联糖米托蒽醌的趋肝性研究

目的：合成肝靶向药联糖米托蒽醌（ＮＧＡＤＨＡＱ）的趋肝性研究。方法：以合成配体半乳糖基拟糖白蛋白（ｎｅｏｇｌｙｃｏａｌｂｕｍｉｎ,ＮＧＡ）为载体,与抗癌药物米托蒽醌（ｍｉｔｏｘａｎｔｒｏｎｅ,ＤＨＡＱ）偶联得肝靶向抗癌药物ＮＧＡＤＨＡＱ。采用紫外光谱和ＨＰＬＣ确证其偶联的形式及在血液中的稳定性。用９９ｍＴｃ标记后进行家兔放射性显像及小鼠体内的分布实验。结果：ＮＧＡＤＨＡＱ为化学偶联物且在血中很稳定,家兔及小鼠肝中药物的量均在５ｍｉｎ时达最大,分别占全身放射量的６５．１％和６５．４％±４．３％（ｎ＝３）。结论：说明ＮＧＡＤＨＡＱ具肝靶向分布性。     

阿柔比星A聚乳酸毫微粒冻干针剂的研制及体外药物释放规律的研究

研究阿柔比星Ａ聚乳酸毫微粒（ＡＣＲＢ－Ａ－ＰＬＡ－ＮＰ）冻干针剂的制备,并对其体外释药进行考察。根据低共熔点测定结果,以及外观、色泽、再分散性等质量参数为指标,制备出ＡＣＲＢ－Ａ－ＰＬＡ－ＮＰ冻干针剂,采用动脉透析法研究其体个释放规律。结果,制得的ＡＣＲＢ－ＡＰＬＡ－ＮＰ冻干针剂色泽均匀,再分散性良好。其体外释药可用３种方式表达。提示ＡＣＲＢ－Ａ－ＰＬＡ－ＮＰ冻干针剂有明显的缓释特征。     

柔红霉素毫微粒冻干针剂的研究

目的：制备易再分散、稳定的柔红霉素聚氰基丙烯酸正丁酯毫微粒（ＤＮＲ－ＰＢＣＡ－ＮＰ）冻干针剂。方法：选用适宜支架剂制得ＤＮＲ－ＰＢＣＡ－ＮＰ冻干针剂,并评价其相关理化性质。结果：冻干前后毫微粒形态、粒径、ｐＨ、包封率及载药量均无明显变化,含水量合格,再分散性良好,制剂稳定。其临界相对湿度为７５．３３％。结论：在适宜的处方及工艺条件下制备ＤＮＲ－ＰＢＣＡ－ＮＰ冻干针剂是可行的。     

米托蒽醌毫微球在裸小鼠人肝癌模型体内的靶向性研究

采用液体闪烁计数技术研究厂氖标记米托惠醌聚氰基丙烯酸正丁酯毫微球（￣（３）Ｈ－ＤＨＡＱ－ＰＢＣＡ－ＮＳ）在常位及异位（腋下）裸小鼠人肝癌模型体内各脏器、肌肉、肝常位肿瘤组织和腋下肿瘤组织中的分布。证明该制剂具有良好的肝靶向作用，肝脏中的含量为体内总药量的７１．３１±１０．４９％（ｎ＝５）。并发现其在常位肿瘤组织中的含量高于肝组织中的含量，腋下肿瘤组织中的含量高于腋下肌肉组织中的含量，但均无显著性差异。为该制剂的进一步研究提供了一定的科学依据。     

阿柔比星A聚乳酸毫微粒冻干针剂小鼠体内分布研究

对阿柔比星Ａ冻干针剂与阿柔比星Ａ聚乳酸毫微粒冻干针剂给予小鼠尾静脉注射后体内分布比较，采用ＨＯＬＣ法分别测定小鼠给药后血液及主要脏器中ＡＣＲＢ０Ａ浓度。结果阿柔比星Ａ聚乳酸毫微粒在小鼠肝脏中的浓度高于对照品浓度。     

蟾酥固体脂质纳米粒冻干针剂小鼠体内分布的研究

分别对小鼠尾静脉注射给予蟾酥冻干固体脂质纳米粒（1-SLN）及其水溶液，采用HPLC法分别测定小鼠血浆和心、肝、脾、肺、肾、脑等各脏器中的华蟾酥毒基和脂蟾毒配基浓度，以药物靶向指数（DTI）和药物选择性指数（DSI）定量评价了1—SLN冻干针剂在小鼠体内的分布情况。结果表明，1-SLN组中肝脏的DTI值均大于1，且DSI值均大于1水溶液组的相应值，说明1-SLN具有较好的肝靶向性。     

蛇床子水煎剂对D—半乳糖衰老小鼠脑和肝组织中谷胱革肽过氧化 …

为探讨蛇床子水煎剂的抗氧化机制，本实验采用Ｄ－半乳糖衰老小鼠，灌喂蛇了水煎剂，分别于１５，３０，４５ｄ处死，测定小鼠脑和肝组织谷胱甘肽过氧化物酶（ＧＳＨ－Ｐｘ）丙二醛（ＭＤＡ）丙二醛（ＭＤＡ）的活性。实验结果表明：与Ｄ－半乳糖衰老模型组比较，蛇床子水煎剂能明显提高衰老小鼠脑和肝的ＧＳＨ－Ｐｘ活性，明显降低ＭＤＡ的含量，揭示蛇床子水煎剂对衰老小鼠有抗氧化作用，可延缓小鼠脑和肝的衰老。     

补肾健脾化瘀方对老年小习免疫功能及自由基代谢的影响

目的：为验证“正虚挟瘀”是中医衰老的重要原因／机制的可靠性及合理性，我们观察了补肾健脾化瘀对老年小鼠免疫功能、自由基代谢的影响。方法：老年小鼠连续四周灌服中药后，检测腹腔巨噬细胞产生的ＩＬ－１、脾淋巴细胞产生的ＩＬ－２、红细胞清除自由基酶（ＳＯＤ、ＣＡＴ、ＧＳＨ－Ｐｘ）的活性以及肝脑的ＬＰＯ含量，结果：老年小鼠ＩＬ－１、ＩＬ－２的产生以及ＳＯＤ、ＣＡＴ、ＧＳＨ－Ｐｘ的酶活性均明显低于青年小鼠，而肝     

万乃洛韦毫微粒对肝脏和肝细胞胞内靶向性的研究

目的：测定静注万乃洛韦聚氰基丙烯酸正丁酯毫微粒（ＶＡＣＶＰＢＣＡＮＰ）冻干剂和万乃洛韦小鼠体内的分布。方法：用体外肝细胞培养及摄取实验研究ＶＡＣＶＰＢＣＡＮＰ对肝细胞的胞内靶向性。结果：ＶＡＣＶＰＢＣＡＮＰ静注后１５ｍｉｎ即有７４．４９％的ＶＡＣＶ集中在肝脏，比ＶＡＣＶ注射液提高了２．９９倍，肾脏分布量降低了５．４６倍。结论：ＶＡＣＶ制成毫微粒后可明显增加肝细胞的摄取量     

注射用纳米羟喜树碱与注射用羟喜树碱在小鼠体内的组织分布比较

目的:观察注射用纳米羟喜树碱(HCPT纳 米针剂)静脉推注后小鼠体内组织分布情况,并与 注射用羟喜树碱(HCPT针剂)比较组织分布特征。 方法:BALB/c小鼠分别给予HCPT纳米针剂或 HCPT针剂,10mg·kg-1尾静脉推注给药。给药后 15min,1和2h,采用HPLC方法检测小鼠各组织和 血浆中羟喜树碱的含量,并对不同剂型和不同取样 时间进行比较。结果:(1)HCPT纳米针剂在肝组 织中浓度最高,分布顺序:肝>肾>脾>肠>胃> 肺>心。(2)HCPT纳米针剂在肝、肾、脾、肺、胃的 药物浓度均显著高于HCPT针剂(P<0.05),肝组 织药物浓度最高,是HCPT针剂组的37.66倍 (15min)。(3)HCPT纳米针剂给药后在肝组织保 留时间长,而HCPT针剂组给药后没有显著蓄积的 靶组织。结论:HCPT纳米针剂与HCPT针剂相比, 能够更多地进入组织器官并具有明显的肝组织靶向 性,在肝组织中可较长时间保持较高药物浓度。     

ETHANOL METABOLISM IN THE LIVER

Summary: Ethanol elimination by the liver, a relatively constant process, may be increased at high concentrations of ethanol, when certain substances like fructose or pyruvate are metabolized together with ethanol or after prolonged exposure for ethanol. The metabolic effects on the liver are different at high and at low concentrations of ethanol. A number of enzymes or enzyme systems, – liver alcohol dehydrogenase, catalase and mixed-function oxidase – can in vitro catalyze the oxidation of ethanol, but little is known about the actual role of each enzyme at different metabolic conditions. The existence of more than one pathway for ethanol metabolism in the liver is now becomming increasingly evident, but whether the non-ADH mediated ethanol oxidation occurs via catalase, or mixed-function oxidase system, or both, cannot at present be decided. The activity of liver alcohol dehydrogenase cannot be induced by continuous use of ethanol. The ADH-mediated ethanol oxidation may be increased when the steady state concentration of free NADH in the cytoplasm is lowered. The rate of ethanol oxidation under in vivo conditions seems not to be determined by the rate of acetaldehyde elimination, although acetaldehyde is a product of ethanol metabolism. The reoxidation of NADH may proceed by NADH-linked substrate system, by transhydrogenation to NADP⁺ or by transporting reducing equivalents into mitochondria where they are oxidized. In this review an attempt is made to examine the effects of a number of substrates or metabolic conditions which may enhance ethanol oxidation (concentration of ethanol, fructose, pyruvate, D-glyceraldehyde, oxygen, CO₂ and 2,4-dinitrophenol) and to discuss the mechanisms involved in this action. It is concluded that the effect of pyruvate and fructose (maybe also CO₂ and D-glyceraldehyde) proceeds via ADH-mediated pathway (possibly involving the so-called “malic enzyme shuttle”) whereas the acceleration in ethanol metabolism, observed in rat liver preparations when high concentrations of ethanol are metabolized, is associated with the participation of non-ADH pathway (s) in ethanol metabolism.     

EXTRACTION OF NEUROTENSIN BY THE LIVER

1. Neurotensin is released from the intestine into the portal circulation and to exert a systemic effect it must traverse the liver intact. 2. The role of the liver in neurotensin clearance was examined using the isolated perfused rat liver preparation. Two concentrations of neurotensin were used to determine the extraction capacity of the liver. 3. Approximately 10% of the added neurotensin (with either dose) was extracted in a single pass through the liver. This extraction rate was low when compared to previous studies with cholecystokinin (60% extraction in a single pass) and vasoactive intestinal peptide (100%). 4. It is concluded that there is a small but high capacity for direct extraction of neurotensin. This low direct extraction percentage supports our previous contention that the major influence of the liver on the metabolism of neurotensin is by the release of neurotensin degrading peptidases into the circulation.     

催醒宁在大鼠离体灌流肝脏中的生物转化

用离体大鼠肝脏灌流方法,研究了胆碱酯酶抑制剂CXN的生物转化过程。径HPLC分离纯化及光谱分析,鉴定了CXN的六个脂溶性代谢产物的化学结构。产物Ⅰ为CXN原形,其余均为氧化产物。其中产物Ⅲ尚保留部分抑酶活力,而产物Ⅱ,Ⅴ及Ⅵ对小鼠全脑胆碱酯酶的抑酶活力明显下降。另外还观察到,代谢产物Ⅱ及Ⅴ对小鼠的急性毒性也明显减小。     

F30066对家兔肝肾功能的影响

F30066, N-(isopropyl)-β-(5-nitro-2-furyl)-acrylamide, is a new oral drug for Schis- tosomiasis japonica. The present work studied the effect of F30066 on the liver and kidney functions of uninfected and infected rabbits six weeks after the cercarial infection of Schistosoma japonicum. The experimental results indicate that the drug causes some damages to the liver and the kidney, but the damages are reversible. The authors also observed the normal-value distributions of several useful tests for liver and kidney func- tions in about 200 animal-times of rabbits.     

EFFECT OF ETHANOL ON THE METABOLISM OF TRICHLOROETHYLENE IN THE PERFUSED RAT LIVER

The effect of 2 m M ethanol, a concentration indicative of daily alcohol consumption, was investigated on trichloroethylene (TRI) metabolism in perfused Wistar rat liver. The study consisted of two parts: The first part studied TRI administration with or without ethanol. In the second study chloral hydrate (CH), an intermediate in TRI metabolism, was administered in the absence or presence of ethanol to phenobarbital (PB) treated or non-PB-treated rats. The concentrations of the metabolites, total trichloroethanol (TCE), and trichloroacetic acid (TCA) were measured by gas chromatography and intracellular reduced pyridine nucleotides by surface fluorometry. In the first study, ethanol infusion significantly increased the TCE/TCA ratio, TCE production rate, and percentage of reduced pyridine nucleotides, and decreased TCA production rate without an associated change in the sum of TCE and TCA formation rates. In the second study, ethanol infusion in the absence or presence of PB produced similar significant increases in the TCE/TCA ratio, TCE production rate, and percentage of reduced pyridine nucleotides, accompanied by a decrease in TCA formation. The observed shift in TRI metabolism in the presence of ethanol, from oxidation to TCA to reduction to TCE, suggests that alcohol exerts alterations in hepatic intracellular oxidation-reduction (redox) states.     

肝靶向氟尿嘧啶类脂纳米粒的研究

目的　为了提高氟尿嘧啶(5-Fu)的疗效,降低其毒副作用,制备具肝靶向的5-Fu类脂纳米粒。方法　利用氟尿嘧啶与硬脂酰氯进行反应,制备了5-Fu前体药物N₁-硬脂酰-5-Fu,通过红外光谱及核磁共振谱对合成的目标化合物进行结构确认。同时研究了前体药物的性质及稳定性。采用物理凝聚法制备类脂纳米粒,并研究其形态、粒径及粒径分布、载药量、体外释药特征、动物体内分布与药代动力学参数等。结果　平均粒径d_av=240.19 nm,载药量为20.53%。体外释药速率符合一级动力学模型。与5-Fu水针剂比较,类脂纳米粒组在肝脏中药物含量平均增加了一倍以上。家兔体内主要药动学参数为：V_c=0.04336 L.kg^-1,T_1/2β=1.2834 h,CL=0.1632 L.h^-1。结论　利用前体药物可提高药物的脂溶性,首次以物理凝聚法制备类脂纳米粒,小鼠体内分布研究表明类脂纳米粒有明显的肝靶向,有一定的优越性和参考价值。