培高利特对黑质多巴胺神经元放电活动的激动作用(英文)

目的:研究D_2受体激动剂培高利特(pergolide,Per)对大鼠黑质多巴胺(DA)神经元放电活动的影响,并与溴隐亭(bromocriptine,Bro)作比较,同时验证Per在整体动物有无D_1激动剂性质.方法:胞外单细胞电活动记录技术. 结果:二个药物均能抑制敏感及不敏感的DA神经元自发放电活动.Per的ID_(50)值为11.9μg kg~-1),而Bro为7.8 mg kg~(-1),Per比后者强很多.选择性D_2受体拮抗剂螺哌隆(spiperone,0.25 mg kg~(-1))或者选择性D_1受体拮抗剂Sch-23390(1—2 mg kg~(-1))可以减弱放电抑制.然而Bro引起的放电抑制并不都能为spiperone所减弱.结论:Per在整体动物有很强的D_2受体激动剂作用,比Bro强650倍.也有弱的D_1受体激动剂的性质.     

氯代斯阔任旋光异构体作用于多巴胺受体对动物行为的比较(英文)

目的:比较氯代斯阔任(CSL)旋光异构体对DA受体的作用特性。方法:采用小牛纹状体DA受体结合分析和小鼠、大鼠的行为实验。结果:d-CSL对D_1和D_2受体的K_i值分别是135和9150nmol·L~(-1),而l-CSL对D_1和D_2的亲和力(K_i)均为5.7nmol·L~(-1),分别为d-CSL的24倍和1605倍。dl-CSL对D_1和D_2受体的K_i值分别为8.9和9.6nmol·L~(-1),比l-CSL稍弱。大鼠刻板活动和木僵实验、小鼠的跳跃和自发活动实验均证明CSL旋光异构体对DA受体有阻滞作用。结论:CSL旋光异构体为DA受体阻滞剂的作用特性,其作用强度为:l-CSL>dl-CSL>>d-CSL。     

阿片受体三重激动剂KUST201的大鼠镇痛、耐受与戒断反应研究

目的通过大鼠模型研究δ/μ/κ阿片受体三重激动剂KUST201(DPI-125)的镇痛、耐受和戒断反应。方法选用♂SD大鼠,肌肉注射给药,通过夹尾镇痛和热板镇痛模型实验测定KUST201的镇痛时效、ED_(50)和δ拮抗剂纳曲吲哚联用的影响。大鼠慢性耐受实验在每天给药后测量,同时考查纳曲吲哚联用的影响。戒断反应实验每天给药2次,连续4 d递增给药,d 4给药3 h后,用纳洛酮催促戒断,观察戒断反应。结果 KUST201的夹尾镇痛ED_(50)为0.34 mg·kg~(-1),热板镇痛ED_(50)为0.68 mg·kg~(-1),镇痛作用可维持1 h,2 h后作用消失。慢性耐受实验中,从d 3开始产生镇痛耐受,d 7作用消失。δ拮抗剂NTI可降低KUST201的镇痛作用。戒断反应实验中,剂量关系曲线在2~8倍夹尾镇痛ED_(50)范围内上升明显。结论与已报道的δ/μ/κ三重激动剂DPI-3290相比,KUST201的镇痛活性相似,慢性耐受反应较不明显,而戒断反应稍强。δ受体激动能协同增强μ受体激动的镇痛效果。     

左旋千金藤立定对溴隐亭诱导的哺乳期大鼠促乳素水平低下的拮抗作用

目的:研究左旋千金藤立定(SPD)对溴隐亭(Bro)诱导的促乳素(PRL)水平低下的对抗作用。方法:哺乳期母鼠sc Bro 0.5mg·kg~(-1)·d~(-1),PRL显著降低,乳腺组织发育不良,而且仔鼠体重增长缓慢。用放免法测定母鼠PRL,检查乳腺发育状况,评价SPD的对抗作用。结果:SPD30及100mg·kg~(-1)·d~(-1)ip,能够显著对抗Bro诱导的母鼠PRL降低,分娩后d15PRL为11±4及23±6μg·L~(-1)(生理盐水为7±2),而且乳腺组织发育正常,仔鼠在出生后d11—15内迅速生长发育。结论:SPD能阻断大鼠脑垂体前叶的D_2受体,是一个D_2受体的拮抗剂。     

左旋千金藤立定对大鼠血清中催乳素水平的影响(英文)

目的:观察左旋千金藤立定(SPD)对血清催乳素(PRL)水平的影响,研究SPD的药理作用。方法:成熟♀鼠ip多巴胺受体激动剂、拮抗剂或SPD后断头取血,然后用放射免疫法测定血清中的催乳素水平。结果:SPD引起血清PRL水平迅速而显著的增加,效应持续约1h,具有剂量依赖性。SPD的半数有效剂量为3.7mg·kg~(-1)(95％可信限为2.6—4.3mg·kg~(-1))。剂量为20mg·kg~(-1)时产 生最大效应,使血清PRL水平达到448±64μg·L~(-1),0.2mg·kg~(-1)则无效。对于多巴胺受体激动剂培高利特(pergolide)引起的PRL水平低下,SPD5mg·kg~(-1)有部分对抗作用,10mg·kg~(-1)能够完全对抗。结论:SPD是D_2多巴胺受体拮抗剂。     

氯丙嗪对小鼠肠道活动的抑制作用及其拮抗药

Chl和Sco ip或icv均可抑制排便和肠道转运功能。Chl和Sco iv抑制排便的ED_(50)分别是0.85和3.49mg·kg~(-1),Sco的作用可被Phy(0.08 mg·kg~(-1),sc)拮抗,不被icv Pil(100—200μg)和4-AP(1μg)拮抗,而ChL的作用不被Phy(0.08mg·kg~(-1))拮抗,可被icvCil(100μg)和4-AP(1μg)拮抗。这提示Chl抑制小鼠肠道运动是抑制中枢释放ACh所致,Neo和Car也可拮抗Chl抑制排便。     

国产头孢三嗪噻肟的体内抗菌作用研究

国产头孢三嗪噻肟对2株大肠杆菌感染小鼠的体内抗菌活性ED_(50)分别为0.0463mg·kg~(-1)和0.0386 mg·kg~(-1).与进口的头孢氨噻肟的ED_(50).0.0404mg·kg~(-1)和0.415mg·kg~(-1)相似.而比头孢三嗪噻肟的ED_(50)0.0617 mg·kg~(-1)和0.0561 mg·kg~(-1)低.国产头孢三嗪噻肟对2株克雷伯肺炎杆菌感染小鼠的体内抗菌活性ED_(50)为0.148 mg·kg~(-1)和0.147mg·kg~(-1).与进口的头孢三嗪噻肟的ED_(50)0.182mg·kg~(-1)和0.115 mg·kg(-1)相似.而比头孢氨噻肟的ED_(50)0.347 mg·kg~(-1)和0.799 mg·kg~(-1)明显的低.国产头孢三嗪噻肟对2株绿脓杆菌感染小鼠的体内抗菌活性ED_(50)24.579 mg.kg~(-1)和44.158 mg·kg~(-1)与进口头孢三嗪噻肟ED_(50)28.364 mg·kg~(-1)和34.818 mg·kg~(-1)相似.而比头孢氨噻肟ED_(50)>250和224.985 mg·kg~(-1)明显的低.对金黄色葡萄球菌感染小鼠的体内抗菌活性国产和进口头孢三嗪噻肟及头孢氨噻肟之间差异均没有显著性.     

川芎嗪对大鼠缺血再灌注肾脏功能的影响

目的:通过研究不同浓度的川芎嗪(tertramethylpyrazine,TMP)在大鼠肾脏缺血再灌注损伤过程中的作用,探讨川芎嗪对肾脏组织发挥保护作用的最佳浓度。方法:建立大鼠肾脏缺血再灌注模型,分别检测假手术组、模型组、川芎嗪用药组(川芎嗪15,30,45,60,90 mg·kg~(-1))血肌酐(Cr)和尿素氮(BUN)水平,观察肾组织形态并测定其中的诱导型一氧化氮合酶(induced nitric oxide synthase,iNOS)活性。结果:15 mg·kg~(-1)和30 mg·kg~(-1)组川芎嗪显著降低肾组织内iNOS的活性,降低血浆Cr和BUN水平,减轻肾小管上皮细胞坏死程度,以15 mg·kg~(-1)最为显著;45 mg·kg~(-1)组血Cr和BUN水平及肾小管坏死程度低于模型组,但高于假手术组,且均有显著性差异;60 mg·kg~(-1)组和90 mg·kg~(-1)组血Cr和BUN反而上升,小管上皮细胞坏死比模型组明显加重,肾组织内iNOS较模型组变化不明显。结论:合适剂量(15～45 mg·kg~(-1))的川芎嗪可以通过降低iNOS活性,保护缺血再灌注肾功能,减轻肾组织病理损害,以15 mg·kg~(-1)最为显著,随剂量增加保护作用减弱。而较高浓度(45～90 mg·kg~(-1))川芎嗪失去对缺血再灌注肾脏的保护作用。     

用位置偏爱法评价二氢埃托啡的精神依赖性潜力

本文报道应用条件性位置偏爱法,研究了DHE的精神依赖性的潜力及其与受体的关系。结果表明,DHE在1倍镇痛ED_(50)的剂量0.6μg·kg~(-1)sc下,就可产生明显的位置偏爱,且偏爱程度随药物剂量增加(3倍ED_(50),9倍ED_(50))而加强。但是DHE产生偏爱的受体机制可能与Mor不同,它不为M_(5050)(3 mg·kg~(-1)ip)所阻断。这些结果说明,DHE有较强的精神依赖潜力,而且在形成机制上,有其独特之处。     

氟他胺的主要代谢产物2-羟基氟他胺在正常及CCl_4中毒大鼠的药物动力学

目的:研究氟他胺的一个主要活性代谢产物2-羟基氟他胺(HF)在正常及CCl_4中毒大鼠的药物动力学。方法:正常及CCl_4中毒大鼠灌胃HF 25mg·kg~(-1),采用高压液相色谱法测定HF浓度,以氟他胺为内标,色谱柱填料为YWG C18,流动相为甲醇:水=3:2(体积比),检测波长为295nm。结果:与正常大鼠比较,HF在CCl_4中毒大鼠的消除明显受到抑制。K由(0.11±0.05)h~(-1)减小到(0.05±0.01)h~(-1)(P<0.01),T_(1/2)由(6.8±1.9)h延长到(14±4)h(P相似文献   

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.     

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.