Effects of propafenone and its enantiomers on action potentials of isolated guinea pig papillary muscles 1

用细胞内微电极法研究普罗帕酮消旋体及两对映体对豚鼠右心室乳头肌快反应动作电位（ＦＡＰ）和慢反应动作电位（ＳＡＰ）的作用．普罗帕酮消旋体及两对映体均浓度依赖性地降低ＦＡＰ和ＳＡＰ的０相最大除极速率（Ｖｍａｘ）和动作电位幅值（ＡＰＡ）,３药≤３μｍｏｌ·Ｌ－１时均延长动作电位时程（ＡＰＤ）．１０μｍｏｌ·Ｌ－１时,ＡＰＤ５０和ＡＰＤ９０反缩短至给药前水平,（Ｒ）－普罗帕酮延长ＦＡＰ的ＡＰＤ２０而（Ｓ）－普罗帕酮则无影响,两组间有显著性差异（Ｐ＜０．０５）．３药对ＦＡＰ和ＳＡＰ静息电位,Ｖｍａｘ,ＡＰＡ,ＡＰＤ５０及ＡＰＤ９０影响均无显著性差异．结果表明,普罗帕酮两对映体的钠通道阻滞作用及钙拮抗作用无差异,对心肌动作电位平台期内向钠和／或钙离子流的作用可能表现立体选择性．     

阿司匹林与硝苯地平单用合用对麻醉犬血液动力学的影响

研究阿司芬林与硝苯地平并用对麻醉犬血液动力学的影响。ＴＴＩ，ＬＶＷＩ，ＭＡＰ，ＴＰＶＲ，ＦＢＦ，ＬＶＳＰ，ｄｐ／ｄｔｍａｘ，ＬＶＥＤＰ，ＨＲ，均同步记录于多道生理记录仪及电磁流量计上。Ａｓｐ５，１０ｍｇ．ｋｇ＾－１ｉｖ对麻醉犬血液动力学各项指标均无明显影响。     

地诺帕明对·OH致大鼠异常血流动力学的保护作用

ｉｖ羟自由基（·ＯＨ）生成液５ｍｌ·ｋｇ－１使麻醉大鼠心功能明显受损，表现为ＬＶＳＰ、ＬＶＳＰ×ＨＲ、ＭＡＰ、＋ｄｐ／ｄｔｍａｘ和－ｄｐ／ｄｔｍａｘ明显降低，而ＬＶＥＤＰ显著升高。在给ＯＨ前５ｍｉｎｉｖ地诺帕朗１８μｇ·ｋｇ－１，再以３０μｇ·ｋｇ－１·ｍｉｎ－１于给·ＯＨ后立即静脉输注，可不同程度地改善上述异常血流动力学指标，其中对ＬＶＥＤＰ的改善尤为显著。地诺帕朗还明显对抗·ＯＨ所致血浆丙二醇含量的升高。本文就其临床意义作了讨论。     

四丙酰关附醇胺的抗心律失常作用及其与关附甲素的比较

在几种动物模型上观察了四丙酰关附醇胺（ＴＰＧＦＡ）的抗心律失常作用．ＴＰＧＦＡ使引发室性早搏，室性心动过速和心室纤颤所需乌头碱用量增加５０％的剂量分别为１．６，１．４ＦＫ和１．８ｍｇ·ｋｇ－１；ＴＰＧＦＡ２ｍｇ·ｋｇ－１可提高豚鼠心脏毒毛花苷Ｇ中毒的耐受量和家兔心脏电致室颤阈；ＴＰＧＦＡ还降低Ｃａ－Ｃｌ２诱发的大鼠室颤发生率和死亡率，以及麻醉大鼠心脏冠脉结扎—再灌性室性心动过速和室颤的发生率．ＴＰＧＦＡ的上述抗心律失常作用较关附甲素强．ＴＰＧ－ＦＡ显著延长大鼠心电图的ＱＴｃ间期，而对Ｐ－Ｒ间期和ＱＲＳ时程影响不明显．小鼠ｉｖＴＰＧＦＡ的ＬＤ５０为４２ｍｇ·ｋｇ－１．     

2－［对－（二甲氨基）苯乙烯］氯化甲基吡啶对大鼠心电图、豚鼠左心房收缩及乳头肌动作电位的影响

２－［对－（二甲氨基）苯乙烯］氯化甲基吡啶（ＤＳＰＭ－ＣＩ），是由氯取代２－［对－（二甲氨基）苯乙烯］碘化甲基吡啶（ＤＳＰＭ）上的碘而得。本文应用心电图、机械收缩描记方法及细胞内标准微电极技术，研究ＤＳＰＭ－Ｃｌ对大鼠心电图（ＥＣＧ）、豚鼠心房肌量效曲线及对豚鼠乳头肌快反应动作电位（ＡＰ）、高钾除极慢反应动作电位（ＳＡＰ）的影响。结果显示，ＤＳＰＭ－Ｃｌ（２ｍｇ·ｋｇ￣（－１））对大鼠有明显的负性频率、负性传导作用，分别使ＰＰ间期、ＰＲ间期延长达６６．２％（Ｐ＜０．０１），１７．０％（Ｐ＜０．０１），５０μｍｏｌ·Ｌ￣（－１）能明显抑制左心房收缩力，非竟争性拮抗Ｉｓｏ及ＣａＣｌ＿２对豚鼠左心房的正性肌力作用，ＰＤ￣２＇分别为４．６，４，３４，１００μｍｏｌ·Ｌ￣（－１）ＤＳＰＭ－Ｃｌ延长动作电位时程ＡＰＤ＿（９０），有效不应期（ＥＲＰ），降低高钾除极豚鼠乳头肌０期最大上升速率Ｖｍａｘ，其作用与Ｖｅｒ相似，提示ＤＳＰＭ－Ｃｌ可能为钙拮抗剂。     

甲基黄酮醇胺对麻醉犬的心血管效应

本文观察了甲基黄酮醇胺（ＭＦＡ）对麻醉犬冠脉血流和心功能的影响。静脉注射５ｍｇ／ｋｇ可降低血压和心率，并增加主动脉流量和冠脉流量，但对左室收缩压（ＬＶＳＰ）、左室舒张末期压（ＬＶＥＤＰ）及左室收缩压、舒张压变化最大速率（±ｄｐ／ｄｔ＿ｍａｘ）无明显影响；ＭＦＡ降低心肌耗氧指数、总外周阻力和冠脉阻力，并增加心搏出量，作用时间超过３０ｍｉｎ。研究表明ＭＦＡ可望成为防治缺血性心脏病的有效药物。     

前胡丙素对大鼠离体缺血再灌注心脏血流动力学的影响

在大鼠离体心脏缺血再灌注损伤模型上，研究前胡丙素对缺血再灌注后血流动力学的影响。与缺血组比较，大鼠预先ｉｐ前胡丙素１５ｍｇ·ｋｇ￣（－１），每日２次，共３ｄ，可以减轻大鼠离体心脏缺血再灌注损伤，促进冠脉流出量的恢复；防止左室收缩（ＬＶＳＰ，＋ｄｐ／ｄｔ＿（ｍａｘ））和舒张（－ｄｐ／ｄｔ＿（ｍａｘ））功能的下降；抑制肌酸激酶释放；以上结果与硝苯地平（６０μｇ·ｋｇ￣（－１）ｉｐ，每日２次，共３ｄ）类似，结果表明前胡丙素对心肌缺血再灌注的血流动力学变化有改善作用。     

粉防己碱对自发性高血压大鼠血管平滑肌细胞增殖及对PDGF-B,bFGF和相关癌基因表达的影响

用［３Ｈ］胸腺嘧啶核苷（［３Ｈ］ＴｄＲ）参入法，电镜，免疫组化，原位杂交方法，在自发性高血压大鼠（ＳＨＲ）观察了粉防己碱（Ｔｅｔ，０．０３μｍｏｌ·ｋｇ－１·ｄ－１×８周ｉｇ）对血管平滑肌细胞（ＶＳＭＣ）增殖的作用及对生长因子ＰＤＧＦ－Ｂ，ｂＦＧＦ的抗原表达及其相关癌基因ｃ－ｓｉｓ，ｃ－ｍｙｃｍＲＮＡ表达的影响．结果发现：Ｔｅｔ在降低ＳＨＲ血压（Ｐ＜０．０１）同时，能减少ＶＳＭＣ的线粒体，粗面内质网和［３Ｈ］ＴｄＲ参入量（Ｐ＜０．０１），并能逆转ＶＳＭＣ增殖时ＰＤＧＦ－Ｂ，ｂＦＧＦ抗原（Ｐ＜０．０５）及ｃ－ｓｉｓ，ｃ－ｍｙｃｍＲＮＡ的表达增强．提示：Ｔｅｔ抑制ＳＨＲ的ＶＳＭＣ增殖与生长因子及癌基因调控的分子生物学机制有关     

槐定碱对实验性心衰豚鼠心功能的影响

对戊巴比妥钠所致实验性心力衰竭豚鼠，静注不同剂量的槐定碱（ＳＯＰ）可明显增加左心室内压力变化速率最大值）（ＬＶ＋ｄｐ／ｄｔｍａｘ），左心室内压力变化峰值（ＬＶＳＰ），平均动脉压（ＭＡＰ），加快心率（ＨＲ），降低左室舒张末压（ＬＶＥＤＰ），与不给药组、ＮＳ对照组比较差异显著。其作用于１ｍｉｎ左右达高峰。静脉注射毒毛旋花子甙Ｋ（９０μｇ／ｋｇ），对±ｄｐ／ｄｔｍａｘ，ＬＶＳＰ，ＭＡＰ，ＨＲ的影响较ＳＯＰ强，不同剂量ＳＯＰ可提高心肌组织Ｃａ２＋含量，但弱于毛旋花子甙Ｋ，与不给药组及ＮＳ对照组比较差异显著；结果表明ＳＯＰ能明显改善心衰豚鼠心脏功能，其作用机制可能与增加心肌组织Ｃａ２＋含量有关。     

地奥心血康对肾性高血压大鼠血流动力学的影响

肾性高血压大鼠（ＲＨＲ）较对照假手术大鼠的ＳＢＰ，ＤＢＰ，ＬＶＥＳＰ，ＬＶＥＤＰ，＋ｄｐ／ｄｔ及｜－ｄｐ／ｄｔ｜值均显著增加（Ｐ均＜０．０１）。应用地奥心血康较用生理盐水对照的ＲＨＲ上述指标分别减少３１．２％，３５．９％，３２．６％，５０．８％，２５．７％和３０．２％（Ｐ＜均＜０．０１）。心率降低１７．５％（Ｐ＜０．０１）。提示地奥心血康对大鼠心脏具有负性变时，变力作用，可明显改善左心室的舒缩性能     

Synthesis,Cytotoxicity and Antileishmanial Activity of Some N-(2-(indol-3-yl)ethyl)-7-chloroquinolin-4-amines

We report herein the condensation of 4,7-dichloroquinoline (1) with tryptamine (2) and D-tryptophan methyl ester (3) . Hydrolysis of the methyl ester adduct (5) yielded the free acid (6) . The compounds were evaluated in vitro for activity against four different species of Leishmania promastigote forms and for cytotoxic activity against Kb and Vero cells. Compound (5) showed good activity against the Leishmania species tested, while all three compounds displayed moderate activity in both Kb and Vero cells.     

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.     

Lung disease and PKCs

The lung offers a rich opportunity for development of therapeutic strategies focused on isozymes of protein kinase C (PKCs). PKCs are important in many cellular responses in the lung, and existing therapies for pulmonary disorders are inadequate. The lung poses unique challenges as it interfaces with air and blood, contains a pulmonary and systemic circulation, and consists of many cell types. Key structures are bronchial and pulmonary vessels, branching airways, and distal air sacs defined by alveolar walls containing capillaries and interstitial space. The cellular composition of each vessel, airway, and alveolar wall is heterogeneous. Injurious environmental stimuli signal through PKCs and cause a variety of disorders. Edema formation and pulmonary hypertension (PHTN) result from derangements in endothelial, smooth muscle (SM), and/or adventitial fibroblast cell phenotype. Asthma, chronic obstructive pulmonary disease (COPD), and lung cancer are characterized by distinctive pathological changes in airway epithelial, SM, and mucous-generating cells. Acute and chronic pneumonitis and fibrosis occur in the alveolar space and interstitium with type 2 pneumocytes and interstitial fibroblasts/myofibroblasts playing a prominent role. At each site, inflammatory, immune, and vascular progenitor cells contribute to the injury and repair process. Many strategies have been used to investigate PKCs in lung injury. Isolated organ preparations and whole animal studies are powerful approaches especially when genetically engineered mice are used. More analysis of PKC isozymes in normal and diseased human lung tissue and cells is needed to complement this work. Since opposing or counter-regulatory effects of selected PKCs in the same cell or tissue have been found, it may be desirable to target more than one PKC isozyme and potentially in different directions. Because multiple signaling pathways contribute to the key cellular responses important in lung biology, therapeutic strategies targeting PKCs may be more effective if combined with inhibitors of other pathways for additive or synergistic effect. Mechanisms that regulate PKC activity, including phosphorylation and interaction with isozyme-specific binding proteins, are also potential therapeutic targets. Key isotypes of PKC involved in lung pathophysiology are summarized and current and evolving therapeutic approaches to target them are identified.     

Gender-related symptoms and correlates of alcohol dependence among men and women with a lifetime diagnosis of alcohol use disorders

This study explored gender-related symptoms and correlates of alcohol dependence in a crosssectional study of 150 men and 150 women with a lifetime diagnosis of alcohol use disorders (AUD). Participants were recruited in equal numbers from treatment settings, correctional centres and the general community. Standardized measures were used to determine participants' use of substances, history of psychiatric disorders and psychosocial stress, their sensation seeking and family history of substance use and mental health disorders. Multivariate analyses were used to detect patterns of variables associated with gender and the lifetime severity of AUD. Men had a longer history of severe AUD than women. Women had similar levels of alcohol dependence and medical and psychological sequelae as men, despite 6 fewer years of AUD. More women than men had a history of severe psychosocial stress, severe dependence on other substances and antecedent mental health problems, especially mood and anxiety disorders. There were differences in family history of alcohol-related problems approximating same-gender aggregation. The severity of a lifetime AUD was predicted by its earlier age at onset and the occurrence of other disorders, especially anxiety, among both men and women. The limitations in the generalizability of these findings due to sample idiosyncrasies are discussed.     

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.