甲苯喹哌对培养爪蟾胚胎肌细胞和神经细胞离子通道的作用(英文)

目的:研究新型抗心律失常药甲苯喹哌对离子通道的作用.方法:通过膜片钳技术记录培养爪蟾胚胎肌细胞和神经细胞全细胞离子通道电流.结果:甲苯喹哌(0.1,1,10,100μmolL~(-1))可浓度依赖性地抑制肌细胞的钠通道,其IC_(50)为7.2μmol L~(-1)(5.3—9.8μmol L~(-1)).甲苯喹哌(10μmol L~(-1))可抑制神经细胞的高电压激活的钙通道.然而,肌细胞上的稳态外向钾电流却受到甲苯喹哌(10μmol L~(-1))的激活.结论:甲苯喹哌抑制钠、钙通道,但激活稳态外向钾通道.     

喹硫平、阿立哌唑与氨磺必利治疗精神分裂症的疗效与安全性研究

目的研究喹硫平、阿立哌唑与氨磺必利治疗精神分裂症的疗效与安全性。方法选择2014年1-10月在我院精神科住院的300例精神分裂症患者,随机分为喹硫平组、阿立哌唑组、氨磺必利组,分别给予喹硫平[400~800 mg/d,平均(512±128)mg/d]、阿立哌唑[10~30 mg/d,平均(20±6)mg/d]、氨磺必利[400~800 mg/d,平均(635±147)mg/d]治疗8周。于分组前及治疗后4、8周用评估阳性和阴性症状量表(PANSS)、不良反应量表(TESS)评定疗效和不良反应,用社会功能量表(PSP)评定患者的社会功能。结果喹硫平组总有效率为68.4%,阿立哌唑组总有效率为70.0%,氨磺必利组总有效率为69.6%,三组总有效率比较,差异无统计学意义(P>0.05);三组患者CGI评分及PSP评分均显著增加。结论喹硫平、阿立哌唑与氨磺必利治疗精神分裂症的疗效相当,但不良反应特点不同。     

长效抗疟药—喹哌防治鼠疟的实验研究

1,3双[4′-(7′氯-喹啉基-4′)哌哔嗪-1]丙烷(简称:喹哌-Piperaquine)的碱或盐,对鼠疟均有长效抑制性预防作用,其作用的持续时间长短,随给药剂量增大而延长。喹哌碱每天50 mg/kg和200 mg/kg,连续灌胃3天,对鼠疟分别有15和60天预防作用;喹哌盐100 mg(碱基)/kg和300 mg(碱基)/kg一次灌胃,对鼠疟分别有30和45天预防作用。相同的给药剂量,喹哌盐的长效作用比喹哌碱好。喹哌碱、喹哌盐及磷酸氯喹,在相同给药剂量对比下,磷酸氯喹无长效预防作用。喹哌碱对鼠疟亦有良好治疗效果,从原虫血症转阴和治疗后的动物存活看,喹哌优于氯喹。     

甲苯喹哌对培养爪蟾胚胎肌细胞和神经细胞离子通道的作用

研究新型抗心律失常药甲苯喹哌对离子通道的作用。通过膜片钳技术记录培养爪蟾胚胎肌细胞和神经细胞全细胞的钠通道，其ＩＣ５０为７．２μｍｏｌＬ＾－１（５．３－９．８μｍｏｌＬ＾－１）。甲苯硅派（１０μｍｏｌＬ＾－１）可抑制神经细胞的高电压激活的钙通道。然而，肌细胞上的稳态外向钾电流却受甲苯喹哌的激活。甲苯喹哌抑制钠、钙通道、但激活稳态外向钾通道。     

氟哌噻吨美利曲辛片联合甲磺酸倍他司汀片治疗脑梗死后焦虑抑郁患者头晕症状的临床研究北大核心CSCD

目的观察氟哌噻吨美利曲辛片联合甲磺酸倍他司汀片治疗脑梗后焦虑抑郁患者头晕症状的临床疗效和安全性。方法将72例脑梗后焦虑抑郁患者随机分为对照组36例和试验组36例。对照组予以甲磺酸倍他司汀片12 mg,口服,每日1次,共4周;试验组在对照组的基础上加用氟哌噻吨美利曲辛片10.5mg,口服,早、午各1次,共4周。比较2组患者头晕评定量表(DHI)、汉密尔顿焦虑量表(HAMA)、汉密尔顿抑郁量表(HAMD)评分差异,以及药物不良反应发生率。结果治疗后,试验组和对照组总有效率分别为80.56%(29例/36例)和16.67%(6例/36例),差异有统计学意义(P<0.05)。治疗后,试验组和对照组的DHI评分分别为(34.50±15.54),(44.72±20.92)分;HAMA评分分别为(11.89±3.75),(16.83±5.70)分;HAMD评分分别为(13.50±4.70),(19.14±6.45)分,差异均有统计学意义(均P<0.05)。试验组出现头晕加重1例,口干2例,药物不良反应发生率8.33%(3例/36例);对照组出现恶心2例,头痛1例,便秘1例,药物不良反应发生率11.11%(4例/36例)。2组药物不良反应发生率比较,差异无统计学意义(P>0.05)。结论氟哌噻吨美利曲辛片联合甲磺酸倍他司汀片对脑梗后焦虑抑郁患者的头晕症状疗效显著,且安全性高。     

醋酸戈舍瑞林缓释植入剂长期应用对前列腺癌患者去势后的临床疗效与安全性北大核心CSCD

目的观察醋酸戈舍瑞林缓释植入剂长期应用对前列腺癌患者去势后的临床疗效及安全性。方法 42例前列腺癌患者随机分为对照组及试验组,每组21例。双侧睾丸切除术后,对照组给予口服比卡鲁胺片50 mg qd;试验组在对照组基础上加用醋酸戈舍瑞林缓释植入剂3.60 mg,每28 d一次,腹前壁皮下注射。2组均持续治疗6个月。比较2组患者治疗前后血清前列腺特异性抗原、α-甲酰基辅酶A消旋酶水平、总有效率及安全性。结果治疗后,试验组和对照组的总有效率分别为90.48%(19/21例)和61.91%(13/21例),差异有统计学意义(P<0.05)。治疗后,试验组和对照组患者血清前列腺特异性抗原(PSA)分别为(6.74±0.73),(13.27±1.17)μg·L-1;α-甲酰基辅酶A消旋酶(P504S)水平分别为(1.26±0.12),(1.85±0.21)μg·L-1,差异均有统计学意义(P<0.05)。试验组的药物不良反应主要有潮热4例,乏力2例,腹泻1例,乳房肿痛2例,对照组的药物不良反应主要有潮热3例,乏力3例,乳房肿痛2例。试验组和对照组的药物不良反应发生率分别为42.86%(9/21例)和38.09%(8/21例),差异无统计学意义(P>0.05)。结论醋酸戈舍瑞林缓释植入剂长期应用能够显著降低前列腺癌患者去势后患者的血清前列腺特异性抗原、α-甲酰基辅酶A消旋酶水平,提高临床疗效,安全性较高。     

格列喹酮片在健康人体生物等效性研究

目的:研究两种格列喹酮片在健康人体内的药动学特征,并评价两种制剂间的生物等效性。方法:18名健康男性志愿受试者随机交叉单剂量口服试验制剂和参比制剂60 mg,清洗期1周,采用HPLC法测定血清中格列喹酮浓度。结果:受试者口服试验制剂和参比制剂后,主要药代动力学参数如下:t1/2分别为(4.78±1.87),(4.19±1.57)h,tmax分别为(3.06±1.08),(3.28±1.49)h,Cmax分别为(0.87±0.35),(0.90±0.33)μg.mL-1,AUC0-t分别为(4.35±1.66),(4.62±1.23)μg.h.mL-1,AUC0-∞分别为(4.98±1.72),(5.19±1.42)μg.h.mL-1。试验制剂的相对生物利用度AUC0-t为(95.8±34.1)%,AUC0-∞为(97.7±29.4)%。结论:两种格列喹酮片为生物等效制剂。     

衍生化LC-MS测定人血浆中消旋卡多曲活性代谢物浓度及生物等效性

目的建立一种衍生化LC-MS检测人血浆中消旋卡多曲活性代谢物thiorphan(TP)浓度,同时评价消旋卡多曲2种规格散剂(10mg·袋-1和30mg·袋-1)和国产颗粒剂在健康人体内的药动学及生物等效性。方法采用3制剂3周期二重3×3拉丁方设计,18名健康男性志愿者交叉单剂量口服受试制剂2种规格消旋卡多曲散(10mg·袋-1和30mg·袋-1)和参比制剂消旋卡多曲颗粒剂各300mg后,采用衍生化LC-MS测定不同时间血浆中活性代谢物TP浓度,用DAS药动学程序进行药动学参数的计算及生物等效性评价。血浆样品中加入p-BPB衍生化试剂,得到稳定的TP衍生化产物,经乙酸乙酯萃取后,选替米沙坦作内标。色谱柱为Zorbax SB-C18(150mm×2.1mm,5μm);流动相为5mmol·L-1甲酸铵(甲酸调节pH至3.0)-乙腈(45姮55);流速为0.2 m L·min-1;采用ESI+SRM方式监测;TP衍生化产物m/z 452.10[M+H]+,内标替米沙坦m/z 515.30[M+H]+。结果 TP线性范围为6.28~1 256 ng·m L-1,最低检测浓度为6.28 ng·m L-1,提取回收率在77.5%~80.4%,日内、日间精密度RSD<15%。受试制剂消旋卡多曲散(10mg·袋-1),消旋卡多曲散(30mg·袋-1)和参比制剂消旋卡多曲颗粒的主要药动学参数:Tmax分别为(1.8±1.2),(1.9±1.3)和(0.7±0.2)h,t1/2分别为(1.4±0.4),(1.2±0.7)和(1.1±0.8)h,Cmax分别为(802.0±356.5),(804.2±459.8)和(845.6±285.8)ng·m L-1,AUC0-8分别为(1 617.0±532.6),(1 628.9±672.1)和(1 621.0±532.2)ng·h·m L-1,AUC0-∞分别为(1690.8±567.2),(1673.8±681.7)和(1 649.4±561.4)ng·h·m L-1。2种受试制剂的相对生物利用度分别为99.8%和100.5%。结论本方法灵敏,有效,可准确检测人体血浆中TP的浓度。2种受试制剂和参比制剂具有生物等效性。     

HPLC同时测定复方双氢青蒿素片中磷酸哌喹与甲氧苄啶的含量

目的　建立HPLC法 ,测定复方双氢青蒿素片中磷酸哌喹与甲氧苄啶的含量。方法　LichrospherCN色谱柱 (2 5 0mm×4 .6mm ,5 μm) ,流动相为 0 .0 4mol·L-1磷酸二氢钾溶液 (稀盐酸调pH 2 .5 ) -乙腈 (90∶10 ) ,检测波长 2 80nm。结果　磷酸哌喹在 1.6～ 8μg范围内、甲氧苄啶在 0 .4 5～ 2 .2 5 μg范围内 ,其峰面积与进样量呈良好的线性关系。磷酸哌喹的平均回收率为 99.6 % ,RSD =1.17% (n =9) ;甲氧苄啶的平均回收率为 98.7% ,RSD =1.2 6 % (n =9)。结论　所用方法准确、快速、简便 ,适用于复方制剂中磷酸哌喹与甲氧苄啶的同时测定 ,可作为同类产品的质量控制方法。     

新哌喹型化合物烷氨基二哌喹及四哌喹的合成

在二哌喹(Ⅰ)类化合物的中间碳链结构与抗疟作用关系研究的基础上,我们设计合成了两类新的哌喹型化合物:烷氨基二哌喹(Ⅱ)和四哌喹(Ⅲ)。经鼠疟抑制性初筛,所合成的此二类化合物其抗疟活性并不高于哌喹。它们的实验数据见表1。实验部分一、7-氯-4-(γ-羟丙基)氨基噎啉的制备参照Elderfield等的方法,由氨基醇与4,7-二氯喹啉反应制得。7-氯-4-(β-羟乙基)氨基喹啉的收率为94％,熔点214.5～216.5℃;7-氯-4-(γ-羟丙基)氨基喹啉的收率为91.33％,熔点153～154℃。     

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.     

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.     

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.