Effects of dl-3-n-butylphthalide on region al cerebral blood flow in right middle cerebral artery occlusion rats

目的：观察ｄｌ３ｎ丁基苯酞（ＮＢＰ）对右大脑右中动脉阻断（ＲＭＣＡＯ）大鼠缺血区局部脑血流（ｒＣＢＦ）的影响．方法：氢清除法动态监测ＲＭＣＡＯ大鼠ｒＣＢＦ变化．结果：ＲＭＣＡＯ后１０ｍｉｎｉｐＮＢＰ（５，１０，２０ｍｇ·ｋｇ－１）可明显增加ｒＣＢＦ（与溶剂对照组相比Ｐ＜００１），４０ｍｉｎ给药有类似作用但作用较弱（与给药前相比Ｐ＜００５），６０ｍｉｎ给药不能增加ｒＣＢＦ（与给药前相比Ｐ＞００５）．此外，ＲＭＣＡＯ前４０ｍｉｎｉｐＮＢＰ也可使ＲＭＣＡＯ后不同时间点ｒＣＢＦ明显增加．尼莫地平（０５ｍｇ·ｋｇ－１，ｉｐ）与ＮＢＰ（１０ｍｇ·ｋｇ－１，ｉｐ）具有相似的作用．结论：ＮＢＰ预防给药或治疗给药能使ＲＭＣＡＯ后减少的ｒＣＢＦ明显增加．     

dl—3—n—丁基苯酞对右大脑右中动脉阻断大鼠纹状体脑血流的影响

观察ｄｌ－３－ｎ－丁基苯酞（ＮＢＰ）对右大离右中动脉阻断（ＲＭＣＡＯ）大鼠缺血区局部脑血流（ｒＣＢＦ）的影响。方法：氢清除法动态监测ＲＭＣＡＯ大鼠ｒＣＢＦ变化。结果：ＲＭＣＡＯ后１０ｍｉｎ ｉｐ ＮＢＰ（５，１０，２０ｍｇ·ｋｇ＾－１）可明显增加ｒＣＢＦ（与溶剂对照组相比Ｐ〈０．０１），４０ｍｉｎ给药有类似作用但作用较弱（与给药前相比Ｐ〈０．０５），６０ｍｉｎ给药不能增加ｒＣＢＦ（与给药前相比Ｐ〉     

人参皂甙对顺铂所致大鼠肾损害的保护作用

通过药物与肾皮质薄片直接孵育法和注射给药法观察了人参皂甙（Ｇｉｎ）对顺铂（ＣＰ）所致大鼠肾损害的作用。结果表明：ＣＰ１．０ｍｍｏｌ·Ｌ￣（－１）在含有对氨基马尿酸（ＰＡＨ）的生理盐水溶液中与肾薄片孵育１２０ｍｉｎ，导致薄片中ＰＡＨ的蓄积明显减少，Ｇｉｎ８０ｍｇ·Ｌ￣（－１）增加ＰＡＨ的蓄积并抑制ＣＰ引起的ＰＡＨ蓄积减少。ＣＰ７．５ｍｇ·ｋｇ￣（－１）ｉｐ导致时间依赖性的血浆尿素氮（ＢＵＮ）升高，肾皮质组织中超氧化物歧化酶（ＳＯＤ）活性降低和脂质过氧化代谢产物丙二醛（ＭＤＡ）升高Ｇｉｎ５０ｍｇ·ｋｇ￣（－１）每日２次ｉｐ抑制ＣＰ所致的ＢＵＮ和ＭＤＡ升高及ＳＯＤ活性降低，推测Ｇｉｎ对ＣＰ所致大鼠肾损害的保护作用可能与其增强肾小管细胞的内在反应性和抗脂质过氧化作用有关。     

牛膝多糖的抗肿瘤活性及其免疫增强作用

牛膝多糖（ＡＢＰ）５０ｍｇ·ｋｇ＾－１ｉｐ或２５０ｍｇ·ｋｇ＾－１ｉｇ显抑制小鼠移植性肉瘤Ｓ１８０生长，提高荷瘤小鼠低下的血清ＩｇＧ含量和抗体形成细胞数量及脾淋巴细胞增殖反应。ＡＢＰ ｉｐ还提高荷瘤鼠ＮＫ细胞活性及ＬＰＳ诱生的血清ＴＮＦ－α产生。ＡＢＰ５０－８００μｇ·ｍｌ＾－１体外对Ｓ１８０细胞无直接细胞毒作用，但能增强ＭФ对Ｓ１８０的杀伤作用。提示ＡＢＰ抗肿瘤作用与其增强宿主免疫功能有关。     

~(19)F体内核磁共振技术观测5-氟尿嘧啶在小鼠植入肿瘤中的摄取与代谢

应用体内１９ＦＮＭＲ谱观察并定量评价了５－氟尿嘧啶（５－ＦＵ）在荷Ｓ１８０瘤和Ｂ１６瘤小鼠肿瘤内的摄取和代谢动力学过程．５－ＦＵ２００ｍｇ·ｋｇ－１ｉｖ后，药物在Ｓ１８０和Ｂ１６瘤内的主要产物为其活性产物氟代核苷／核苷酸（ＦＮＵＣ），同时可检测到少量的降解产物α－氟－β－丙氨酸（ＦＢＡＬ）和α－氟－β－脲基丙酸（ＦＵＰＡ）．在Ｓ１８０瘤内，５－ＦＵ摄取，消除以及ＦＮＵＣ的生成有较大的个体变异，５－ＦＵ的消除半衰期ｔ１／２ｋｅ为４１．５－８４．８ｍｉｎ，ＦＮＵＣ生成ｔ１／２ｒ为２６．０－９１．９ｍｉｎ．当甲氨蝶呤（ＭＴＸ）与５－ＦＵ合用时，５－ＦＵ在Ｓ１８０瘤内的活化代谢过程明显加快，ｔ１／２ｋｅ缩短为２９．９－４３．４ｍｉｎ，ＦＮＵＣ的生成速率显著提高，生成量增加．５－ＦＵ在Ｂ１６瘤内的摄取及代谢过程的个体波动较小，其ｔ１／２ｋｅ为３９±５ｍｉｎ，ＦＮＵＣ的生成ｔ１／２ｒ为６０±７ｍｉｎ，在Ｂ１６瘤内，ＭＴＸ的合用不能明显加快５－ＦＵ转化为ＦＮＵＣ的反应，也不改变５－ＦＵ在瘤内的消除模式．上述结果表明，５－ＦＵ对肿瘤的化疗作用与肿瘤灌注５－ＦＵ在瘤组织内的摄取和活化代谢过程密切相关，亦可受到合用药物的影响．     

~(19)F体内核磁共振技术观测5-氟尿嘧啶在小鼠肝脏中的代谢

应用１９Ｆ体内核磁共振技术（１９ＦＮＭＲ）直接观测了５－氟尿嘧啶（５－ＦＵ）在小鼠肝脏中的代谢产物和代谢动力学，昆明种（ＫＭ）小鼠和Ｃ５７小鼠ｉｖ５－ＦＵ２００ｍｇ·ｋｇ－１后，用１９Ｆ表面线圈测得５－ＦＵ在肝脏中依次代谢为α－氟－β－脲基丙酸（ＦＵＰＡ）和α－氟－β－丙氨酸（ＦＢＡＬ）．在荷Ｓ１８０瘤ＫＭ小鼠肝脏中还可检测到活化产物氟代核苷／核苷酸（ＦＮＵＣ）．５－ＦＵ在ＫＭ和Ｃ５７小鼠肝脏中清除较快，消除半衰期分别为１６．７±３．０和３６．６±２．４ｍｉｎ，其主要产物ＦＢＡＬ的最大生成ｒｍａｘ（相对强度比）分别为８４±１４和９２±１０．但在ＫＭ小鼠肝脏中由ＦＵＰＡ进一步降解为ＦＢＡＬ的速率明显快于Ｃ５７小鼠，ｔ１／２ｒ分别为３１±８和５７±１３ｍｉｎ．相应地，在Ｃ５７小鼠肝脏中ＦＵＰＡ能维持一定的水平并达到ｒｍａｘ２６．２±２．２．     

马钱子碱对小鼠淋巴细胞功能的影响

目的　观察镇痛剂量的马钱子碱（ Ｂｒｕ） 对小鼠淋巴细胞功能的影响。方法　测定绵羊红细胞（ Ｓ Ｒ Ｂ Ｃ） 致敏小鼠血清溶血素及脾抗体分泌细胞（ Ａ Ｆ Ｃ） 水平, 二硝基氯苯（ Ｄ Ｎ Ｃ Ｂ） 所致小鼠迟发性超敏反应（ Ｄ Ｔ Ｈ） ,以及丝裂原诱导小鼠脾淋巴细胞增殖和产生 Ｉ Ｌ ２ 能力。结果　 Ｂｒｕ（１０ 及２０ ｍｇ·ｋｇ － １ ,ｉｐ 显著增强小鼠对 Ｄ Ｎ Ｃ Ｂ 的特异性细胞免疫反应,但５ ,１０ 及２０ ｍｇ·ｋｇ － １ 不影响对 Ｓ Ｒ Ｂ Ｃ 的特异性体液免疫反应。对环磷酰胺（ Ｃｙｃ） 降低的上述反应,３ 个剂量的 Ｂｒｕ均有显著恢复作用（ Ｐ＜ ００５ ～００１） 。 Ｂｒｕ １０ ｍｇ·ｋｇ－ １ ｉｐ增强 Ｃｏｎ Ａ 及 Ｌ Ｐ Ｓ 诱导的脾淋巴细胞增殖（ Ｐ＜ ００５） ,对 Ｃｙｃ 所降低的脾淋巴细胞尤其 Ｔ 细胞增殖反应, Ｂｒｕ ５ ～２０ｍｇ·ｋｇ － １ 范围内均使其恢复（ Ｐ＜ ００５ ～００１） 。 Ｂｒｕ ０１ ～１００ ｍｇ· Ｌ－ １ 在体外对丝裂原诱导小鼠脾淋巴细胞产生 Ｉ Ｌ ２能力无明显影响。结论　镇痛有效剂量的 Ｂｒｕ 对小鼠淋巴细胞具有功能依赖性的免疫调节作用     

氰戊菊酯对细胞色素P450 2B1/2B2的诱导

１５只ＳＤ大鼠随机分为氰戊菊酯（Ｆｅｎ）组（１２０ｍｇ·ｋｇ－１·ｄ－１×７,ｉｇ）,苯巴比妥（ＰＢ）诱导组（８０ｍｇ·ｋｇ－１·ｄ－１×３,ｉｐ）及溶剂对照组（给予Ｆｅｎ组等体积的二甲亚砜,处理同Ｆｅｎ组）．应用不连续ＳＤＳ－ＰＡＧＥ电泳分离细胞色素Ｐ４５０,用ＣＯ差示光谱法和细胞色素Ｃ还原法测定Ｐ４５０含量及ＮＡＤＰＨ－细胞色素Ｐ４５０还原酶活性,用ＣＹＰ２Ｂ１／２Ｂ２抗体及ＣＹＰ３Ａ１／３Ａ２抗体进行Ｗｅｓｔｅｒｎ印迹法分析,用免疫组化和半定量ＲＴ－ＰＣＲ等技术观察Ｆｅｎ影响大鼠脑,肝组织细胞色素Ｐ４５０亚型的特异性．结果显示,与溶剂对照组相比Ｆｅｎ可使脑和肝中Ｐ４５０含量及ＮＡＤＰＨ－Ｐ４５０还原酶活性增高;Ｐ４５０２Ｂ１／２Ｂ２增加,Ｐ４５０３Ａ１／３Ａ２未见改变;Ｐ４５０２Ｂ１／２Ｂ２ｍＲＮＡ含量相应增加．由于正常大鼠脑,肝组织中Ｐ４５０２Ｂ１／２Ｂ２表达很低,Ｆｅｎ对该亚型Ｐ４５０的诱导可能会干扰机体对内,外源化合物的正常代谢,从而产生毒作用．     

丁基苯酞对线粒体呼吸链复合酶活性的影响

目的：阐明正丁基苯酞（ｄｌ３ｎｂｕｔｙｌｐｈｔｈａｌｉｄｅ,ｄｌＮＢＰ）改善缺血脑能量代谢的机制。方法：用分光光度法测定局灶性脑缺血大鼠脑线粒体呼吸链复合酶Ｉ,Ｉ,ＩＩ和ＩＶ活性的改变,并观察ｄｌＮＢＰ对这些变化的影响。结果：缺血时复合酶ＩＩ活性升高,ＩＶ的活性显著降低;再灌后,复合酶Ｉ活性升高,ＩＩ的活性降低。在缺血前１０ｍｉｎ给予ｄｌＮＢＰ（５ｍｇ·ｋｇ－１或１０ｍｇ·ｋｇ－１,ｉｐ）能逆转缺血再灌引起的上述复合酶活性改变,尤其是使缺血后急剧降低的复合酶ＩＶ活性得到明显提高。同时ＮＢＰ（ｄ,ｌ,ｄｌ）还能逆转低糖低氧造成的原代培养大鼠皮质细胞呼吸链复合酶ＩＶ活性降低。结论：ＮＢＰ能够改善缺血脑内能量状态是直接作用于脑线粒体的结果,而ｄＮＢＰ起着主要作用。     

3,4,5-三甲氧基苯甲酸-8-(二乙胺基)-辛酯对大鼠脑血流及其自动调节功能的影响

用激光多谱勒血流仪连续测量脑血流量（ＣＢＦ），观察３，４，５－三甲氧基苯甲酸－８－（二乙胺基）－辛酯（ＴＭＢ－８）对麻醉大鼠ＣＢＦ及脑血流自动调节功能的影响．结果表明，ＴＭＢ－８０．５，１．０和２．０ｍｇ·ｋｇ－１呈剂量依赖性地增加ＣＢＦ５％，２０％和３４％．其中仅２．０ｍｇ·ｋｇ－１组使平均动脉压（ＭＡＢＰ）降低６％．而尼莫地平（Ｎｉｍ）０．０１ｍｇ·ｋｇ－１在使ＣＢＦ增加２１％的同时，使ＭＡＢＰ降低了２７％．麻醉大鼠脑血流自动调节的ＭＡＢＰ低限是５．３ｋＰａ．在ＭＡＢＰ４．０ｋＰａ时ＴＭＢ－８２．０ｍｇ·ｋｇ－１能增加脑血流自动调节能力，而Ｎｉｍ０．０１ｍｇ·ｋｇ－１则无明显作用．提示ＴＭＢ－８增加ＣＢＦ和增强脑血流自动调节能力是其抗脑缺血作用的机理之一．     

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.     

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.     

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.