新凝血因子Ⅹa抑制剂Bg115-2的抗血栓作用及药代动力学

目的 探讨Bg115-2的抗血栓功效和初步药代动力学性质。方法 试剂盒测定小鼠半体内凝血酶原时间（PT）和活化部分凝血活酶时间（APTT）;采用小鼠下腔静脉结扎模型评价对静脉血栓的作用;采用尾尖测定出血时间法;用FⅩa活性测定Bg115-2的血药浓度。结果 sc给予Bg115-2 0.19~3.0 mg·kg^-1可明显地、剂量依赖地延长PT (P<0.05, P<0.01)和APTT (P<0.01);Bg115-2 0.75~3.0 mg·kg^-1可显著地减轻血栓质量,其抑制50%血栓形成的剂量（ID₅₀）为0.19 mg·kg^-1;ig给予Bg115-2 1.5~6.0 mg·kg^-1也明显地减轻血栓质量(P<0.01)。Bg115-2的出血反应与那曲帕林钙相似,有较高的出血风险效益比,ED₂/ID₅₀为26.8。另外单次sc给予Bg115-2 3.0 mg·kg^-1显示出二室模型的药代动力学特点,t_1/2为（6.18±1.45)h, c_max为(5.20±0.66)mg·L^-1, AUC为(43.75±8.20)mg·L^-1·h。结论 Bg115-2为一注射和口服均可的、强效的静脉血栓形成抑制剂,出血不良作用较轻。它具有较长的半衰期和二室模型的分布特征。     

新型多肽bg115-2体外对活化凝血因子X的抑制作用

目的研究基因重组的新型多肽bg115-2体外对活化凝血因子X(FXa)的抑制作用、与酶结合的动力学特点及抗凝血活性.方法用发色底物法测定bg115-2的FXa抑制活性、特点和酶结合性质;用活化的部分凝血活酶时间(A PTT)和凝血酶原时间(PT)试剂盒测定bg115-2对于大鼠血浆凝血时间的影响.结果bg115-2具有浓度依赖的FXa抑制活性,IC50为13.1×10-9mol·L-1,Ki为7.3×10-9mol·L-1;bg115-2对FXa的抑制活性随时间延长而增强;稀释反应混合物未使FX a的活性恢复;bg115-2可浓度依赖性延长APTT及PT,使APTT延长1倍的浓度为1.3×10-7mol·L-1,使PT延长1倍的浓度为3.0×10-7mol·L-1.结论bg115-2为一强活性的、慢结合的、不可逆的FXa抑制剂,具有较强的抗凝血活性.     

TY602-1的抗凝血作用研究

目的:探讨TY602-1的抗凝血作用及其作用机制。方法:采用离体FⅩa酶活性测定法、小鼠体内凝血酶原时间(PT)、活化部分凝血酶时间(APTT)和凝血酶时间(TT)的测定实验、大鼠动静脉旁路丝线上血栓形成实验、大鼠下腔静脉血栓模型实验,观察TY602-1的抗凝血药效。结果:TY602-1能抑制FⅩa活性;口服1.25,2.5,5和10 mg·kg-1剂量时明显延长小鼠PT和APTT,但对TT无明显影响;口服10 mg·kg-1剂量能明显抑制大鼠动静脉旁路血栓和下腔静脉血栓形成。结论:TY602-1是一种具有较强抗凝血作用的FⅩa抑制剂,可作为预防和治疗深度静脉血栓和肺动脉栓塞的药物使用。     

氟伐他汀对骨质疏松大鼠ALP、P、Mg2+及Ca2+的影响

目的 观察氟伐他汀(Fluvastatin,Flu)对骨质疏松大鼠血清中Ca2+、Mg2+、P及ALP的影响,探讨其调节骨质疏松无机离子平衡的机制.方法 采用雌性大鼠去卵巢法制备骨质疏松大鼠动物模型,同时给予不同剂量的Flu(20、10、5 mg·kg-1)干预,实验12周后测定大鼠血清中碱性磷酸酶(ALP) 、Ca2+、P、Mg等的含量.结果 20 mg· kg-1 F1u可使骨质疏松大鼠血清中ALP、P水平下降,使Mg2+及Ca2+含量升高(P ＜0.05,P＜0.01);10 mg·kg-1 Flu可使骨质疏松大鼠血清中ALP含量下降,Mg2+及Ca2+含量升高(P ＜0.05,P ＜0.01);5 mg·kg-1 Flu可使骨质疏松大鼠血清中ALP含量降低(P＜0.05).结论 Flu对骨质疏松大鼠血清中的离子代谢失衡具有调节作用.     

延胡索乙素抗大鼠血栓作用研究

目的:研究延胡索乙素对大鼠体内动静脉血栓形成和凝血指标的影响.方法:分别采用大鼠下腔静脉结扎、动静脉旁路和FeCl3动脉血栓模型,将SD大鼠随机分为空白对照组、阿司匹林组(40 mg· kg-1)、延胡索乙素组(20、40、80 mg· kg-1),各组动物连续灌胃7d,末次给药2h后建立各血栓模型,测定延胡索乙素对血栓形成的影响;并测定了各组大鼠给药后2h血浆PT和APTT.结果:延胡索乙素各剂量组能抑制大鼠静脉血栓形成(高剂量抑制率达54.2％),有效的降低FeCl3刺激动脉血栓和动静脉旁路血栓重量(高剂量时抑制率分别为32.8％和43.7％);延长大鼠血浆活化部分凝血酶时间(APTT)、凝血酶原时间(PT).结论:延胡索乙素能抑制大鼠静脉血栓、动脉血栓和动静脉旁路血栓的形成.     

四氢异喹啉类衍生物P91024对实验性心律失常和豚鼠离体心房肌的作用

目的:研究四氢异喹啉类衍生物P91024[化学名:1-{1-(6-甲氧基-2-萘基)乙基}-2-对硝基苄基-6,7-二甲氧基-1,2,3,4-四氢异喹啉氢溴酸盐]对实验性心律失常和豚鼠离体心房肌的作用.方法:采用氯化钙、氯化钡、肾上腺素诱导心律失常动物模型,观察灌胃给P91024对实验性心律失常的作用.采用豚鼠离体心房肌实验方法,测定P91024给药前后对心房静息后增强及正性阶梯现象的影响.结果:P91024 30和60 mg·kg-1能降低氯化钙诱发大鼠室颤的发生率(P＜0.01),缩短窦律恢复时间(P＜0.05).P91024 60mg·kg-1可缩短氯化钡诱发大鼠心律失常的持续时间(P＜0.05).并且,P91024 26.1和52.2 mg·kg-1能缩短肾上腺素诱发豚鼠心律失常的持续时间(P＜0.05).P91024 5×10-5mol·L-1能明显翻转豚鼠离体心房肌的正性阶梯作用(P＜0.01)和降低静息后增强作用(P＜0.01).结论:P91024具有明显的抗实验性心律失常作用,抑制豚鼠离体心房肌静息后增强现象及翻转正性阶梯现象.显示本品可能是一种特异性钙拮抗剂.     

异钩藤碱对血小板聚集与血栓形成的抑制作用

目的研究异钩藤碱(isorhynchophylline,Isorhy)对血小板聚集与血栓形成的影响,并探讨其机制。方法以比浊法测定Isorhy体外给药对大鼠血小板聚集的影响;采用动-静脉旁路血栓形成法制作大鼠血栓模型,观察Isorhy对血栓形成的作用;以放免法测定Isorhy对ADP作用下cAMP含量的影响。结果Isorhy0.65mmol.L-1和1.30mmol.L-1对ADP(1.5×10-5mol.L-1)和凝血酶(thrombin,Thr,3U.ml-1)诱导的大鼠血小板聚集均有抑制作用(P<0.01)。静脉注射Isorhy10mg.kg-1和5mg.kg-1可明显降低大鼠血栓形成湿重(P<0.01)。Isorhy0.33~1.30mmol.L-1可升高ADP作用后的血小板cAMP浓度(P<0.01)。结论Isorhy明显抑制血小板聚集与大鼠血栓形成,其抗ADP所致血小板聚集的作用机制至少部分地与升高cAMP水平有关。     

川芎、当归萃取液对大鼠血栓形成的影响

目的 :评价川芎、当归萃取液抗血栓形成的作用。方法 :采用超临界CO2 流体萃取技术 ,分离出川芎、当归的萃取液。参照动 静脉旁路血栓形成法 ,建立大鼠血栓形成模型。以不同浓度的川芎、当归萃取液及阳性药物阿司匹林用于实验大鼠 3d后 ,分别测定血栓湿重。结果 :川芎、当归萃取液高剂量组 (80mg·kg-1)和阿司匹林 (30 0mg·kg-1)对照组的血栓湿重显著减少 ,与溶剂对照比较 ,P均 <0 0 5 ;但 2组间比较 ,P >0 0 5 ;而川芎、当归萃取液 2 0 ,4 0mg·kg-1组的血栓湿重与溶剂对照组比较 ,P均 >0 0 5。结论 :川芎、当归萃取液高剂量对实验性大鼠血栓形成有拮抗作用     

蝙蝠葛苏林碱在兔体内的药代动力学及组织分布

目的:研究蝙蝠葛苏林碱(DS)在兔体内的药代动力学和组织分布特征.方法:兔耳缘静脉注射给予DS后,采用高效液相色谱法测定各时间点血浆和组织器官药物浓度,并用3p97程序计算药代动力学参数.结果:兔DS 2.5、5、10 mg·kg-1静脉注射给药后,体内动力学行为符合二房室开放模型.T1/2β分别为 3.0±0.6、3.4±0.9 和 6.9±0.6 h;Cls分别为 3.1±0.6、3.6±0.4 和 4.4±0.3 L·h·kg-1;Vd分别为 13.1±2.7、18.0±6.2 和 43.6±4.4 L·kg-1;AUC0～t分别为 0.84±0.13、1.41±0.17 和 2.30±0.18 mg·h·L-1.在DS 2.5～5 mg·kg-1范围内主要药动学参数无显著性差异(P>0.05),但DS 10 mg·kg-1静脉注射后,C0超比例增加(P＜0.01),T1/2β明显延长(P＜0.01).结论:在 2.5～5 mg·kg-1范围内DS的消除为线性动力学,而10 mg·kg-1静脉注射后,本品在兔体内的消除未呈线性动力学.组织分布以肺脏含量最高,其次为肾、脾和肝脏.各组织器官中药量均显著高于血浆药物浓度.     

1,6-二磷酸果糖镁对异丙肾上腺素所致大鼠心肌损伤的保护作用

研究 1 ,6-二磷酸果糖镁 ( FDP- Mg)对异丙肾上腺素 ( Iso)所致心肌损伤的保护作用 .大鼠 sc Iso( 8mg· kg-1· d-1,3d)造成心肌损伤模型 ,测定心肌组织和血清肌酸激酶 ( CK) ,乳酸脱氢酶( LDH) ,超氧化物歧化酶 ( SOD)活性及丙二醛( MDA) ,Mg2 ,P和 K 含量 .结果 :每天给予 Iso的同时给予 FDP- Mg( 2 50 - 1 0 0 0 mg· kg-1· d-1,3d)能明显降低血清 CK,LDH水平 ,抑制心肌组织中 CK,LDH释放 ,提高血清和心肌 SOD活性 ,降低MDA水平 ,提高心肌及血清 Mg2 和 P含量 ,降低血清 K 浓度。综合了 FDP- Na2 ( 530 mg· kg-1·d-1,3d)和硫酸镁 ( 1 50 mg· kg-1· d-1,3d)的作用特点。结果表明 ,FDP- Mg对 Iso所致大鼠心肌损伤具有保护作用 ,与其抗氧化及改善心肌代谢有关 .     

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.     

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.