力学差异不明显。     

液-质联用法考察单硝酸异山梨酯片的人体生物等效性

目的：建立液-质联用法（LC-MS／MS）的检测方法，评价受试与参比的单硝酸异山梨酯片在健康人体的生物等效性。方法：健康志愿者20名，随机交叉试验设计，单剂量口服受试或参比制剂，给药剂量均为20mg，应用LC-MS／MS法测定各受试者给药后不同时间点的血药浓度，计算药动学参数，应用BAPP 2．0软件进行生物等效性评价。结果：受试与参比制剂的药动学参数如下，AUC0-24分别为（3．4±0．6）mg·h·L^-1、（3．3±0．7）mg·h·L^-1，AUC0-∞分别为（3．6±0．7）mg·h·L^-1、（3．5±0．7）mg·h·L^-1；tmax分别为（1．2±0．9）h、（1．0±0．6）h；Cmax分别为（464．9±108．2）μg·L^-1、（433．6±115．3）μg·L^-1；t1／2分别为（5．4±0．7）h、（5．5±0．9）h。单硝酸异山梨酯片的相对生物利用度为（106．0±16．0）％，主要药动学参数经统计学分析无显著性差异。结论：受试与参比制剂具有生物等效性。     

甲磺酸帕珠沙星氯化钠注射液在健康人体的药代动力学

目的研究甲磺酸帕珠沙星氯化钠注射液在健康人体的药代动力学。方法8名健康受试者单次静脉滴注甲磺酸帕珠沙星300,600mg后,用高效液相色谱法测定体内帕珠沙星的血药浓度,用DAS统计软件进行数据处理。结果结果符合一级消除药代动力学的二室模型,300,600mg2个剂量组的药代动力学参数:Cmax分别为(7.38±0.85),(18.36±2.39)mg·L-1;AUC0-t分别为(31.34±5.67),79.20±18.43)mg·h·L-1;t1/2β分别为(1.63±0.31),(1.71±0.21)h;CL/F分别为(0.10±0.02),(0.08±0.01)L·kg·h-1,V/F分别为(0.23±0.03),(0.19±0.05)L·kg-1。24h尿药累积排泄率分别为(92.2±2.6)%和(93.2±3.0)%。结论甲磺酸帕珠沙星每日给药300mg,每日2次,可达到有效治疗浓度,在600mg内可安全耐受。     

中国健康志愿者单剂静脉滴注甲磺酸帕珠沙星氯化钠注射液的药动学研究

目的对中国健康成年志愿者单剂静脉滴注甲磺酸帕珠沙星氯化钠注射液的药动学研究。方法按GcP指导原则设计试验方案,选择10名健康受试者分别在30min内空腹静脉滴注甲磺酸帕珠沙星氯化钠注射液300和500mg,用HPLC-荧光法测定血浆、尿液中帕珠沙星的浓度,并采用3P97软件进行试验数据统计处理,求出药动学参数。结果帕珠沙星的血药浓度经时变化符合二房室模型,300和500mg的主要药动学参数如下：峰浓度Cmax分别为(7．716±1．373)和(11．652±2．197)μg／ml；半衰期t1/2分别为(2．00±0．26)h和(2．13±0．22)h；药时曲线下面积AUCo-∞分别为(14．170±3．244)和(25．370±3．234)μg·h／ml；表观分布容积Vc分别为(28．83±12．92)L和(31．62±8．91)L。尿药浓度测定结果表明,帕珠沙星0-24 h累积排出量分别为(261．82±30．92)mg和(452．27±32．35)mg,0-24 h累积排出百分比分别为(87．27±10．31)％和(90．45±6．47)％。结论帕珠沙星单次给药在中国健康人体耐受性良好,药时曲线符合二房室模型,帕珠沙星在300-500mg剂量范围内药物体内过程呈线性动力学特征,药物主要经肾脏排泄。     

甲磺酸帕珠沙星氯化钠注射液健康志愿者单剂给药药动学

目的研究健康志愿者静脉滴注单剂甲磺酸帕珠沙星氯化钠注射液后药动学特征,为该药Ⅱ期临床试验提供依据。方法采用2剂量2周期交叉试验设计。10名健康受试者单剂静脉滴注甲磺酸帕珠沙星氯化钠注射液300、500mg,HPLC法测其血清、尿药物浓度。结果受试者静脉滴注甲磺酸帕珠沙星氯化钠注射液后,人体耐受良好,体内过程符合二室开放模型。主要药动学参数与给药剂量呈线性关系,cmax分别为8.3和11.07μg/ml,AUC0-∞分别为13.66和24.04μg.h/ml,V值分别为28.9和40L,t1/2β分别为1.77和2.27h,36h尿药累积回收率约为79%。结论甲磺酸帕珠沙星氯化钠注射液静脉滴注血峰浓度高,组织分布较广,消除半衰期短,300mg每日2次可用于治疗敏感菌感染。     

氨咖黄敏胶囊中对乙酰氨基酚和咖啡因的人体药动学

目的研究氨咖黄敏胶囊中对乙酰氨基酚和咖啡因的人体药动学。方法本试验采用HPLC法测定了18名健康男性受试者口服氨咖黄敏胶囊后不同时刻血浆中对乙酰氨基酚和咖啡因的浓度，用31：97软件拟合房室模型并求出主要药动学参数。结果受试者口服含对乙酰氨基酚750mg和咖啡因45mg的氨咖黄敏胶囊制剂后，血浆中对乙酰氨基酚的tmax为（1．03±0．76）h，ρmax为（12．00±3．10）mg·L^-1，t1/2为（4．33±1．18）h，用梯形法计算AUC0→t为（52．51±16．81）mg·h·L^-1，AUC0→∞为（54．34±17．72）mg·h·L^-1；血浆中咖啡因的tmax为（0．89±0．50）h，ρmax为（1．290±0．379）mg·L^-1，t1/2为（5．37±2．15）h，用梯形法计算AUC0→t为（7．19±3．03）mg·h·L^-1，AUC0-∞。为（8．26±3．69）mg·h·L^-1。结论对乙酰氨基酚在人体内符合二房室模型，咖啡因在人体内符合一房室模型。     

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.