壳聚糖和壳聚糖-EDTA接合物双层包覆胰岛素口服纳米脂质体的研究

目的研究壳聚糖和壳聚糖-EDTA接合物(CEC)双层包覆胰岛素脂质体的性质、降血糖作用和药代动力学。方法采用逆相蒸发法制备胰岛素脂质体；用胃蛋白酶、胰蛋白酶溶液和胃肠道内容物试验考察脂质体对胰岛素的保护作用；用酶-苯酚法测定小鼠血糖值；用放射免疫法测定血清胰岛素含量，并采用Pkanalyst程序进行拟合。结果在胃蛋白酶、胰蛋白酶和胃肠道内容物中，壳聚糖-CEC双层包覆胰岛素脂质体对胰岛素具有较好的保护作用；在正常大鼠葡萄糖耐药量试验中，与PBS对照组比较，壳聚糖及其CEC包覆胰岛素脂质体对负载葡萄糖大鼠的血糖升高均有一定的抑制作用，其中壳聚糖-CEC双层包覆胰岛素脂质体的抑制作用最佳；在大鼠降血糖试验中，壳聚糖及其CEC包覆胰岛素脂质体均具有一定降血糖作用，以壳聚糖-CEC双层包覆胰岛素脂质体的降血糖作用最佳，血糖在1 h降至最初血糖值的45.98%，作用时间延长；以皮下注射胰岛素(Ins)为对照，其相对生物利用度为17.02%；对血清Ins浓度-时间曲线进行拟合计算，均符合一室线性模型，以皮下注射Ins为对照，壳聚糖-CEC双层包覆胰岛素脂质体的相对生物利用度为8.91%。结论采用壳聚糖-CEC双层包覆的胰岛素脂质体更有利于胰岛素口服吸收。     

壳聚糖和壳聚糖-EDTA轭合物双层包覆脂质体对胰岛素口服吸收的影响

目的研究壳聚糖和CEC双层包覆胰岛素脂质体的吸收状况,并验证其有效性。方法采用逆相蒸发制备胰岛素脂质体;用酶-苯酚法测定血糖值;用放射免疫法测定血清胰岛素含量,并采用Pkanalyst程序进行拟合。结果 Ch-CEC双层包覆的胰岛素脂质体对负载葡萄糖的正常大鼠的血糖升高具有抑制作用;以皮下注射胰岛素(Ins)为对照,Ch-CEC双层包覆的胰岛素脂质体经糖尿病模型大鼠和beagle犬给药后的相对药理生物利用度均大于9%,具有较好的降血糖作用。另外,在beagle犬降血糖实验中,根据血清胰岛素浓度-时间曲线的曲线下面积(AUC)计算Ch-CEC双层包覆的胰岛素脂质体灌胃给药的相对生物利度为12.67%。结论壳聚糖-CEC双层包覆胰岛素脂质体有利于改善胰岛素口服生物利用度。     

壳聚糖及其EDTA轭合物双层包覆胰岛素脂质体的处方工艺优化

目的:研究制剂因素对壳聚糖(CH)及其EDTA轭合物(CEC)双层包覆胰岛素脂质体降血糖作用的影响.方法:采用逆相蒸发法制得胰岛素脂质体,并用CH和CEC进行双层包覆.以小鼠口服降血糖效果作为实验指标,分别应用L16(215)和L8(27)正交实验设计优化CH-CEC双层包覆胰岛素脂质体的处方与工艺.结果:最佳处方组成为胰岛素100IU,pH 7.4磷酸盐缓冲液,磷脂150mg,胆固醇25mg,维生素E 15mg,0.2% CH 1.5mL和1% CEC 1.5mL.最佳制备工艺为乙醚10mL,旋转蒸发温度20℃,探针式超声时间0.5min,加CH和CEC后的孵化时间30min,孵化温度10℃,CH要先于CEC加入.经优化得到的双层包覆胰岛素脂质体经糖尿病模型大鼠口服后,具有平稳持久的降血糖作用,以皮下注射胰岛素为对照,其相对药理生物利用度(PA)达14.78%.结论:CH-CEC双层包覆胰岛素脂质体的组成和制备因素的变化会影响降血糖效果,用CH-CEC双层包覆的胰岛素脂质体具有较好降血糖作用.     

猪胰岛素及去四肽猪胰岛素舌下滴剂对大鼠的降血糖作用

目的在月桂氮 卓艹 酮等复合促进剂的作用下 ,分别研究了猪胰岛素及去四肽猪胰岛素 (DTI)舌下滴剂对正常SD大鼠的降血糖作用。方法大鼠麻醉后食管结扎 ,按 4u kg分别给予胰岛素及DTI舌下滴剂 ,测定给药后不同时间的血糖变化情况。结果胰岛素及DTI舌下滴剂给药组与空白对照组相比有显著差异 (P <0 .0 5 ) ,对大鼠的总血糖降低率分别为 4 6 .2 %及 5 3.5 % ,相对生物利用度分别为 19.5 %及 2 5 .4 %。结论溶液中单体浓度的提高 ,有助于胰岛素透过口腔黏膜进入血液。     

胰岛素气雾剂经正常及糖尿病大鼠肺部给药后的降血糖作用

目的：研究胰岛素气雾剂经肺部给药后的降血糖作用。方法：建立了大鼠的肺部给药模型,通过经口有入及气管内给药两种途径将溶液型胰岛素气雾剂导入大鼠肺内,采用葡萄糖氧化酶法测定给药后正常大鼠及糖尿病大鼠的血糖水平,并计算其药理生物利用度。结果：在同一种剂量下,经口吸入和气管内给药两种途径在正常及糖尿病大鼠体内均呈现显著的降血糖作用,其药理生物利用度在正常大鼠体内分别为6．0％和11．4％,在糖尿病大鼠体内分别为5．6％和8．7％,结论：胰岛素气雾剂能有效地降低正常及糖尿病大鼠血糖,为进一步开发临床治疗糖尿病的新剂型打下基础。     

脂质体对胰岛素经呼吸道吸收的影响

研究胰岛素经呼吸道吸收的可能性,评价脂质体对胰岛素经呼吸道吸收的影响。方法：选用糖尿病模型大鼠,以胰岛素皮下注射为对照(1IU／kg),采用气管插管给药技术,测定模型大鼠的血糖浓度,评价药效。结果：胰岛素溶液(1IU／kg)经呼吸道给药的相对生物利用度为79.30％,而胰岛素脂质体混悬液(1IU／kg)经呼吸道给药的相对生物利用度为95.83％。结论：胰岛素经呼吸道给药相对生物利用度高;而胰岛素脂质体经呼吸道给药,其生物利用度与皮下注射相当。     

胰岛素粉雾剂肺部给药对大鼠的降血糖作用

目的:观察胰岛素吸入粉雾剂肺部给药后的降血糖效果.方法:胰岛素与合适辅料制成的干粉经大鼠肺气管切口吹入肺中,测定随后7小时的血糖浓度,以血糖曲线上面积(AAC)为指标对其药效进行评价.结果:吸入胰岛素剂量为20,10,5和2.5U/kg时,最低血糖浓度可分别降至给药前的6.5％,16.6％,24.6％和57.0％;剂量为5 U/kg吸入给药的AAC值和5U/kg皮下注射给药的AAC值相近;AAC值与对数剂量间存在线性关系.结论:胰岛素肺部给药的降血糖效果明显且作用迅速.     

胰岛素聚乳酸纳米粒的初步研究

目的　研制一种新型的胰岛素 (INS)纳米粒 (NP)制剂。方法　以聚乳酸 (PLA)为载体材料 ,采用溶剂 -非溶剂法制备了INS -PLA -NP ,观察形态并测定粒径。给正常大鼠皮下注射 2U·kg-1INS溶液和 2U·kg-1INS -PLA -NP并观察降血糖作用。结果　INS -PLA -NP平均粒径为 84 34± 14 76nm ,给药后 0 5h血糖即降至最低(43 82 %± 10 4 1% ) ,并具有良好的缓释作用 ,药理相对生物利用度达到 133 5 1%。结论　制备工艺可行且制得的INS -PLA -NP在形态、粒径、载药特性、释药过程等方面令人满意     

纳米级胰岛素颗粒的制备和使用

目的通过使用逆相蒸发法制备胰岛素脂质体颗粒,对颗粒进行壳聚糖外壳包裹并做进一步的颗粒粒径,包封率和稳定性的测试。结果所制备的胰岛素亚微球颗粒粒径范围为(451.1±46.1)nm,包封率为61.4%,颗粒在水相和油相溶液中均结构稳定。通过大鼠肠道吸收测试,有效降低血糖浓度。结论壳聚糖包裹胰岛素脂质体包封效果良好,粒径稳定并且能够口服后有效降低血糖浓度。     

胰岛素磷脂油溶液的制备和降糖效果评价

目的:制备胰岛素磷脂油溶液,并考察其降血糖效果.方法:以超声-冻干法制备胰岛素磷脂油溶液,糖尿病大鼠分组口服,不同时间点测血糖值并对结果进行统计学分析.结果:胰岛素磷脂复合物包封率为(81.1±6.4)%,复合物冻干粉复溶后平均粒径为(99.5±27.4) nm,多分散指数为0.19±0.09,Zeta电位 (-14.9±0.2) mV.胰岛素磷脂油溶液给药0.5 h 后血糖开始下降,8 h 后血糖才开始恢复,有明显的口服缓释降血糖作用.结论:胰岛素磷脂油溶液制备工艺简单,稳定性高,药效显著,有望成为新型胰岛素口服给药系统.     

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.