尼群地平的抗血小板聚集和抗血栓作用

国产尼群地平(1)对凝血酶(0.15u/ml)诱导的血小极聚集的 IC_(50)是47.5μmol/L,对 ADP(4μmol/L)诱导作用的 IC_(50)是93.9μmol/L。大鼠 iv 1 0.8μg/g 对凝血酶诱导血小板聚集的抑制率为89.8%,对 ADP、AA 诱导血小板聚集的效应也有非常显著的抑制作用。1尚可明显抑制血栓形成。     

益康唑和克霉唑对血小板聚集及TXB_2和PGE_2生成的影响

益康唑,克霉唑,咪康唑和酮康唑体外抑制AA诱导兔血小板聚集比抑制ADP诱导大鼠血小板聚集的作用强。其中益康唑和克霉唑抑制AA诱聚兔血小板的IC_(50)分别是6.4及11.6μmol/L。放射免疫法测定大鼠血小板产生的TXB_2及PGE_2发现益康唑和克霉唑在5～50 nmol/L浓度下,能抑制TXB_2产生,同时增加PGE_2生成量,并呈良好的剂量效应相关。浓度为0.1～100μmol/L时,TXB_2的生成仍被抑制,而PGE_2的生成量反而逐渐降低。两药对TXB_2生成的抑制作用比Daz强。     

3,6—[二甲氨基]—二苯骈碘杂六环枸橼酸盐对家兔血小板功能cAMP水平的影响

3,6—[二甲氨基]—二苯骈碘杂六环枸橼酸盐(IHC—6~(5))在体外明显抑制ADP、花生四烯酸和胶原诱导的血小板聚集,对这些诱导剂的抑制作用无明显的选择性,IC_(50)分别为:51.9,55.1和57.4μmol/L,同时促进ADP、花生四烯酸诱导血小板聚集的解聚,减慢胶原诱导血小板聚集的速度,延长聚集潜伏期。其效应与剂量间呈现依赖关系。IHC-65也明显抑制胶原诱导的血小板5—羟色胺的释放,但对血小板内cAMP的水平无明显影响。结果提示:IHC—65是一个非选择性的血小板功能抑制剂,作用机理可能与抑制血小板释放反应及钙拮抗作用等有关,并非通过升高血小板内cAMP水平而发挥作用。     

BM13505对血小板聚集和血栓形成的影响

BM13505在体外对花生四烯酸(AA)诱导的家兔血小板聚集有抑制作用且呈剂量依赖性,其IC_(50)为20μmol/L;对 ADP 和胶原诱导的血小板聚集则无显著影响。大鼠 ivBM13505 0.23mg/kg 能显著,延长血管闭塞时间,与阿司匹林30mg/kg 药效相近。小鼠 ivBM13505 1.13mg/kg 可明显延长尾出血时间效应与阿司匹林30mg/kg 相近。     

新型血小板GPⅡb/Ⅲa受体拮抗剂Z4A5抗血小板作用的研究

目的研究血小板GPⅡb/Ⅲa受体拮抗剂Z4A5抑制血小板聚集的活性、稳定性以及对已聚集血小板的解聚作用。方法采用比浊法测定Z4A5对体外二磷酸腺苷(aden-osine diphosphate,ADP)诱导血小板聚集的抑制作用和稳定性及对ADP诱导聚集血小板的解聚作用。结果 Z4A5浓度依赖性的抑制ADP诱导的血小板聚集,半数抑制浓度(50%concentration of inhibition,IC50)为(0.46±0.05)μmol.L-1(n=10,P<0.05);Z4A5在血浆中孵育3 h仍保持85.55%(P<0.05)的活性;10μmol.L-1 Z4A5在加入ADP诱导聚集的血小板3 min及7 min后的解聚率为分别为22.66%(P<0.05)及30.93%(P<0.01)。结论 Z4A5在体外有较强的、稳定的抑制血小板聚集作用,而且对聚集血小板有一定的解聚作用。     

海兰地嗪对血小板聚集的影响及机理探讨

海兰地嗪(Her)体外对胶原,ADP,A23187和AA诱导的大鼠血小板聚集有明显抑制作用,其IC_(50)分别为14.5,41.6,44.1和48.3μg/ml。Her对AA诱导的大鼠血小板MDA生成不能抑制,但能升高兔血小板cAMP水平和抑制凝血酶诱导的人血小板胞浆内游离钙离子浓度升高。Her的抗血小板聚集作用机理可能与升高血小板内cAMP水平和抑制细胞内游离钙离子浓度升高有关。     

四肽KRDS对犬血小板功能及动脉血栓形成的抑制作用

来自人乳转铁蛋白的四肽(赖—精—门冬—丝氨酸,K RDS)能抑制ADP诱导的犬血小板聚集反应(IC_(50):350μmol/L)和花生四烯酸诱导的血栓烷B_2的产生(IC_(50):175μmol/L),同时,KRDS能抑制凝血酶诱导的血小板表面α—颗粒膜蛋白(GMP-140)的表达(IC_(50):350μmol/L及5—羟色胺的释放(IC_(50):525μmol/L)。另外,KRDS能抑制犬股动脉实验血栓的形成,制备血栓模型4h后,离体血栓的重量为对照组的50%,以~(125)Ⅰ—SZ-51(抗GMP-140的单抗)为示踪剂,离体血栓与血液的放射活性比值仅为对照组的16%。结果提示:四肽KRDS不仅能抑制犬血小板的聚集和释放功能,对体内血栓的形成也有明显的抑制作用,为一生理性抗血栓寡肽。     

甲基莲心碱对兔血小板聚集功能的影响

用比浊法和放射免疫分析技术研究甲基莲心碱(Nef)抗血小板聚集作用及其对TXA₂/PGI₂与cAMP/cGMP浓度的影响。结果显示,Nef在体外明显抑制ADP,胶原,AA及PAF诱导的家兔血小板聚集,IC₅₀分别为16,22,193及103μmol·L^-1;Nef明显抑制AA诱导的血小板TXA₂的生成和释放,对动脉环PGI₂的生成有促进作用;Nef剂量依赖性地升高血小板cAMP浓度,对cGMP无明显影响。结果提示Nef抗血小板聚集作用的机理与抑制TXA₂生成,增加血管PGI₂及血小板cAMP含量有关。     

6-(αα-二苯基乙酰哌嗪基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮对兔血小板聚集及TXB_2,cAMP的影响

6-(αα-二苯基乙酰哌嗪基苯基)-4,5-二氢-5-甲基-3(2H)-哒嗪酮(简称DMDP)是我院新合成的哒嗪酮的衍生物。DMDP可以显著抑制由花生四烯酸(AA(?),ADP和血小板活化因子(PAF)诱导的免血小板聚集,其IC_(50)分别为1.12±0.1.4.19±0.5和2.97±0.1μmol/L。实验还表明DMDP在1～500 μmol/L浓度范围内呈剂量依赖性地抑制兔血小板内血栓素B_2含量,但升高兔血小板内环腺苷酸水平,这可能是其抑制血小板聚集的作用机理之一。     

2-萘-3-(3,4-二甲氧基)苯丙烯酸抗血小板聚集作用及其机理

研究发现,NMPA在体外可抑制花生四烯酸、胶原及凝血酶诱导的家兔血小板聚集,IC_(50)分别为189±9,105±11.0,49.8±16.6μM。小鼠ig NMPA(25mg/kg)后,以ADP诱导的血小板聚集明显受到抑制。大鼠ig NMPA后(52mg/kg一次或10mg/(kg·d)连续7d,出血时间延长、胶原诱导的血小板聚集率下降、丙二醛生成减少、但对动脉壁PGI_2样物质影响较小。说明MNPA的作用机理可能在于改变体内TXA_2/PGI_2比值,而达到抑制血小板聚集的效应。     

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.     

Pharmacological treatment of COVID-19: an opinion paper

The precocity and efficacy of the vaccines developed so far against COVID-19 has been the most significant and saving advance against the pandemic. The development of vaccines has not prevented, during the whole period of the pandemic, the constant search for therapeutic medicines, both among existing drugs with different indications and in the development of new drugs. The Scientific Committee of the COVID-19 of the Illustrious College of Physicians of Madrid wanted to offer an early, simplified and critical approach to these new drugs, to new developments in immunotherapy and to what has been learned from the immune response modulators already known and which have proven effective against the virus, in order to help understand the current situation.     

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.