盐酸埃他卡林对高血压心脏重构的作用

目的　在自发性高血压大鼠 (spontaneouslyhyperten siverat,SHR)和脑卒中易感型自发性高血压大鼠 (stroke pronespontaneouslyhypertensiverat,SHRsp)上 ,评价盐酸埃他卡林 (iptakalimhydrochloride ,Ipt)对高血压心脏重构的实验治疗学作用。方法　SHR于第 12周龄进入实验 ,赖诺普利 (lisinopril,Lis) 12mg·kg-1,Ipt 3mg·kg-1灌胃每天 1次 ,连灌 4wk ;SHRsp于第 11周龄进入实验 ,实验设Ipt0 2 5、1和 4mg·kg-13个剂量组及溶剂对照组 ,灌胃给药每天 1次 ,持续给药 12wk ,观察药物对高血压心脏重构的影响。结果　实验期 4wk内 ,SHR对照组血压和心率进行性增高。Ipt能有效控制SHR的血压 ,降压效果确切 ,且可抑制SHR心率加快的趋势 ,但对SHR高血压心脏重构无明显作用。相同实验条件下 ,Lis也能有效控制SHR的血压 ,降压效果确切 ,对心率无明显影响 ;Lis治疗可减轻SHR高血压心脏重构。实验期 12wk内 ,SHRsp溶剂对照组血压持续性进行性增高。Ipt 3个剂量组均能降低SHRsp血压 ,Ipt 4mg·kg-1组在给药后第 4周开始出现心率减低。Ipt 3个剂量组的左心室和室间隔 (LV +S)重量及其与体重的比值[(LV +S) /BW ]低于溶剂对照组。 4组动物之间的右室重量(RV)均无差异。结论　Ipt能有效地控制SHR和SHRsp的血压 ,其对     

两种不同结构类型的钾通道开放剂埃他卡林和吡那地尔联合用药降压作用的特征

目的 :观察两种不同种类的钾通道开放剂(potassiumchannelopeners ,KCOs)埃他卡林 (iptakal im ,Ipt)和吡那地尔 (pinacidil ,Pin)联用降压作用的特征。方法 :用无创性套尾法观察药物对清醒大鼠血压和心率的影响。结果 :Pin在 2 .0和 4 .0mg·kg-1剂量下 ,可剂量依赖性降低清醒大鼠的血压 ,加快其心率。Ipt在 2 .0 ,4 .0和 8.0mg·kg-1剂量下 ,可剂量依赖性降低血压 ,但不影响心率。Ipt(2 .0～8.0mg·kg-1)与Pin(4 .0mg·kg-1)合用时 ,其降压作用产生协同效应 ,但加快心率的作用与Pin相同。结论 :Ipt和Pin降压特点不同 ,二者联用的降压作用增强。     

盐酸埃他卡林对麻醉正常血压犬血流动力学的影响

目的:评价盐酸埃他卡林(iptakalim hydrochloride,Ipt)对麻醉正常血压犬血流动力学的影响。方法:Ipt设置0.125,0.25,0.5mg·kg~(-1)三个剂量组,以吡那地尔(pinacidil,Pin)为阳性对照药,生理氯化钠溶液为阴性对照,观察麻醉正常血压犬血流动力学的变化。结果:Ipt0.125,0.25,0.5mg·kg~(-1)静脉注射可轻度降低血压,平均动脉压(MAP)分别下降0.80,1.07和1.33kPa,收缩压(SBP)与舒张压(DBP)下降幅度基本相当。与Pin相比,Ipt降压起效较慢,但作用平稳。Ipt0.125和0.25mg·kg~(-1)静注在降低血压的同时,对心率、心脏收缩、舒张和泵血功能无明显影响,对心脑血流量也无明显影响;对总外周阻力和心电图均无显著影响,但Ipt0.25和0.5mg·kg~(-1)对心脏泵血功能有轻微抑制作用。Pin加快心率且明显抑制心脏舒张功能。结论:Ipt对戊巴比妥钠麻醉正常血压狗有轻度的降低血压作用,对心脏泵血功能有轻微抑制作用。     

生技霉素药代动力学性能研究

目的　研究生技霉素药代动力学过程。方法　测定狗口服生技霉素 10mg·kg-1,2 0mg·kg-1,30mg·kg-1血药浓度并与乙酰螺旋霉素比较 ;测定大鼠灌胃生技霉素 40mg·kg-1,80mg·kg-1,12 0mg·kg-1血药浓度及大鼠灌胃生技霉素 40mg·kg-1后尿、胆汁活性产物回收率。血药浓度及尿、胆汁药物浓度以微生物法测定。 3P87程序拟合计算药物动力学参数。结果　狗口服 3组剂量生技霉素 ,结果表明药物吸收较快 ,lag time为 10～ 30min ;Tmax1 43～ 2 44h ;Cmax1 0 2～ 2 94g·L-1;T1/ 2α0 48～ 1 81h ;T1/ 2 β8 40～10 5 2h ;3组剂量AUC值分别为 15 2 5 ,2 3 70 ,31 40mg·L-1·h-1,表明药物在此剂量范围内呈线形药代动力学特征 ;MRT值分别为 8 11,8 38,8 71h ,不随剂量增减而改变。大鼠口服 3组剂量生技霉素 ,Tmax1 5 7～ 2 45h ;Cmax0 39～ 3 14mg·L-1;T1/ 2α 1 36～ 1 77h ;T1/ 2 β15 6 3～2 0 6 4h ;MRT值约为 13 0h。AUC值分别为 8 44、16 5 4、37 5 8mg·L-1·h-1,同样呈线形药代动力学特征。在相同的实验条件下 ,进行狗口服 3组剂量乙酰螺旋霉素药物动力学对比实验 ,测得ASPM药物动力学参数为 :lag time为0 37～ 0 44h ;Tmax1 49～ 2 2 6h ;Cmax 0 87～ 3 34mg2 0 0 0 0 3 0 5收稿 ,2 0 0     

萘哌地尔衍生物BWYJ对大鼠血压及猫血流动力学的影响

目的:观察萘哌地尔衍生物BWYJ对高血压模型和正常大鼠血压及猫血流动力学的影响。方法:分别对高血压和正常大鼠静脉及灌胃给药,观察血压变化;利用麻醉开胸测定猫血流动力学的变化;采用侧脑室给药、猫在体瞬膜神经肌肉标本初步探讨降压机制。结果:BWYJ1.2及2.4mg·kg-1iv,降低正常及高血压大鼠收缩压(SAP)和舒张压(DAP),且随剂量的增加效应增加,作用时间延长。BWYJ10、20及40mg·kg-1灌胃给药,降低清醒正常大鼠SAP(最大效应分别下降4.6%、13.0%、16.8%)和DAP(分别下降7.1%、17.9%、20.5%),3h后恢复。BWYJ5、10及20mg·kg-1灌胃清醒高血压大鼠,降低SAP(下降7.3%、16.5%、20.4%)和DAP(8.5%、14.8%、24.5%),强于正常大鼠且时间明显延长。麻醉猫十二直肠给药,BWYJ2.5mg·kg-1仅DAP、LVWI降低,BWYJ5mg·kg-1使SAP、DAP、TPR、±dp/dtmax及LVWI明显降低,其他无明显变化。结论:BWYJ静脉或灌胃给药对正常和肾性高血压大鼠产生降压作用,降压作用与中枢、神经节无关。     

盐酸埃他卡林对内皮素系统的影响

目的　研究新型抗高血压药物盐酸埃他卡林 (iptakaimhydrochloride,Ipt)对内皮素 (ET)系统的作用。方法　以放射免疫法测定大鼠血浆内皮素水平和培养的血管内皮细胞释放的内皮素量;以RT PCR技术,测定内皮素及其转化酶(ECE)基因表达的变化;在离体血管标本上,观察内皮素对血管平滑肌张力的影响;在麻醉大鼠上,插入肺内动脉导管测定肺动脉压。结果　①在SHRsp上,Ipt0 25 ~4 0m·kg-1,po, 1次 /d, 3个月,可对抗血浆中内皮素水平的病理性增高;②在培养的新生小牛主动脉内皮细胞 (BAEC)上Ipt在 1~1000μmol·L-1浓度范围内,能剂量依赖性地抑制培养的新生小牛主动脉内皮细胞分泌内皮素;③并能抑制培养的新生小牛主动脉内皮细胞内皮素和内皮素转化酶基因的表达;④在离体大鼠主动脉标本上,Ipt0 5 ~100μm·L-1可浓度依赖性地对抗ET 1的缩血管作用,此作用在无钙营养液中明显减弱;⑤在麻醉的SD大鼠上,经肺内动脉注入ET 1可以诱发肺动脉收缩,肺动脉压增高。Ipt0 5和1 0mg·kg-1可对抗肺动脉内注射ET 1诱发的肺动脉高压,但对正常肺动脉压无明显影响。结论　盐酸埃他卡林可对抗内皮素系统的功能,其特征包括抑制血管内皮细胞内皮素转化酶和内皮素基因的表达,抑制内皮素的释放,对抗高血压状态下血浆内皮素水平的病理性增?     

雷米普利对两种高血压大鼠模型降压作用的比较

目的　比较雷米普利片对肾血管性高血压大鼠 (RHR)及自发性高血压大鼠 (SHR)的降压效果。方法　采用经典的二肾一夹法复制RHR模型 ,手术后 4周按血压水平随机分为雷米普利治疗组与模型对照组 ,以假手术大鼠作为正常对照组 ;SHR随机分为雷米普利治疗组和模型对照组 ,以WKY大鼠作为正常对照组。药物治疗组ig 1mg·kg-1·d-1的雷米普利 ,对照组ig等体积空白溶媒 ,连续治疗 8周。给药前及给药期间每 4周测定一次尾动脉收缩压 ,每周称体重。结果　给药 4周时 ,与模型组比较雷米普利对RHR和SHR有非常显著的 (P <0 .0 1)和显著性 (P <0 .0 5 )的降压作用 ;给药 8周时 ,雷米普利对RHR和SHR都有非常显著的降压作用 (P <0 .0 1) ,RHR治疗组收缩压降低值都大于有效血压降低值 ,降压有效率为 10 0 % ;而SHR治疗组 2只大鼠的血压降低值 (0kPa和 0 .7kPa)小于有效血压降低值 ,降压的有效率为 6 6 .7%。结论　雷米普利可有效降低RHR及SHR两种高血压模型大鼠的血压。     

白川降压胶囊对肾性高血压大鼠血压的影响

目的　观察白川降压胶囊 (BC)对肾性高血压模型大鼠的急性降压作用和对心率的影响。方法　采用颈动脉插管直接测压法测量血压和心率。结果　给予 BC 0 .1 5 ,0 .3 ,0 .6 g· kg-13 0 ,6 0 ,90 ,1 2 0 min后大鼠收缩压、舒张压均明显降低 ,与对照组比较 P <0 .0 5。 BC各剂量给药后大鼠心率无明显变化 ,与对照组比较 P >0 .0 5。结论　BC对肾性高血压大鼠具有明显的急性降压作用 ,对心率无影响     

3,6-二[二甲氨基]-二苯骈碘杂环甲酸盐(IHC-64)的降压作用

IHC-64能显著降低清醒和麻醉动物血压,起效迅速,作用短暂,且无快速耐受性。麻醉犬IHC-640.5,1.5mg·kg~(-1)iv后,血压立即下降,持效10～30min左右.麻醉兔IHC-64 0.75,1.50,3.0mg·kg~(-1)iv后0.5～1.0min血压下降,持效10～5min。其降压作用比可乐定强,降压剂量对清醒兔和麻醉犬心率无明显影响.     

沙苑子总黄酮对高血压大鼠的降压作用及血管紧张素含量的影响

目的　研究沙苑子总黄酮对肾血管性高血压大鼠 (RHR)有无降压作用及可能机理。方法　应用二肾一夹法制作RHR模型 ,沙苑子总黄酮急性灌胃给药 ,尾袖法测量清醒RHR尾动脉收缩压 ,八导生理记录仪检测麻醉RHR血压及心率 ,放射免疫法检测RHR血浆血管紧张素Ⅱ (AngⅡ )含量。结果　单次ig沙苑子总黄酮 10 0和 2 0 0mg·kg- 1,1h后清醒RHR血压显著降低 ,75min时分别下降了 8.5 %和10 .5 %;麻醉RHR在 4 5～ 6 0min时平均动脉压分别下降了 8.0 %和 14 .9%,与给药前或生理盐水对照组相比均有统计学显著性差异 ,2h时恢复至原来水平 ,心率无明显变化 ;单次ig后 30min ,AngⅡ含量分别下降了 2 2 %和 31%。结论　沙苑子总黄酮对RHR有明显降压作用 ,其机理可能与其降低AngⅡ水平有关。     

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.     

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.     

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.