双苯氟嗪对血小板聚集和血栓形成的影响(英文)

在体内外实验中观察我国首创合成的新钙拮抗剂双苯氟嗪(Dip)对血小板聚集和实验性血栓形成的作用。Dip iv 1—2mg·kg~(-1)和1—100μmol·L~(-1)体外温育可剂量或浓度依赖性地抑制ADP和AA诱发的家兔血小板聚集。Dip iv 2.5—10 mg·kg~(-1)和ip 50—100 mg·kg~(-1)可抑制大鼠体内血栓形成;Dip iv 10mg·kg~(-1)和200μmol·L~(-1)体外给药可抑制体外血栓形成。提示,减轻紊乱的血小板与血管壁反应是其抗血栓作用的主要因素,Dip的作用强于Cin。     

双苯氟嗪、氟桂利嗪、桂利嗪对5-羟色胺所致离体猪基底动脉收缩的拮抗作用(英文)

目的:探索双苯氟嗪(Dip,一种我国自行合成的桂利嗪衍生物),对5-羟色胺所致的脑动脉收缩的影响。方法:比较双苯氟嗪、氟桂利嗪(Flu)、桂利嗪(Cin)对5-羟色胺所致离体猪基底动脉收缩的抑制及两种收缩成分的影响。结果:三者的拮抗作用强度顺序(IC_(50))为Dip 4.0μmol·L~(-1)>Flu15.6μmol·L~(-1)>Cin 25.2umo·L~(-1)。这三种药对5-羟色胺所致离体猪基底动脉的两种收缩成分均有拮抗。Dip和Cin抑制收缩的快速相强于持续相,而Flu对二者的作用无显著差异。结论:在Dip,Flu和Cin三种药之中,Dip对脑血管的扩张作用最强,其原因主要与抑制内钙的释放有关。     

双苯氟嗪对大鼠缺血脑皮层诱发电位和氨基酸含量的影响(英文)

目的:测定双苯氟嗪(Dip)对大鼠缺血脑细胞内外氨基酸含量及皮层体感诱发电位(SEP)的影响。方法:在结扎双侧颈总动脉雌性Wistar大鼠,用HPLC法测定脑透析液和脑组织中的氨基酸含量,用电生理技术测定SEP。结果;Dip ip 50 mg·kg~(-1)可防止缺血所致SEP潜伏期的延长及其幅度的过分增大,降低脑透析液中的谷氨酸、天冬氨酸和甘氨酸浓度以及减轻脑组织中谷氨酸、天冬氨酸、甘氨酸、牛磺酸和γ-氨基丁酸的消耗。结论:Dip能够改善脑缺血所致的皮层功能紊乱和脑内兴奋性与抑制性氨基酸释放失调,为其抗缺血性脑损伤作用提供了进一步的实验证据。     

双苯氟嗪对大鼠实验性脑水肿的保护作用

用结扎双侧颈总动脉雌性Ｗｉｓｔａｒ大鼠比较双苯氟嗪（Ｄｉｐ）与桂利嗪（Ｃｉｎ）对实验性脑水肿的作用。Ｄｉｐ２５－１００ｍｇ·ｋｇ＾－１ ｉｐ可对抗脑水肿引起的大鼠脑缺血性症状，作用强于Ｃｉｎ，两药预处理加后处理作用也强于单独后处理作用。Ｄｉｐ ５０ ｍｇ·ｋｇ＾－１ｉｐ能减小缺血脑的梗死范围和ＣＢＦ降低，但并不改变缺血前ＣＢＦ，提示Ｄｉｐ可能通过维持缺血区的ＣＢＦ而治疗缺血性脑水肿。     

双苯氟嗪对麻醉狗椎动脉的选择性扩张作用

用恒速泵法比较Dip对麻醉狗VVR，CVR和FVR的作用，Dip 0.1-3mg.kg^-1 iv可显著降低VVR，强于对FVR和CVR的降低和Cin的作用；两种1mg.kg^-1iv仅短暂降SBP，DBP，MAR和TPR，而对其它血液动力学参数均无显著影响，提示Dip对血管床的不同部位有选择性，是一个比Cin更强的选择性脑血管扩张剂。     

双苯氟嗪的体内外致突变性评价

双苯氟嗪(Dipfluzine，Dip)系由河北医科大学药学院研制并合成的桂利嗪类钙拮抗剂。先期的实验表明，Dip可以选择性地扩张椎动脉、基底动脉及冠状动脉，且作用强于桂利嗪；也有增加脑血流量，改善脑缺血、缺氧，及抗血小板凝集和血栓形成的作用，因此，Dip很可能是治疗心脑血管疾病且极具临床开发价值的新型钙拮抗剂。目前，关于Dip的特殊毒性尚未见报道。本实验对Dip的体内体外致突变毒性进行了研究，以便为进一步研究此药提供遗传学资料。     

双苯氟嗪对局灶性脑缺血再灌注损伤的保护作用(英文)

目的　评价双苯氟嗪 (Dip)和氟桂利嗪 (Flu)在大鼠局灶性脑缺血再灌注模型中的神经保护作用。方法　将内皮素 1(ET 1)灌注到大脑中动脉附近制备大鼠局灶性脑缺血再灌注模型 ,并于灌注ET 1后 30min和 4 .5h腹腔注射溶剂、Dip 10 ,2 0和4 0mg·kg- 1和Flu 2 0mg·kg- 1,采用氢清除法监测灌注ET 1前、后纹状体血流变化 ,并对缺血后 2 4h脑梗塞面积、血清中超氧化物歧化酶 (SOD)活性和丙二醛 (MDA)含量的变化进行了测定。结果　Dip 2 0和 4 0mg·kg- 1于灌注ET 1后 70和 10 0min明显改善缺血侧纹状体血流量下降 ;Flu 2 0mg·kg- 1的作用较弱 ,仅于灌注ET 1后 10 0min明显改善缺血侧纹状体血流量 ;Dip可以剂量依赖性的降低脑梗塞面积 (r =0 .9797,P <0 .0 1) ,同剂量Flu可产生相似的作用 ;各剂量组Dip和Flu均可增加血清中SOD活性、降低MDA含量。结论　Dip和Flu对脑缺血再灌注损伤有明显的保护作用 ,Dip改善脑血流的作用略强于Flu ,其保护作用的机制与改善脑血流和抗氧化作用有关。     

咪苯嗪酮对花生四烯酸诱导的大鼠脑血栓形成的影响

花生四烯酸(AA)0.25～1 mg·kg~(-1)经颈内动脉注射能诱发大鼠同侧大脑半球脑内血栓形成,明显增加伊文思蓝通过血脑屏障渗入脑实质的量,峰值为205±s 50 mg·kg~1脑组织,相应对照组为10±s 5mg·kg~1,咪苯嗪酮0.25～0.5mg·kg~1 iv能对抗AA引起的大鼠脑血栓形成,显著降低脑实质内伊文思蓝的含量,作用呈剂量依赖性,且强于哒唑氧苯     

白三烯受体拮抗剂0N0-1078对大鼠局灶性脑缺血的神经保护作用(英文)

目的:观察白三烯受体拮抗剂ONO-1078(pran-lukast)对大鼠局灶性脑缺血是否具有神经保护作用.方法:以大脑中动脉阻塞30分钟诱导局灶性脑缺血,并再灌注24小时.ONO-1078(0.003-1.0mg·kg~(-1))或生理盐水(1 mL·kg~(-1))在脑缺血前30分钟和缺血后2小时各腹腔注射1次.脑缺血24小时后,测定神经症状评分、脑梗死体积、神经元密度(皮质、海马和纹状体)、脑水肿以及小血管周围白蛋白渗出.结果:ONO-1078轻度改善神经症状;但显著减少脑梗死体积和神经元缺失,呈钟型量效关系,以 0.01-0.3 mg·kg~(-1)作用最明显;0.01-1.0 mg·kg~(-1)可减轻缺血半球面积增大以及白蛋白渗出.结论:ONO-1078可保护大鼠局灶性脑缺血,可能部分由于抑制了脑水肿.本研究提示白三烯受体拮抗剂可能代表一类治疗急性脑缺血新药.     

盐酸苯环壬酯对大鼠后循环缺血性眩晕和小鼠位置性眩晕的改善作用

目的研究盐酸苯环壬酯的抗眩晕作用。方法利用双侧颈总动脉结扎法制备大鼠脑缺血模型,大鼠ig给予盐酸苯环壬酯0.1~4.0 mg·kg~(-1),每天2次,连续3 d,结合激光多普勒脑血流仪检测盐酸苯环壬酯对脑血流量变化的影响。通过XY-5双轴变速旋转刺激制备小鼠眩晕症模型,小鼠ig给予盐酸苯环壬酯1.4~5.6 mg·kg~(-1)后变速旋转刺激30 min,检测自发活动的变化;小鼠ig给予盐酸苯环壬酯1.4~8.4 mg·kg~(-1)30 min后,通过检测胃酚红排空率指标观察盐酸苯环壬酯对小鼠胃平滑肌的影响。结果大鼠双侧颈总动脉结扎24 h后脑血流量显著减少(P<0.01);与模型组比较,盐酸苯环壬酯0.5,2.0和4.0 mg·kg~(-1)可显著增加缺血大鼠脑血流量(P<0.05)。通过旋转刺激后,模型小鼠自发活动的总路程减少(P<0.05),运动速度减慢(P<0.05);与模型组比较,盐酸苯环壬酯2.8和5.6 mg·kg~(-1)可增加眩晕小鼠总路程和运动速度(P<0.05);盐酸苯环壬酯5.6和8.4 mg·kg~(-1)降低小鼠胃酚红排空率(P<0.05)。结论盐酸苯环壬酯增加脑血流量,改善后循环缺血,对眩晕的呕吐症状和运动功能具有显著的改善作用。     

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.     

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.