双氯芬酸钠贴剂相对生物利用度与局部组织药物浓度测定

目的 研究兔经皮给予双氯芬酸钠贴剂的相对生物利用度和局部组织药物浓度,为临床用药提供参考.方法 单剂量给予贴剂和凝胶剂,采用反相高效液相色谱法测定血浆和局部组织中的双氯芬酸钠浓度.结果 兔表皮给予双氯芬酸钠贴剂的药动学参数如下.AUC：22.63 μg•h•mL^-1,t1/2Ka：0.82 h,t1/2Ke：8.51 h,tmax：2.53 h,Cmax：1.64 μg•mL^-1,CL/F（s）：1.52 L•h^-1, Ka：1.15 h^-1,Ke：0.12 h^-1;凝胶剂在兔体内的药动学参数为AUC：13.07 μg•h•mL^-1, t1/2Ka：0.27 h,t1/2Ke：1.92 h,tmax：0.88 h,C_max：1.45 μg•mL^-1,CL/F（s）：1.71 L•h^-1;Ka：2.62 h^-1,Ke：0.37 h^-1,求算得双氯芬酸钠贴剂的相对生物利用度为173.14%.对2种制剂的药动学参数进行双侧t检验,均差异有显著性（均P＜0.05）.再对给予贴片和凝胶剂的兔皮肤、关节腔、血液3组之间进行LSD检验,各组差异有显著性,给予贴剂的皮肤中药物浓度是血浆的36.5倍,给予凝胶剂的皮肤中药物浓度是血浆的18.68倍.结论 双氯芬酸钠贴片的Cmax高于双氯芬酸钠凝胶外擦给药,贴片的AUC大于凝胶给药的AUC,但具有达峰时间长和在体内时间长的特点,具有长效作用,贴片的生物利用度优于凝胶.     

双氯芬酸钠缓释栓相对生物利用度研究

目的 :研究兔直肠给予双氯芬酸钠缓释栓的相对生物利用度 ,为临床合理用药提供参考。方法 :多剂量给予普通栓和缓释栓 ,采用反相高效液相色谱法测定血浆中双氯芬酸钠的浓度。结果 :兔直肠给予双氯芬酸钠缓释栓的药动学参数为 :AUC 71.8μg·mL 1 ·h ;t1 2 (ka) 0 .19h ;t1 2 (ke) 1.4h ;tmax0 .5 4h ;Cmax2 7.6μg·mL 1 ;CL 0 .76L 1 ·kg 1 ·h 1 ;Ka 5 .12h 1 ;Ke0 .5 6h 1 。普通栓在兔体内的药动学参数为 :AUC 61.5 8μg·mL 1 ·h ;t1 2 (ka) 0 .15h ;t1 2 (ke) 1.0 9h;tmax0 .49h ;Cmax2 9.3 8μg·mL 1 ;CL 0 .82L 1 ·kg 1 ·h 1 ;Ka8.90h 1 ;Ke0 .67h 1 。求算得双氯芬酸钠缓释栓的相对生物利用度 116.5 % ,对两种制剂的药动学参数进行双、单侧t检验 ,均差异无显著性 (P >0 .0 5 ) ,缓释栓的Cmax低于普通栓 ,tmax及t1 2 (ka) 均长于普通栓。表明该栓剂在体内吸收与代谢较慢 ,具有缓释长效的特点。结论 :缓释栓的AUC比普通栓的AUC大 ,并具有达峰时间长 ,在体内时间长的特点 ,具有长效、缓释作用。且缓释栓与普通栓具有生物等效性。     

国产双氯芬酸钠缓释栓的人体药代动力学研究

目的 :研究国产双氯芬酸钠缓释栓人体内的药代动力学特征。方法 :2 0名健康志愿者单剂量给予 10 0mg双氯芬酸钠缓释栓 ,采用反相高效液相色谱法测定血浆中双氯芬酸钠的浓度。用 3p87程序计算其药代动力学参数。结果 :主要药代动力学参数Cmax 为 1.1± 0 .3mg·L-1;Tmax 为 1.7± 0 .7h ;T1 2 (ke) 为 2 .4± 0 .6h ;CL为 2 7± 6L·h-1;Vd 为 74±2 5L ;AUC0 -∞ 为 4 .0± 1.2mg·h-1·L-1。结论 :双氯芬酸钠缓释栓在健康人体内的药代动力学符合单室模型特征。     

艾拉莫德在大鼠体内的药动学研究

目的 研究艾拉莫德在正常与佐剂性关节炎大鼠体内的药动学行为.方法 用高效液相色谱法测定血清中艾拉莫德的浓度,并计算其药动学参数.结果 连续给药后正常组(6 mg/kg)的主要药动学参数为:t1/2Ke:6.30 h;tpcak:4.00 h;Cmax:8.87 μg/ml;AUC0.24:98.52 μg·ml-1.连续给药后,关节炎大鼠低、中、高三个剂量组(3、6、12 mg/kg)的主要药动学参数分别为:t1/2Ke:6.03、6.24、6.89 h;tpcak:3.83、3.83、4.67 h;Cmax:3.84、8.31、12.69μg/ml;AUC0.24:48.67、91.02、145.10μg·ml-1·h-1.经检验,除Cmax和AUC外,关节炎大鼠三个剂量组的药动学参数之间差异无统计学意义,Cmax和AUC值与剂量成正比.正常与关节炎大鼠的药动学参数比较,差异无统计学意义.结论 艾拉莫德在正常和佐剂性关节炎大鼠体内的药动学行为符合开放型一室模型一级速率过程.     

甲巯咪唑乳膏透皮吸收的体内动力学

目的:研究甲巯咪唑乳膏经皮给药体内动力学及血清药物含量测定。方法:兔颈前甲状腺局部经皮给药,以高效液相色谱法测定血清中甲巯咪唑浓度,以3P87药动学软件计算药物体内动力学参数。结果:药时曲线符合一室模型,药物吸收速率常数(Ka)为2.590h-1;消除半衰期(T1/2β)为2.258h;峰浓度(Cmax)为1.480μg·ml-1;达峰时间(Tmax)为0.934h;曲线下积分面积(AUC)为6.230μg·ml-1·h。结论:甲巯咪唑乳膏局部给药有良好的透皮吸收性。     

克拉霉素分散片与克拉霉素片人体生物利用度比较研究

目的比较克拉霉素分散片与克拉霉素片(利迈先)的生物等效性。方法采用双交叉单剂口服给药法 ,以藤黄八叠球菌为指示菌 ,采用微生物法测定健康志愿者克拉霉素分散片和利迈先经时血药浓度。数据经3p97药代动力学程序处理及双单侧t检验和(1 -2α)置信区间分析。结果克拉霉素分散片和利迈先药物动力学参数Ka 为0.7843和0.5893h-1,t1/2(α)为1.7324和2.3140h ,t1/2(β)为4.1449和3.8635h,Cmax 为2.2308和1.8742μg·ml-1,AUC为17.741和16.2751μg·h·ml-1。克拉霉素分散片的相对生物利用度为106.21 %。结论两种制剂AUC值剂型间、阶段间和个体间均无显著性差异(P>0.05) ,两制剂为生物等效制剂。     

红景天苷在大鼠体内的药物代谢动力学研究

目的研究大鼠血浆中红景天苷的口服及静脉给药的药代动力学,并进行生物利用度的评估。方法将健康SD大鼠16只随机分组,采用静脉注射和灌胃2种不同的方式给药(48mg/kg),采血测定血浆内红景天苷的血药浓度。结果主要药物代谢动力学参数:灌胃:t1/2为(0.64±0.11)h,ρmax为(13.9±2.9)μg/mL,AUC0¹2和AUC012和AUC0^∞分别为(16±4)μg·h-1·mL-1和(16±4)μg·h-1·mL-1;静脉注射:t1/2为(1.16±0.44)h,AUC0∞分别为(16±4)μg·h-1·mL-1和(16±4)μg·h-1·mL-1;静脉注射:t1/2为(1.16±0.44)h,AUC0¹2和AUC012和AUC0^∞分别为(38±11)μg·h-1·mL-1和(39±12)μg·h-1·mL-1;绝对生物利用度为41.9%。结论红景天苷吸收迅速,生物利用度良好。     

单剂口服利巴韦林片在健康人体的药代动力学

目的 对国产利巴韦林片(抗病毒药)在健康中国男性受试者中空腹单剂量口服时的药代动力学特点进行评价.方法 受试者单剂量口服利巴韦林300 mg,用液相色谱-串联质谱法测定血浆中利巴韦林浓度,并用非房室模型计算药代动力学参数.结果 药代动力学参数AUC0-t为(5584.91±1659.34)ng·h·mL-1;AUC0-∞为(7166.33±2224.28)ng·h·mL-1;Cmax为(442.60±148.97)ng·mL-1;tmax为(1.40±1.20)h;t1/2为(22.93±6.38)h;Ke为(0.03±0.01)h-1;Vd为(1484.37±491.50);CL为(45.67±13.90)L·h-1.结论 单剂口服利巴韦林在健康人体的代谢特征基本与文献报道参数[2-5]一致.     

西替利嗪透皮贴剂的制备及药代动力学研究

目的制备西替利嗪透皮贴剂并研究其药代动力学。方法用西替利嗪原料药及基质制备透皮贴剂,用家兔为实验动物研究其药代动力学。结果其Cmax（4.28±0.84）μg/ml,Tmax（24±5.69）h,T1/（28.34±2.67）h,AUC0→t（243.4±46.86）μg/（ml·h）,AUC0→∞（248.96±31.56）μg/（m·h）。结论西替利嗪透皮贴剂能成功控释药物,且工艺简单,实用性强。     

奥拉西坦健康人体药代动力学研究

目的进行健康志愿者单次和多次静脉给药后奥拉西坦人体药代动力学研究. 方法 10名健康志愿者单次静脉输注2 000 mg奥拉西坦和每次2 000 mg, 静脉输注7天后, HPLC法测得奥拉西坦血清浓度, DAS软件进行药代动力学参数计算.结果单次给药, 奥拉西坦AUC0～12, AUC0～∞, Ke, t1/2, MRT分别为256.26±16.84 μg·mL-1·h-1, 276.74±18.11 μg·mL-1·h-1, 0.18±0.03 h-1, 3.84±0.64 h和4.39±0.39 h; 多次给药后AUC0～12, AUC0～∞, Ke, t1/2, MRT分别为259.36±25.43 μg·mL-1·h-1, 285.59±27.38 μg·mL-1·h-1, 0.17±0.04 h-1, 4.14±0.82 h和4.87±0.69 h.结论奥拉西坦单次和多次给药后药动学参数无明显差异, 奥拉西坦多次给药后无蓄积.     

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.

---

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.     

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.     

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.     

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.