静脉注射伊布利特对中国健康受试者及房颤与房扑患者心电图QTc间期的影响

目的 静脉注射伊布利特(抗心律失常药物)对健康人及房颤与房扑患者用药后心电图QTc间期变化的比较研究.方法 40例健康男性随机分为6组(每组分别为4,10,6,6,6,8人),分别静脉注射伊布利特5,10,20μg·kg-1及单次给药0.5,0.75,1.0mg.房颤、房扑患者各100例应用伊布利特(1 mg iv;体质量小于60 kg者,按0.01 mg·kg-1)转复心律治疗,必要时重复给药1次.结果 健康受试者药后QTc间期明显延长,峰值出现于给药完成后.5,10,20μg·kg-1组R QTc均值最大值分别为(469±7),(592±35)及(678±14)ms;0.5,0.75,1.0 mg组的最大值分别为(605±39),(616±8)及(683±9)ms.100例房颤、房扑患者的药后QTc间期延长,峰值出现于静脉注射结束即刻;1次给药者QTc峰值为(476±9)ms;2次给药者QTc峰值为(510±8)ms,于4 h恢复基线水平.相同给药方式,健康受试者较患者的QTc间期延长更为显著(P<0.05).有43%接受2次给药的患者,QTc可延长至500～600 ms;9%可延长至600 ms以上.发生1例尖端扭转型室性心动过速(1%)、2例室性心动过速(2%).结论 静脉注射伊布利特后,中国健康受试者和房颤、房扑患者QTc间期均明显延长,最大可达600 ms以上;但健康人QTc延长较房颤、房扑患者更显著.要严密监测QTc间期至少应到药后4 h.     

白藜芦醇对兔实验性骨关节炎白细胞介素-1β表达的影响

目的:研究白藜芦醇干预兔实验性骨关节炎模型动物后关节软骨、滑膜细胞白细胞介素-1β合成的变化,探讨其治疗骨关节炎的效果和作用机制。方法:36只新西兰大白兔,随机抽取6只,作为正常对照组(A组),其余30只参考文献方法,制备兔OA模型,术后4周,经X线和病理改变证实造模成功后,将造模动物随机分为:模型组(B组)、阳性药物对照组(C组)(双醋瑞因1 mg·kg-1·d-1)、受试药物高剂量组(D1组)(白藜芦醇120 mg·kg-1·d-1)、中剂量组(D2组)(白藜芦醇60 mg·kg-1·d-1)、低剂量组(D3组)(白藜芦醇30 mg·kg-1·d-1),每组6只。并按设定剂量每日灌胃给药,连续给药6周后,处死动物,切取股骨内髁软骨标本,脱水石蜡包埋后切片,用免疫组化法检测软骨细胞中IL-1β水平。结果:受试药物组(D1组、D2组、D3组)软骨细胞中IL-1β阳性细胞分别为(21.8±3.8)%,(26.1±13.3)%,(30.4±4.9)%,明显低于模型组(B组)(49.1±5.5)%和阳性药物对照组(C组)(36.0±4.0)%,(P<0.01)。结论:高、中剂量的白藜芦醇能抑制模型组动物软骨细胞合成IL-1β,其能力优于阳性对照药物。     

氯诺昔康和曲马多术后静脉自控镇痛的临床观察

目的:比较等效剂量的氯诺昔康及曲马多在术后患者自控镇痛(PCIA)时的镇痛效果及不良反应的发生情况.方法:术后中至重度疼痛成年患者100例,随机分为L组及T组,每组50例.应用静注负荷剂量加上维持剂量和患者自控镇痛量(LCP)方式作镇痛治疗.L组应用氯诺昔康0.15mg·kg-1负荷量后,以0.02mg·kg-1·h-1静注维持,T组应用曲马多2.25mg·kg-1负荷量后,维持量是0.3mg·kg-1·h-1,两组自控量均为2mL.结果:镇痛效果VAS评分、48h累积用药量(DT)两组间无显著差异(P>0.05),L组的不良反应明显少于T组,但胃肠道刺激反应的发生率T组较多(P<0.05).结论:使用氯诺昔康治疗外科手术后中至重度疼痛,能取得与曲马多相当的镇痛效果,不良反应发生率较低,但需注意其胃肠道刺激症状.     

伊布利特注射液的中国人人体药动学

目的：评价健康中国人单次静脉注射伊布利特后的药动学特征。方法：40例健康男性受试者随机分为6组,分别静脉注射伊布利特0．005 mg·kg~(-1)(n=4),0．01 mg·kg~(-1)(n=10),0．02 mg·kg~(-1)(n=6),0．5 mg (n=6),0．75 mg(n=6)和1．0 mg(n=8)。采用液相色谱-质谱联用法测定血浆伊布利特浓度。结果：给药后各剂量组的c_(max)和AUC随给药剂量的增加而成比例增加,c_(max)为(1．9±s0．6)～(7．2±1．9)μg·L~(-1),AUC_(0～24)为(69±21)～(236±63)μg·min·L~(-1),线性相关显著(P＜0．01)。伊布利特的t_(1/2)为8 h左右(4～11 h),V_d为(47±12)～(63±18)L·kg~(-1),CJ为(68±20)～(85±26)mL·min~(-1)·kg~(-1),在各剂量组之间没有显著差别(P＞0．05)。结论：在本研究剂量范围内,静脉注射伊布利特耐受性良好,其体内处置过程符合线性动力学特征而无饱和性。     

氟比洛芬酯用于腹腔镜术后早期镇痛效果的观察

目的:观察氟比洛芬酯注射液应用于瑞芬太尼全身静脉麻醉下的腹腔镜胆囊切除术(LC)后的早期镇痛效果.方法:选择行LC的患者117例,随机分为Ⅰ,Ⅱ,Ⅲ三组,Ⅰ组(n=40)于气管插管后切皮前10 min静注氟比洛芬酯50 mg;Ⅱ组(n=38)于术毕缝皮时静注氟比洛芬酯50 mg,Ⅲ组(n=39)术毕缝皮时静注曲马朵2 mg·kg-1.全麻用药为咪达唑仑、异丙酚、维库溴铵和瑞芬太尼(诱导剂量0.5 μg·kg-1·min-1,维持剂量0.15～0.3 μg·kg-1·min-1),切口缝完后停用瑞芬太尼,术毕送入麻醉后监测治疗室(PACU).在PACU中记录拔管后5,15,30,60 min时的疼痛评分,疼痛评分标准采用视觉模拟评分(VAS).结果:术后1 h内,Ⅰ组患者的视觉模拟评分(VAS)低于其他两组(P<0.05);Ⅱ,Ⅲ组患者的VAS评分差异无显著性(P>0.05).结论:氟比洛芬酯注射液可以为LC提供较为满意的术后镇痛效果,尤其是术前应用效果最好,为瑞芬太尼麻醉提供了一种较为安全的术后镇痛方案.     

不同剂量雷公藤多苷对寻常型银屑病样小鼠血清炎性因子的影响

目的 观察不同剂量雷公藤多苷对寻常型银屑病样小鼠血清炎性因子白细胞介素-6(IL-6)、白细胞介素-17(IL-17)、白细胞介素-23(IL-23)、肿瘤坏死因子-α(TNF-α)和核转录因子-κB(NF-κB)的影响,并探讨其最佳治疗剂量.方法 2019年2—11月,将40只BALB/c雄性小鼠采用随机数字表法分为五组(n=8):对照组、模型组,低、中、高剂量组给药组.小鼠建模后给药组采用不同剂量雷公藤多苷灌胃,浓度为10 mg·kg-1·d-1、20 mg·kg-1·d-1和40 mg·kg-1·d-1,持续灌胃14 d.收集小鼠病变皮肤组织,对超氧化物歧化酶(SOD)活性及谷胱甘肽(GSH)和丙二醛(MDA)水平进行测定.酶联免疫吸附测定(ELISA)法检测各组小鼠血清IL-6、IL-17、IL-23和TNF-α水平,Western blotting法检测小鼠血清NF-κB水平.细胞处理后流式细胞术检测各组细胞周期.结果 病变皮肤均质化后SOD活性、GSH和MDA水平测定结果显示,模型组小鼠的GSH水平(8.94±0.95)U/mgprot和SOD活性(21.37±3.76)U/mgprot低于对照组(30.93±1.91)U/mgprot、(44.35±4.09)U/mgprot,P=0.002、0.007),给药组小鼠的GSH水平和SOD活性高于模型组,其中中剂量组最高,为(36.03±1.34)U/mgprot、(42.45±2.43)U/mgprot,P<0.001、P=0.003,低剂量组最低为(26.86±2.03)U/mgprot、(30.39±2.04)U/mgprot,均P<0.05;而MDA测定结果相反,模型组小鼠MDA水平高于对照组,(74.64±2.29)nmol/mgprot比(40.51±2.34)nmol/mgprot,P<0.001,经过药物治疗后降低(P<0.001).ELISA结果显示,与对照组相比,模型组小鼠血清中IL-6、IL-17、IL-23和TNF-α表达水平升高为(4.93±0.09)pg/mg、(9.05±0.20)pg/mg、(5.23±0.17)pg/mg、(11.51±1.23)pg/mg,均P<0.05;低剂量组小鼠IL-17和TNF-α的表达水平与模型组相比差异无统计学意义(均P>0.05),中剂量组(2.76±0.23)pg/mg、(6.12±0.27)pg/mg、(3.19±0.21)pg/mg、(8.21±0.44)pg/mg和高剂量组(3.72±0.09)pg/mg、(6.02±0.25)pg/mg、(3.37±0.41)pg/mg、(8.44±0.38)pg/mg小鼠血清炎性因子下降,均P<0.05.Western blotting结果显示,与对照组相比,模型组小鼠的NF-κB表达水平升高(P<0.001),给药组小鼠NF-κB表达水平降低(P=0.005),且高剂量组小鼠的抑制效果最佳(P<0.001).流式细胞术结果显示,与对照组相比,10 mg/L雷公藤多苷处理48 h的HaCat细胞的G1期细胞所占比例差异无统计学意义(P=0.300),而20 mg/L和40 mg/L雷公藤多苷处理48 h后细胞G1期细胞所占比例升高(P<0.001,P=0.013).结论 雷公藤多苷可以降低银屑病样小鼠血清炎性因子,抑制NF-κB表达,调节病变皮肤抗氧化水平,并且最佳使用量在20 mg·kg-1·d-1左右.     

应用麻醉豚鼠对药物引起的QT间期延长的评价

目的为应用麻醉豚鼠评价药物引起的QT间期延长提供方法学验证。方法豚鼠分为5组:阳性对照索他洛尔(2,4和8mg·kg-1)、奎尼丁(3,10和30mg·kg-1)和西沙必利(0.3,1和3mg·kg-1)组;阴性对照维拉帕米(0.3,1和3mg·kg-1)和普萘洛尔(0.3,1和3mg·kg-1)组。豚鼠ip给予乌拉坦1.5g·kg-1麻醉后,各组按生理盐水→低→中→高剂量药物的顺序静脉滴注,滴注持续10min,每个剂量给药前留有30min的平衡时间;于给生理盐水前及静脉滴注各剂量药物后10min记录心电图。根据31只豚鼠给生理盐水前实际记录的QT及RR间期分别采用Bazzet公式、Fridericia公式和Van de Water公式进行校正QT(QTc)间期的计算,选择一个合适的校正公式,计算QTc,评价药物对QT和QTc间期的影响。结果分别使用3个公式计算31只豚鼠给药前的QTc与RR间期进行线性回归评价,Bazett公式为最佳校正公式。阳性对照药索他洛尔、奎尼丁和西沙必利剂量依赖性延长QT及QTc间期;而阴性对照药维拉帕米和普萘洛尔对QTc间期无明显影响。结论麻醉豚鼠可以作为一种评价受试物引起QT间期延长的动物模型。     

阿霉素急性心脏毒性大鼠造模方法研究

目的 研究应用阿霉素制备急性心脏毒性大鼠模型的最佳给药方案.方法 雄性Wistar大鼠45只,分别编号并随机分为对照组(n=12)、模型组1(n=20)和模型组2(n=13).模型组1大鼠按2.5 mg·kg-1ip阿霉素,每2天1次,持续16d,累积剂量为20 mg·kg-1,考察累积剂量为15、20 mg·kg-1...     

双黄连粉针剂对豚鼠心肌电生理的影响

目的探讨双黄连粉针剂对豚鼠心脏电生理的影响,以及其心脏安全性及作用机制。方法①在体实验:双黄连粉针剂325.5,1627.5和3255.0mg·kg-1分别在两组动物进行,每组15只。一组动物按照生理盐水→双黄连粉针剂325.5→1627.5mg·kg-1,另一组按照生理盐水→双黄连粉针剂3255.0mg·kg-1的顺序经颈外静脉缓慢推注,持续5min。于给生理盐水及静脉推注各剂量药物后5min记录心电图,分析P-R间期和校正QT间期(QTc)。②离体实验:按照灌流液(空白对照)→双黄连粉针剂0.3→1.5→3→9g·L-1→洗脱的顺序灌流,持续5min。于灌流5min末记录豚鼠离体心脏心电图,分析7只豚鼠的P-R间期和QTc间期;记录左心室乳头肌动作电位,分析5只豚鼠的动作电位复极50%水平时程(APD50)和90%水平时程(APD90)。结果①在体豚鼠心电图表明,双黄连粉针剂325.5和1627.5mg·kg-1显著延长P-R间期,从生理盐水处理时的(59±5)ms分别延长到(74±10)ms和(88±20)ms(P<0.05),各浓度组的QTc间期无明显变化;双黄连粉针剂3255.0mg·kg-1处理P-R间期则从生理盐水处理时的(58±5)ms延长到(133±29)ms(P<0.05),QTc从(247±16)ms延长到(301±65)ms(P<0.05),并显示明显的室内传导阻滞。②离体豚鼠心电图表明,双黄连粉针剂3和9g·L-1使空白对照组P-R间期从(84±17)ms延长到(113±39)ms和(130±23)ms(P<0.05),伴有明显的室内传导阻滞,而各浓度组的QTc间期无明显变化。双黄连粉针剂各浓度组对正常豚鼠左心室乳头肌动作电位APD50与APD90无明显作用。结论注射用双黄连粉针剂能引起豚鼠房室和室内传导阻滞,其作用机制可能是抑制心肌细胞钠通道。     

高效液相色谱法同时测定马钱子总生物碱脂质体中士的宁和马钱子碱的含量

目的:采用高效液相色谱法测定马钱予总生物碱脂质体中马钱子碱和士的宁的含量.方法:马钱子总生物碱脂质体与甲醇按1:9混合后离心取上清液用甲醇稀释进样.色谱条件:采用Lichrospher C18柱(4.6 mm×250 mm,5μm),乙腈-0.01mol·L-1庚烷磺酸钠与0.02 mol·L-1磷酸二氢钾等量混合(用10%磷酸调pH值2.8)(24:76)为流动相,流速1.0 mL·min-1,检测波长254 nm,柱温30℃,结果:马钱子碱、士的宁的线性范围均为1～20 nag·L～,,.=0.999 9.低、中,高浓度士的宁平均加样回收率分别为(101.2±1.8)%,(99.2±1.3)%,(99.1±1.2)%(n=3);低、中、高浓度马钱子碱的加样回收率分别为(103.9±2.8)%,(100.4±0.4)%,(102.7±1.2)%(n=3).结论:本方法操作简便,是在药典方法基础上的改进,可用于控制马钱子总生物碱脂质体的质量.     

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.