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…

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（ＩＣ５０）为Ｄｉｐ４．０μｍｏｌ．Ｌ＾－１〉Ｆｌｕ１５．６μｍｏｌ．Ｌ＾－１〉Ｃｉｎ２５．２ｕｍｏ．Ｌ＾－１，这三种药对５－羟色胺所致离体猪基底动脉的两种收     

双苯氟嗪对大鼠实验性脑水肿的保护作用(英文)

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。Dip 25—100mg·kg~(-1)ip可又才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~(-1)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。     

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。     

盐酸氟桂嗪的不良反应

盐酸氟桂嗪(Flunarizine,西比灵)系呱嗪双氟化衍生物,新型选择性钙阻滞剂,对血管平滑肌有扩张作用,能选择性明显改善脑循环及冠脉循环;对组胺、5-羟色胺、缓激肽、肾上腺素、增压素等有拮抗作用。已广泛用于治疗脑动脉硬化、脑血栓形成、脑栓塞、高血压所致脑循环障碍、脑出血、蛛网蟆下腔出血、头部外伤及其后遗症,脑循环障碍所致的精神症     

双苯氟嗪对豚鼠心室肌细胞L-钙电流的影响

目的:观察双苯氟嗪(Dip)对豚鼠心室肌细胞L-型钙电流(I_(Ca-L))的影响。方法:酶解法制备单个心室肌细胞。应用全细胞膜片箝技术记录豚鼠单个心室肌细胞钙电流。结果:在0.3-30μmol/L范围内,Dip可浓度依赖性地降低电压依赖性激活I_(Ca-L)峰值,被Dip 3μmol/L所抑制的I_(Ca-L)在冲洗5min后可得到部份恢复。但Dip对I_(Ca-L)的电压依赖特征,最大激活电压,以及I_(Ca-L)稳态激活无明显影响。在Dip3μmol/L存在下,半数激活电压(V_(0.5))和斜率参数(к)与对照组相比,差异均无显著性。V_(0.5)分别为(-12.8±1.7)mV和(-13.2±2.4)mV,к分别为(7.1±0.4)mV和(7.5±0.5)mV(P>0.05)。Dip3μmol/L可明显使钙电流稳态失活曲线左移,加速钙通道电压依赖性稳态失活。V_(0.5)分别为(-19.7±2.4)mV和(-31±6)mV,к分别为(3.6±0.3)mV和(1.8±0.2)mV(P<0.05).Dip 3μmol/L还使I_(Ca-L)从失活状态下的恢复明显减慢。结论:Dip主要作用于L-型钙通道的失活状态,加速钙通道失活,并使其从失活状态下恢复减慢,从而抑制I_(Ca-L)。     

地昔帕明和氟西汀拮抗5,7-二羟色胺对海马和皮质神经元的损伤(英文)

目的:评价抗抑郁剂地昔帕明和氟西汀对5,7-二羟色胺损伤神经元的拮抗作用。方法:原代培养10d的大鼠海马和皮层细胞加入不同浓度的地昔帕明和氟西汀作用30min后,用5,7-二羟色胺600μmol·L~(-1)损伤4h,MTT法结合形态学观察判断药物的保护作用。结果:地昔帕明和氟西汀对神经元损伤具有显著拮抗作用,剂量范围分别为0.8-10μmol·L~(-1)和0.04-0.6μmol·L~(-1)。结论:地昔帕明和氟西汀对5,7-二羟色胺的神经元损伤具有显著拮抗作用,氟西汀效价高于地昔帕明(约一个数量级)。两种抗抑郁剂对神经元的保护作用可能是它们抗抑郁作用的机制之一。     

盐酸氟桂利嗪致可逆性痴呆15例

盐酸氟桂利嗪为选择性钙通道阻滞剂,由于其对组胺、5-羟色胺、缓激肽、肾上腺素、加压素等有拮抗作用,对血管平滑肌有扩管作用.广泛用于临床治疗血管性头痛、ⅱ脑血栓及后遗症、椎基底动脉供血不足引起的中枢性眩晕.但有部分病人长期用药后出现可逆性痴呆,现报告如下:     

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.