口服胰岛素聚乳酸纳米粒的研制

目的　研制一种新型的口服胰岛素 (INS)纳米粒制剂。方法　以溶剂 非溶剂法制备了INS PLA NP ,进行了形态、粒径、包封率、载药量等主要性质的考察。以糖尿病小鼠为动物模型 ,初步考察了口服INS PLA NP后的降血糖药效。结果　制得的INS PLA NP均匀圆整 ,平均粒径为 (84 .34± 14 .76 )nm ,平均包封率为 (6 5 .93± 3.4 5 ) % ,平均载药量为 (0 .6 2± 0 .0 3)u·mg-1。糖尿病小鼠口服 5 0 ,6 0 ,80u·kg-1剂量的INS PLA NP后均表现出显著的降血糖作用。而口服 4 0u·kg-1剂量的INS PLA NP无效。结论　使用PLA NP作INS口服给药的载体具有可行性。     

促吸剂对胰岛素结肠给药降血糖作用的影响

目的　研究促吸剂对胰岛素溶液 (insulinsolution ,INS SOL)经大鼠结肠给药后的降血糖作用的影响。方法　以血糖水平为指标 ,考察不同促吸剂对INS SOL经结肠给药后降血糖作用的影响并计算药理生物利用度 (pharmacologicalbioavailability ,PA)。结果　含桉油醇、癸酸钠、脱氧胆酸钠和薄荷醇的INS SOL(5U·kg-1)均可降低血糖 (P <0 0 5 ) ,而桉油醇的作用最明显 ,最大降糖百分数为 38 8% (P <0 0 1)。无促吸剂的INS SOL(5U·kg-1)经结肠给药后的PA为9 16 % ,桉油醇、癸酸钠、脱氧胆酸钠可使PA增高 ,桉油醇的作用最明显 ,达到 2 3 4 % (P <0 0 5 )。 1U·kg-1的INS SOL在桉油醇促吸作用下PA最高达到 5 3 2 9% (P <0 0 1)。结论　在桉油醇作用下INS SOL结肠给药后有降血糖效果     

胰岛素经口腔给药对正常大鼠的降血糖作用

目的　研究胰岛素溶液 (insulinsolution ,INS SOL)经正常大鼠口腔给药后的降血糖作用。方法　以血糖水平为指标 ,考察各种吸收促进剂经正常大鼠口腔给药后对INS SOL降血糖作用的影响 ,以皮下注射为对照 ,计算不同条件下INS SOL的药理生物利用度 (pharmacologicalbioavailability ,PA)。 结果　不加吸收促进剂的条件下 ,10U·kg-1的INS SOL经口腔给药后的生物利用较低 (PA =6 9% )。十二烷基硫酸钠 (5 % ,PA =14 5 % ) ,苄泽 78(5 % ,PA =2 0 6 % ) ,脱氧胆酸钠 (5 % ,PA =16 5 % )和卵磷脂(10 % ,PA =13 8% )均增加INS SOL的降血糖作用。苄泽78(5 % )可使INS SOL(5U·kg-1)的PA最高达到 33%。结论　在适当的吸收促进剂的作用下INS SOL经口腔给药后具有明显的降血糖效果。     

不同吸收促进剂对大鼠口腔胰岛素吸收作用的影响

目的 :研究胰岛素的口腔吸收及吸收促进剂、酶抑制剂对药物吸收的影响。方法 :以血糖水平为指标 ,考察各种吸收促进剂和酶抑制剂经糖尿病模型的大鼠口腔给药后对胰岛素溶液 (insulinsolution ,INS SOL)和胰岛素贴片 (insulinpatch ,INS PAT)降血糖作用的影响 ,以皮下注射为对照 ,计算不同条件下INS SOL和INS PAT的药理生物利用度。结果 :不加吸收促进剂的条件下 ,32U·kg-1的INS SOL和10U·kg-1的INS PAT经口腔给药后的生物利用度较低 (0 .77%和 1.82 % )。 3%去氧胆酸钠和 5 %壬苯醇醚均能显著增加INS SOL和INS PAT的降血糖作用 (P <0 .0 5 )。其中 3%去氧胆酸钠作用最明显 ,INS SOL和INS PAT的生物利用度增加了近 3倍(2 .83%和 7.2 6 % )。结论 :胰岛素可通过口腔吸收 ,适当的吸收促进剂对其吸收具有显著的促进作用。     

促肝细胞生长素与胰岛素合用对糖尿病大鼠胰岛分泌功能的影响

目的　研究促肝细胞生长素(PHGF)与胰岛素(INS)合用对实验性糖尿病大鼠胰岛分泌功能的影响。方法　链脲霉素性大鼠糖尿病模型75只,分成5组,每组15只:INS(2U·kg-1,im) ;尼克酰胺(1g·kg-1,ig) ;PHGF(2 0mg·kg-1,iv) ;INS(2U·kg-1,im)合并PHGF(2 0mg·kg-1,iv) ;NS(同容量每只1mL ,iv)。3mo后放免法测定血INS和C肽。免疫组化染色法制作病理切片,胰岛β细胞记数并观察切片。结果　与NS组比较,PHGF与INS合用组能显著提高外周血INS和C肽浓度(P <0 . 0 1) ,胰岛β细胞数目显著增多,镜检有大小不等的β细胞。结论　PHGF与INS合用能够明显改善实验性糖尿病大鼠的胰岛β细胞功能,并有胰岛β细胞再生作用。     

口服胰岛素聚乳酸纳米粒的研制

目的　研制一种新型的口服胰岛素(INS)纳米粒制剂。方法　以溶剂 非溶剂法制备了INS-PLA-NP ,进行了形态、粒径、包封率、载药量等主要性质的考察。以糖尿病小鼠为动物模型,初步考察了口服INS PLA NP后的降血糖药效。结果　制得的INS PLA-NP均匀圆整,平均粒径为(84.34±14.76)nm ,平均包封率为(65.93±3.45) % ,平均载药量为(0.62±0.03)u·mg^-1。糖尿病小鼠口服50,60 ,80u·kg^-1剂量的INS-PLA NP后均表现出显著的降血糖作用。而口服4 0u·kg^-1剂量的INS-PLA NP无效。结论　使用PLA NP作INS口服给药的载体具有可行性。     

注射用尖吻蝮蛇凝血酶对兔凝血功能的影响

目的研究注射用尖吻蝮蛇凝血酶(Hem)对兔凝血功能的影响,为临床应用提供实验依据。方法于日本大耳白兔耳静脉分别一次性iv给予Hem 0.25,0.5和1.0 U·kg-1和阳性对照药注射用血凝酶(HAI)1.0克氏单位(KU)·kg-1,于给药前(0 min)和给药后10 min,30 min,2 h和12 h分别采血,应用Lee-White试管法测定全血凝血时间(CT),血球计数仪测定血小板计数(PLT),C2000-4高性能血凝仪测定凝血酶原时间(PT)、凝血酶时间(TT)、血浆纤维蛋白原(FIB)和鞣花酸活化部分凝血活酶时间(APTT)。结果正常对照组不同时间点各指标均无明显变化。与给药前比较,CT在给予Hem 0.25,0.5和1.0 U·kg-1和HAI 1.0 KU·kg-1后10 min～12 h明显缩短(P<0.05);PLT在Hem 1.0 U·kg-1给药后10～30 min明显增加(P<0.05);APTT在Hem 1.0 U·kg-1(10 min～2 h)和HAI 1.0 KU·kg-1(30 min～12 h)明显降低(P<0.05);PT在Hem 0.25 U·kg-1(10 min),0.5 U·kg-1(10 min～2 h)和1.0 U·kg-1(10～30 min)及HAI 1.0 KU·kg-1(10～30 min)明显降低(P<0.05);TT在Hem 1.0 U·kg-1(10 min～12 h)和HAI 1.0 KU·kg-1(30 min)明显降低(P<0.05);FIB在Hem 0.25 U·kg-1(30 min),0.5 U·kg-1(10～30 min)和1.0 U·kg-1(10 min～2 h)及HAI 1.0 KU·kg-1(10～30 min)明显升高(P<0.05)。结论Hem 1.0 U·kg-1在给药后10 min即有促凝血作用,TT缩短可持续12 h。     

重组葡激酶溶栓作用的研究

目的　研究重组葡激酶的溶栓作用。方法　通过测定家兔血浆优球蛋白溶解时间 (ELT)、纤维蛋白原降解产物(FDP)的含量及纤维蛋白原 (Fg)的含量 ,以观察重组葡激酶对家兔纤维溶解活性的影响。采用家兔动静脉旁路血栓形成法、家兔肺栓塞法及大鼠体外血栓形成法模型 ,以观察重组葡激酶的溶栓作用。结果　重组葡激酶 (6 2 5 0U·kg-1,1 2 5万U·kg-1)可明显缩短ELT ,增加FDP含量 ,对Fg含量无明显影响 ;重组葡激酶 (8333U·kg-1,2 5万U·kg-1,7 5万U·kg-1)在 3种血栓形成模型上 ,均有溶栓作用。结论　重组葡激酶具有明显的溶栓作用。     

磷酯酶C抗血小板功能的研究Ⅱ——对血小板释放和代谢的作用

目的　通过检测PLC对家兔血小板释放产物血栓素A2 (TXA2 )、代谢产物前列环素 (PGI2 )以及出血时间的影响 ,以探讨PLC抗血小板聚集的作用。方法　运用放射免疫方法测定以ADP、AA、collagen为诱导剂时 ,PLC对血小板TXB2 、6 Keto PGF1α生成量的影响。常规方法测定PLC对家兔出血时间 (BT)的影响。结果　 6种剂量PLC均能延长出血时间 ,但在给PLC 4h时 ,BT恢复至给药前水平 (P >0 0 5)。以ADP、AA、Collagen为诱导剂时 ,6种剂量的PLC能显著降低TXB2 的生成 (P <0 .0 5) ;以AA为诱导剂时 ,PLC 10 0U·kg- 1及以collagen为诱导剂时PLC 10 0U·kg- 1和PLC 2 0 0U·kg- 1其对TXB2 的生成的抑制作用较ASA组弱 (P <0 0 5) ;以ADP为诱导剂时PLC 10 0～ 40 0U·kg- 1,以AA为诱导剂时PLC 2 0 0～ 60 0U·kg- 1和以collagen为诱导剂时PLC 40 0～ 80 0U·kg- 1其对TXB2 的生成的抑制作用与ASA组相当 (P >0 0 5) ;以ADP为诱导剂时PLC 60 0～ 10 0 0U·kg- 1、以AA为诱导剂时PLC 80 0～ 10 0 0U·kg- 1和以collagen为诱导剂时PLC10 0 0U·kg- 1其对TXB2生成的抑制作用强于ASA组 (P <0 0 5)。 6种剂量的PLC组均明显增加 6 酮 PGF1α的生成量 (P <0 0 5) ,其作用强于ASA组 (P <0 0 5) ,并存在剂量效应关系和时间效?     

罗格列酮的胰岛素增敏作用和胰岛素抵抗改善作用

目的　观察罗格列酮的胰岛素增敏作用和胰岛素抵抗改善作用。方法　大鼠尾静脉注射链佐菌素 (5 0mg·kg-1)制备IDDM模型 ,观察单用罗格列酮、单用小剂量胰岛素 (皮下注射 2 5U·鼠 -1)、罗格列酮并用小剂量胰岛素的降糖作用 ;大鼠尾静脉注射卡介苗 (10mg·鼠 -1)制备免疫性胰岛素抵抗模型 ,观察罗格列酮对模型的葡萄糖输注速率的回升作用。结果　罗格列酮 1,3 ,10 μmol·kg-13个剂量组连续灌胃给药 8d ,均未能降低正常大鼠血糖 ,也未能降低链佐菌素所致糖尿病大鼠血糖 ;但在并用小剂量胰岛素条件下 ,罗格列酮 3 ,10 μmol·kg-1连续灌胃给药 8d ,能降低链佐菌素所致糖尿病大鼠血糖 ;罗格列酮 10 μmol·kg-1连续灌胃给药 8d后 ,用正糖钳技术检测 ,免疫性胰岛素抵抗模型亚极高和极高胰岛素状态下的葡萄糖输注速率均得到回升。结论　罗格列酮具有胰岛素增敏作用和胰岛素抵抗改善作用     

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.     

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.