肝动脉/门静脉早期复流对肝移植大鼠小肠缺血再灌注损伤的影响

背景：当肝动脉与门静脉早期复流时序不同时,是否会加重对肝移植大鼠小肠缺血/再灌注的损伤尚未见大量报道。 目的：探讨肝动脉与门静脉早期复流对肝移植大鼠小肠缺血/再灌注损伤的影响。 方法：采用门静脉灌注的大鼠自体肝移植模型,78只SD大鼠以简单随机化法分为3组：肝动脉组(n=36)：行自体肝移植手术,以40C乳酸林格液由门静脉灌肝40 min,开放肝动脉及下腔静脉,10 min后开放门静脉;门静脉组(n=36)：行自体肝移植手术,门静脉开放恢复肝脏血流后10 min再开放肝动脉血流;假手术组(n=6)：打开腹腔,游离肝脏后关腹。观察各组小肠显微及超微结构变化并测定一氧化氮水平。 结果与结论：术后各实验组不同时段先后出现小肠绒毛排列不整或紊乱,小肠黏膜细胞线粒体大小不一,明显肿胀,呈类圆形,内有空泡变性,严重者可见嵴减少、断裂或消失。小肠组织一氧化氮水平均升高。上述变化在术后12 h达高峰。术后肝动脉先复流组小肠显微及超微结构损伤及小肠组织一氧化氮水平明显高于门静脉先复流组。提示,肝动脉早期复流可以通过早期肝脏供氧以减少移植肝脏的损害,但门静脉的延迟开放则加重了肝移植大鼠小肠的缺血/再灌注损伤。     

肝靶向性壳聚糖基纳米载药体系的研究与应用

目的：阐述肝靶向性壳聚糖基纳米载药体系的研究和应用。 方法：采用电子检索的方式，在万方数据库中检索2002-12/2010-02有关肝靶向性壳聚糖基纳米的研究文章，关键词为“壳聚糖基纳米载药体系，肝靶向性，研究，应用”。排除重复研究、普通综述或Meta分析类文章，筛选纳入18篇文献进行阐述。 结果：壳聚糖纳米粒是一种天然无毒的非病毒药物载体，有良好的生物相容性和生物可降解性，可提高药物的稳定性，可靶向释放药物，增加药物的吸收等，达到控释和靶向治疗的作用。载药壳聚糖纳米粒的制备有离子交联法、沉淀法、超声乳化法、反相微乳法、静电纺丝法、反相悬浮交联法、逆相蒸发一短时超声法、 还原胺化法等8种不同方法。用于肝脏组织工程如肝移植、人工肝，能维持和提高肝细胞活性和功能，有利于肝细胞生长；肝脏肿瘤治疗中使药物靶向释放于肿瘤部位，更有效抑制肿瘤细胞、降低毒副作用等。 结论：肝靶向性壳聚糖基纳米载药体系是一种安全、高效的靶向性基因载体，但它的研究还需不断深入。     

亚甲蓝磁性明胶微球在外磁场作用下对家兔痛阈及体感诱发电位的影响☆

背景：靶向给药系统是一种安全高效的药物传递途径和技术，是一种新的制剂技术和工艺，这种制剂能将药品运送到靶器官或靶细胞，而正常部位几乎不受药物的影响。 目的：实验拟观察亚甲蓝磁性明胶微球在外磁场作用下对家兔痛阈及体感诱发电位的影响，探讨其对脊髓背根神经结靶向神经阻滞的可行性。 设计、时间及地点：随机对照动物实验，于2004-03/2005-04在解放军总医院实验动物中心完成。 材料：雄性新西兰兔24只，体质量2.3~2.8 kg；空白明胶微球（自制）；亚甲蓝磁性明胶微球（自制，载药量为9.8%）。微球系院内药理学实验室高级技师协助制备。 干预：24只家兔随机数字表法分为亚甲蓝磁性微球15 mg 组：在外磁场作用下家兔蛛网膜下腔注射亚甲蓝磁性明胶微球15 mg；空白磁性微球15 mg 组注射单纯磁性微球15 mg；假手术对照组：麻醉和手术步骤同其他组，每组8只。 主要观察指标：连续观察注射药物后家兔下肢的电痛阈、运动功能及脊髓体感诱发电位的变化，最后取脊髓腰骶端作病理切片观察。 结果：24只新西兰兔均进入结果分析。①亚甲蓝磁性微球15 mg 组家兔后肢电痛阈值在给药后第1~6天明显升高，与自身给药前及其他组相比，差异显著（P < 0.05）。②亚甲蓝磁性微球15 mg 组家兔体感诱发电位N1波潜伏期第1~11天明显延长，与自身给药前及其他组相比，差异显著（P < 0.05）；术后13 d 恢复正常。③病理观察显示各组脊髓背角结构、形态正常，神经轴索排列正常，灰白质界限清楚，除假手术对照组外其他组背角均有少数未完全降解的微球，各组的脊髓前角可观察到形态正常的前角运动神经细胞及神经轴索，结构完整。 结论：亚甲蓝磁性明胶微球在外磁场作用下可靶向阻滞脊髓背根神经结，提高家兔的痛阈并延长体感诱发电位，具有“感觉-运动”分离阻滞作用，是一种有效的长效靶向神经阻滞剂。     

肝脏单独与肝肾整块快速获取方法的比较★

目的：目前器官移植尸体供体来源仍占相当的比例，多器官来源于同一供体的需求增多，快速整块获取的技术发展迅速。比较肝脏单独与肝肾整块快速获取的技术特点与脏器损伤情况的差异。 方法：①回顾分析2004-03/2006-07解放军第二军医大学东方肝胆外科医院单个手术组获取并应用于移植的74例供肝资料。②使用快速肝脏获取方法，不进行热解剖，开腹先进行腹主动脉联合门静脉原位冷灌注。肝脏单独切取方法：肾静脉上缘离断腔静脉，胰颈下方离断肠系膜上血管；腹主动脉前解剖法剥离肠系膜上动脉至根部，与肾动脉之间离断腹主动脉，游离胰腺体尾、腹主动脉后方，取下肝脏。肝肾整块获取方法：肝周韧带游离后，游离结肠、输尿管、肾及脾脏，离断肠系膜上血管，横断腹主动脉、腔静脉，游离血管、肝胰脾肾后方，整块切取肝肾。离体腹主动脉后解剖法显露分离肝肾动脉，离断下腔静脉，完全分离肝肾。③记录两种方法的肝脏热缺血、肝脏获取、冷缺血时间，统计肝肾主要部位的获取损伤率并进行比较。 结果：①完成肝脏单独获取28例，肝肾整块获取46例，两组中分别有1例同时获取心脏。未发生因器官获取原因导致的器官损失，获取肝脏全部用于移植，无原发性器官无功能发生，无肝动脉血栓形成。②单独获取患者肝脏获取时间短于肝肾整块获取患者（P < 0.01）。③肝肾整块获取患者的腹腔动脉和肠系膜上动脉的Carrel袖片损伤率低于肝脏单独获取患者（P < 0.05）。 结论：快速肝脏单独和快速肝肾整块获取方法的主要技术差别在于分离肝肾血管的先后顺序及解剖显露肝肾动脉的方法；快速肝脏单独获取在手术耗时上少于快速肝肾整块获取，但更容易出现腹腔动脉和肠系膜上动脉Carrel袖片的损伤。     

肝动脉注射锰锌铁氧体磁性纳米颗粒治疗兔VX2肝癌

背景：与传统的热疗方法相比,磁流体热疗具有很好的磁响应性,在一定高频交变磁场下能实现肿瘤热疗的自动控温和靶向治疗等优点。 目的：制备锰锌铁氧体磁性纳米颗粒,观察其介入治疗兔VX2 肝癌的效果。 方法：采用开腹后瘤粒悬浮液针头注入法制作兔VX2 肝癌模型,造模后14 d随机数字表法分为对照组(生理盐水)、锰锌铁氧体磁性纳米颗粒非热疗组、锰锌铁氧体磁性纳米颗粒热疗组、阿霉素组,均采用3F导管从右侧股动脉选择至肝固有动脉动脉注入药物后拔管。锰锌铁氧体磁性纳米颗粒热疗组于介入后行热疗3次。介入治疗后14 d取肝脏组织测量肿瘤大小,并做病理组织学检查。 结果与结论：透射电镜下观察制备的锰锌铁氧体磁性纳米颗粒为球形,大小为20~30 nm,在交变磁场下有良好的磁感应升温能力。治疗后14 d,锰锌铁氧体磁性纳米颗粒热疗组肿瘤大面积坏死,肿瘤抑制率达到70.84%,明显高于锰锌铁氧体磁性纳米颗粒非热疗组、阿霉素组与对照组(P < 0.05或P < 0.01)。说明锰锌铁氧体磁性纳米颗粒可吸收电磁波转化为热能,通过介入治疗可显著抑制兔VX2 肝癌生长。     

司莫司汀聚乙烯吡咯烷酮磁性脂质体的制备

背景：经作者检索,未见到有关制备司莫司汀聚乙烯吡咯烷酮磁性脂质体方面的相关报道。 目的：制备司莫司汀聚乙烯吡咯烷酮磁性脂质体,并对其表征进行分析。 设计、时间及地点：观察性实验,于2007-03/09在国家卫生部纳米生物技术重点实验室完成。 材料：司莫司汀由浙江瑞新药业股份有限公司提供。聚乙烯吡咯烷酮由美国Sigma公司提供。 方法：加入聚乙烯吡咯烷酮作为磁性粒子包裹剂制备水基磁流体,采用反相蒸发超声法加高速搅拌制备司莫司汀聚乙烯吡咯烷酮磁性脂质体。 主要观察指标：运用透射电镜和PE热分析系统对磁流体进行表征,在高频交变磁场下进行体外加热试验。用透射电镜、图像分析系统和能谱仪对脂质体进行表征,HPLC法检验其中司莫司汀的包封率。 结果：干燥聚乙烯吡咯烷酮磁性粒子近似球形,粒径10~40 nm。居里温度在 120~140 ℃。其磁流体在高频交变磁场下可升温至40~46 ℃并保持恒定。以此磁性材料为载体制成的司莫司汀聚乙烯吡咯烷酮磁性脂质体的平均粒径为126.1 nm,其中含有Fe3O4成分,药物包封率达到65.48%。 结论：采用反相蒸发超声法加高速搅拌可制备纳米级司莫司汀聚乙烯吡咯烷酮磁性脂质体。所制备的脂质体粒径均匀,分布范围窄,药物含量稳定。     

直肠灌注安定在小儿癫痫药物撤换中的应用研究

目的：研究在小儿癫痫药物撤换中应用安定直肠灌注对缩短平均住院日、降低医疗费用、防止癫痫持续状态发生的应用价值。方法：对１６例癫痫患儿以安定注射剂直肠灌注作为抗癫痫药物撤换时的替换药,并与２１例经典药物撤换方法对比分析。结果：应用安定组平均住院日、医疗费用校对照组显著降低。两组均未发生癫痫持续状态。结论：安定直肠灌注用于抗癫痫药物撤换中的替代药是一种简便、安全、经济的方法。     

迟发缺血预处理低温保存肾移植供体中血红素加氧酶1的表达

背景：缺血预适应延迟反应通过诱导保护性蛋白增强组织对缺血再灌注损伤的耐受能力；血红素加氧酶1参与缺血预适应延迟保护作用。迟发缺血预处理对低温保存肾脏的作用及血红素加氧酶1是否参与其中尚不清楚。 目的：观察缺血预处理诱导血红素加氧酶1的迟发缺血预处理反应对低温保存肾脏移植供体的作用。 方法：雄性SD大鼠随机分入5组：空白对照组、低温保存组、缺血预处理组、缺血+低温组(n=12)；缺血+给药+低温组。各组大鼠均行右肾切除，预处理或假手术操作处理后24 h采用大鼠肾脏非循环离体灌注模型获取肾脏，分别于保存24，48，72 h取样。缺血+给药+低温组除上述处理外，还于原位低温灌注术前1 h接受1次血红素加氧化酶1抑制剂锡原卟啉腹腔注射。低温保存肾脏于各保存终点留取保存液，测定pH值和乳酸脱氢酶含量；切取1/2肾脏按照光镜要求制备标本送检；剩余1/2肾脏用于免疫印迹法测定血红素加氧酶1表达，比色法测定皮质Na-K-ATP酶活性、丙二醛和还原型谷胱甘肽含量；未保存肾脏仅通过免疫印迹法测定血红素加氧酶1的基础表达情况。 结果与结论：迟发缺血预处理诱导了肾组织血红素加氧酶1的表达，与单纯低温保存组相比保存24，48 h后，缺血+低温组保存液pH值、乳酸脱氢酶活性降低；肾脏组织Na-K-ATP酶活性、谷胱甘肽含量增加，丙二醛含量降低；同时点预处理组肾组织光镜形态学改变稍好于单纯低温保存组。给予血红素加氧酶1抑制剂后，这种保护作用消失。提示，迟发缺血预处理延长了肾脏低温保存时限，这可能与诱导血红素加氧酶1，增加组织抗氧化能力，减轻低温保存氧应激有关。     

脑胶质瘤经颈内动脉灌注ACNU的疗效观察

目的比较盐酸尼莫司汀（ACNU）经动脉灌注与经静脉灌注的疗效，并了解不同剂量的疗效。方法培养大鼠C6胶质瘤细胞株．建立大鼠C6胶质瘤模型。分为对照组及动、静脉灌注组，将ACNu按15、30、45mg／kg分别通过颈内动脉和股静脉注入荷瘤大鼠体内。10d后处死大鼠，取脑标本，行苏木精-伊红染色，测量肿瘤体积，比较不同给药方式和剂量对肿瘤生长的影响。结果ACNU治疗大鼠颅内肿瘤体积均小于对照组（P≤0．01）；ACNU颈内动脉灌注组肿瘤体积缩小较静脉灌注组更明显（P≤0．05）。结论单次经颈内动脉灌注ACNU较单次经静脉灌注能更有效地抑制脑胶质瘤的生长。     

5000/新型多肽—PAMAM靶向药物载体载药性能及细胞吸收和毒性研究*****★

背景：前期研究通过噬菌体展示体内筛选方法获得了一条NCI-H460非小细胞肺癌特异结合的多肽，将该多肽与修饰的聚酰胺-胺（PAMAM）型树枝状高分子材料连接制备了纳米靶向药物载体（PAMAM-Ac-FITC-LCTP），该载体在体内外对非小细胞肺癌NCI-H460具有很好的靶向性[1]。 目的：以阿霉素为模型药物，研究PAMAM-Ac-FITC-LCTP对阿霉素的包埋、释放，肿瘤细胞对材料和药物复合物的吸收以及复合物的细胞毒性，对载体载药后的性能进行研究。 方法：物理包埋法将PAMAM-Ac-FITC-LCTP与阿霉素连接，通过体外透析实验研究载体对药物的缓释功能，共聚焦显微镜观察细胞对药物的吸收。以游离阿霉素作为对照，MTT法研究载体载药后对NCI-H460细胞的作用。 结果与结论：PAMAM-Ac-FITC-LCTP对阿霉素的最大包埋率为摩尔比1:3.5。载体对药物具有明显的缓释作用，离子浓度、pH和温度对药物的释放具有影响，说明PAMAM-Ac-FITC-LCTP主要是通过静电相互作用与阿霉素结合。PAMAM-Ac-FITC-LCTP/DOX短时间内比单独药物更高效的进入NCI-H460细胞，而复合物24 h 的细胞毒性与阿霉素的细胞毒性基本一致。以上结果表明PAMAM-Ac-FITC-LCTP可能是一个肿瘤治疗和诊断中很有用的药物靶向传输载体     

Pharmacokinetics and Safety of Tiagabine in Subjects with Various Degrees of Hepatic Function

Summary: Purpose: To evaluate the pharmacokinetics and safety of multiple oral doses of tiagabine HC1 in subjects with different degrees of hepatic impairment. Methods: Four subjects with mild hepatic impairment, three subjects with moderate hepatic impairment, and six matched normal subjects received twice daily oral tiagabine HCl for 5.5 days. Serial blood specimens were obtained for 48 h after the final dose. Total and unbound tiagabine plasma concentrations were determined by high-performance liquid chromatography (HPLC) and ultrafiltration, respectively. Pharmacokinetic parameters were compared between the groups by analysis of covariance. Results: For total tiagabine concentrations in normal subjects and subjects with mild and moderate hepatic impairment, C_max values (mean i SD) were 117 ± 54, 172 ± 40, and 172 ± 28 ng/ml; C_min values were 13 ± 4,27 ± 4, and 28 ± 6 ng/ml; areas under the plasma concentration-time curve were 396 ± 59, 633 ± 16, and 675 ± 32 ng Wml, and elimination half-lives (harmonic means) were 7, 12, and 16 h, respectively. Unbound tiagabine coricentrations, area under the unbound plasma concentration-time curve, and the free fractions were increased in the hepatically impaired subjects. Reduced serum albumin and α₁-acid glycoprotein concentrations may have contributed to increases in the unbound fraction. Adverse events observed included dizziness, tremor, nausea, somnolence, incoordination, and unsteady gait. The frequency of these events was increased in the subjects with liver impairment. Conclusions: Because of the decreased drug elimination caused by liver function impairment, reduced doses or increased dosing interval or both may be needed to attain therapeutic plasma drug concentrations. Time to reach steady state also may be prolonged. The patients should be monitored closely for potential neurologic adverse events.     

Influence of meal ingestion time on pharmacokinetics of orally administered levodopa in parkinsonian patients

The influence of meal ingestion time on rate and extent of oral levodopa absorption was evaluated in a group of 17 patients, after administration of their usual second daily dose of levodopa plus carbidopa (Sinemet 10:1) or benserazide (Madopar 4:1). Standard meals were consumed by the patients after they had fasted 15-17 h, on one occasion 30 min before ingestion of the levodopa "study dose" and, at another time, 2 h after ingestion of the same dose. This study dose, ranging from 50 to 250 mg levodopa, was given to the patients at 11 a.m., 4 h after their first morning dose. Time to peak plasma levodopa concentration increased threefold (from 45 +/- 23 to 134 +/- 76 min, p less than 0.001), when levodopa was administered after meals. Area under the 6-h plasma concentration-time curve for levodopa was decreased in 10 subjects, unchanged in three and higher in four after ingestion of meals, the latter finding probably resulting from an erratic absorption even at fasting. On the whole, levodopa absorption proved significantly lower (p less than 0.01), on the average 15%. Similarly, peak plasma levodopa concentrations were lower in 12 patients, unchanged in two, and higher in three, with an overall significant decrease (p less than 0.001) of 30% on the average. The data confirm the importance of meal ingestion time in relation to levodopa dose as a determinant of drug absorption.     

An open study of tolerability and pharmacokinetics of raclopride extended release capsules in psychiatric patients: a Canadian study.

The tolerability and pharmacokinetics of raclopride extended release (ER) capsules have been evaluated after a single oral dose and at steady state, with 3 different daily doses in 4 male patients requiring neuroleptic treatment. In this 3-week open study, the drug was administered to patients in increasing bid doses of 8 mg, 12 mg and 16 mg, respectively, for each 1-week treatment period, following a 1-week placebo washout. With this limited number of patients, assessments of clinical chemistry, hematology, cardiovascular variables and adverse symptoms suggest that raclopride is safe and well-tolerated in the group studied. The administration of repeated doses of raclopride showed linear pharmacokinetics based on parameter values which are either constant (effective elimination half-life, total plasma clearance, and dose-normalized area under the plasma concentration-time curve) or varying proportionally (trough plasma concentration, peak plasma concentration, average plasma concentration and the area under the plasma concentration-time curve for a dosage interval at steady state) with the doses. The linear 1-compartment open model with zero-order absorption was the most appropriate pharmacokinetic model describing the raclopride plasma concentration profile after a single 8 mg dose of raclopride ER capsules. The ER formulation reduced the fluctuation between peak and trough plasma drug concentrations which has been reported before with instant release dosage forms. In this study, the increase of plasma prolactin concentrations above the normal limit was transient and returned to normal levels. Although the plasma prolactin concentration tended to increase with the drug dose, no direct relationship between raclopride dose and prolactin plasma concentrations was found. The correlation of plasma prolactin response with the plasma raclopride concentration showed a low level of hysteresis.     

Multiple-dose pharmacokinetics of fluvoxamine in children and adolescents

OBJECTIVE: To determine the pharmacokinetics of fluvoxamine in children and adolescents and to compare pharmacokinetic data from adolescents to adults from a previous study. METHOD: Fluvoxamine was titrated to a target dose of 100 mg b.i.d. in children (6-11 years) and 150 mg b.i.d. in adolescents (12-17 years) with obsessive-compulsive disorder or other disorder requiring fluvoxamine treatment. Serum samples were collected over 12 hours after 12 or more consecutive doses of 25, 50, 100, and 150 mg. RESULTS: Sixteen children (seven females, nine males) and 18 adolescents (nine females, nine males) were included in the pharmacokinetic analyses. Children demonstrated higher mean peak plasma concentration, higher mean area under the plasma concentration-time curve, and lower apparent oral clearance compared with adolescents. Compared with male children, female children had higher mean area under the plasma concentration-time curve, higher mean peak plasma concentration, and more reports of adverse events. However, the area under the plasma concentration-time curve was not directly correlated with frequency or severity of adverse events. Pharmacokinetics were nonlinear over the dose range studied. No pharmacokinetic differences were apparent between adolescents and adults on 150 mg b.i.d. CONCLUSIONS: These pharmacokinetic results suggest that children (especially females) have a higher exposure to fluvoxamine than adolescents, whereas adolescents and adults appear to have similar exposure to fluvoxamine.     

白细胞介素2、白细胞介素10及人类白细胞抗原G与肝移植的急性排斥

背景：移植肝急性排斥反应是导致移植物功能损伤的主要危险因素，目前诊断主要靠肝组织穿刺活检，带来感染、出血等风险。如何无创、简单、准确地进行诊断成为当前该领域的热点。 目的：观察分析白细胞介素2、白细胞介素10、人类白细胞抗原G的表达与人类肝移植急性排斥之间的关系。 方法：用酶联免疫方法检测59例肝脏移植受者外周血白细胞介素2、白细胞介素10、人类白细胞抗原G的表达情况。将受者按照有无急性排斥反应分为急性排斥组和非排斥组；并将非排斥组按肝功能情况分为肝功能正常组与异常组。结果进行统计学分析，并绘制ROC曲线，比较曲线下面积及其临界值的敏感性和特异性。 结果与结论：急性排斥组外周血中白细胞介素10、人类白细胞抗原G表达均低于与非排斥组(P=0.032, 0.002)，而排斥组中白细胞介素2高于非排斥组(P=0.002)。肝功正常组与异常组间白细胞介素10、人类白细胞抗原G表达差异无显著性意义(P=0.525,0.084)，而肝功能异常组白细胞介素2表达高于肝功能正常组(P=0.02)。ROC曲线下面积为人类白细胞抗原G >白细胞介素2>白细胞介素10。结果提示，白细胞介素2、白细胞介素10、人类白细胞抗原G的表达都与排斥相关，三者中人类白细胞抗原G为诊断急性排斥的最佳指标。     

Metabolism of liposome-encapsulated heparin

In order to elucidate the metabolism of liposome encapsulated heparin (LIPO-HEP), LIPO-HEP containing 3H-heparin (3H-HEP) and/or 14C-phosphatidylcholine (14C-PC) was intravenously administered into rats and the radioactivity as well as the biological activity in plasma and certain organs was investigated. The amount of 3H-radioactivity in plasma was significantly higher in rats receiving LIPO-HEP than in those receiving untreated heparin. The amount of 14C-radioactivity in plasma of rats receiving LIPO-HEP, however, was not proportional to the amount of 3H-radioactivity in the same rats, indicating the dissociation of liposome and heparin in plasma. Incorporation of 3H-radioactivity into various organs examined, i.e., liver, spleen, lung, was significantly higher in rats receiving LIPO-HEP than in those receiving untreated heparin, e.g. 4.7 and 11.8 times higher in the liver and the spleen, respectively at 150 min after the injection. Thereby, in contrast to the untreated heparin, LIPO-HEP was selectively incorporated into the reticuloendothelial system (RES) and it may be suggested that prolonged biological activity in LIPO-HEP is due to a gradual release of heparin from the liposomes entrapped in RES, and that it is not due to prolonged circulation in blood.     

负载As2O3壳聚糖纳米粒的药代动力学及其毒性观察

摘要 背景：As2O3作为抗肿瘤药物具有不同程度的不良反应,目前尚没有可以较好降低As2O3不良反应的方法。 目的：观察负载As2O3壳聚糖纳米粒在体内是否有缓释作用,是否可以延长药物作用时间,减低As2O3毒副作用。 方法：将20只SD大鼠以抽签法随机分为As2O3组和壳聚糖纳米粒-As2O3组进行药代动力学测定,于给药前和给药后不同时间点测定血液中砷浓度;将40只SD大鼠随机分为壳聚糖纳米粒组、壳聚糖纳米粒- As2O3组、As2O3组、生理盐水组进行毒理学检测,检测血浆中谷丙转氨酶、谷草转氨酶、肌酸激酶、肌酐、尿素氮水平,并结合苏木精-伊红染色形态学观察心、肝、肾组织形态学变化。 结果与结论：壳聚糖纳米粒- As2O3组较As2O3组半衰期明显延长(P < 0.05)。除肌酸激酶外,As2O3组其他各指标均高于其他各组(P < 0.05);而含相同浓度As2O3的壳聚糖纳米粒As2O3组与壳聚糖纳米粒组、生理盐水组各项指标差异无显著性意义(P > 0.05)。As2O3组大鼠肝脏和肾脏均有较明显的病理学改变,壳聚糖纳米粒- As2O3组未见明显形态学改变。4组大鼠心脏均未见明显形态学改变。说明负载As2O3壳聚糖纳米粒在体内有缓释作用,可以延长药物作用时间,减轻As2O3的毒副作用。 关键词：壳聚糖纳米粒;As2O3;负载As2O3壳聚糖纳米粒;药代动力学;药物毒理学 doi:10.3969/j.issn.1673-8225.2011.12.019     

Influence of the dopamine agonist alpha-dihydroergocryptine on the pharmacokinetics of levodopa in patients with Parkinson's disease

This study investigated whether chronic coadministration of alpha-dihydroergocryptine (DHEC) altered the plasma pharmacokinetics of individualized treatments with levodopa in 12 patients with Parkinson's disease. Steady-state pharmacokinetics of plasma levodopa (L-Dopa) under combined treatment were compared with those under treatment with L-Dopa alone. There was no evidence of increased exposure to L-Dopa caused by concomitant treatment with DHEC. In contrast, additional treatment with DHEC reduced the overall exposure to L-Dopa (17.5% reduction in area under the curve; 95% CI: 23%-6%). This effect was small but statistically significant for the area under the plasma concentration-time curve, whereas tmax (time of maximum plasma concentration) and peak-to-trough fluctuation were not affected. Cmax (maximum plasma concentration), on average, was reduced to a similar extent (-14.5%; 95% CI: 38% to -17%), albeit not significantly. The magnitude of the interaction does not suggest changing the current clinical practice of up-titrating DHEC and subsequently adapting L-Dopa to the individual needs of patients.     

Saturable transport of gabapentin at the blood-brain barrier.

Gabapentin readily crosses the blood-brain barrier and concentrates in brain tissue via an active transport process believed to be system-L. Blood-brain barrier system-L has a low K(m), making it particularly susceptible to substrate saturation. The purpose of this study was to determine whether the fraction of gabapentin crossing the blood-brain barrier remains constant over a broad range of doses. Using a rat model, microdialysis techniques were employed to determine if fluctuations in gabapentin concentrations in the brain extracellular fluid (ECF) coincided with proportional changes in plasma concentrations. Area under the concentration-time curve was calculated for plasma (AUCplasma) and brain extracellular fluid (AUCECF). The ratios of AUFECF to AUCplasma (AUCratio) and brain extracellular fluid to midpoint plasma gabapentin concentration for each collection interval (Cratio) were determined to provide indicators of the relative (i.e. fractional) amount of gabapentin crossing the blood-brain barrier. Analysis of the association between AUCECF and AUCplasma using linear regression analysis revealed a small, but significant relationship (r = 0.62; p < 0.01). Although higher AUCECF values were obtained with higher AUCplasma values, changes in AUCECF were less than proportional to observed changes in AUCplasma. Blood-brain barrier saturation of gabapentin transport was evident as the AUCratio decreased with increased AUCplasma. Collectively, these results support a trend towards saturation at higher plasma concentrations of the carrier-mediated transport mechanism of gabapentin through the blood-brain barrier.