Antioxidant properties of ursodeoxycholic acid

We have investigated potential antioxidant properties of the clinically relevant bile acid UDCA, which reaches therapeutic concentrations up to 0.09 and 29 mM, respectively, in human plasma and bile. UDCA was an excellent scavenger of OHz.rad; generated by FeCl(3)-EDTA, H(2)O(2) and ascorbate in the deoxyribose oxidation test, showing IC(min) and IC(50) values of 0.02 and 0.2 mM, respectively, and a second-order rate constant for reaction with OHz.rad; of 2+/-0.1 x 10(10)M(-1)s(-1). Notably, the drug could enhance at 1.5 mM concentration the antioxidant capacity of human bile against OHz.rad;-induced deoxyribose oxidation. UDCA also showed antioxidant effects in the deoxyribose test performed with nonchelated iron ions, such as Fe(2+) plus H(2)O(2) (IC(min): 7 mM, IC(50): 20 mM) or Fe(3+) plus H(2)O(2) and ascorbate (IC(min): 0.3 mM, IC(50): 5 mM), and inhibited ferrozine-Fe(2+) and desferrioxamine-Fe(3+) complexes formation with IC(50) values of, respectively, 12 and 0.3 mM, indicating that the drug interacts more with iron(III) than with iron(II). Moreover, UDCA significantly inhibited phospholipid liposome peroxidation induced by the OHz.rad;-generating system FeCl(3)-EDTA, H(2)O(2) and ascorbate (IC(min): 0.75 mM, IC(50): 3 mM), and by peroxyl radicals generated in the aqueous phase by AAPH (IC(min): 8 mM, IC(50): 14 mM). UDCA, even at 25 mM concentration, was ineffective on the lipoperoxidation mediated by Fe(2+) alone, but at the same concentration counteracted significantly that by Fe(3+) plus ascorbate, further pointing to its preferential antioxidant interaction with iron(III).In conclusion, UDCA has direct antioxidant properties, which are especially relevant against Fe(3+)- and OHz.rad;-dependent biomolecular oxidative damage; such properties are evident at therapeutically relevant drug concentrations, suggesting that UDCA could act as an antioxidant in vivo.     

浙贝乙素及其5种衍生物对小鼠的半数致死量测定

目的研究浙贝乙素及其5种衍生物的急性毒性和对小鼠的半数致死量（LD50）。方法取昆明种小鼠，完全随机平均分组后腹腔注射给药，分别给予不同浓度的浙贝乙素乙酰化物、丙酰化物、丁酰化物、苯甲酰化物和氧化物药液。以小鼠急性死亡率为指标，求浙贝乙素各衍生物的LD50和LD50的95%可信区间。结果浙贝乙素乙酰化物、丙酰化物、丁酰化物、苯甲酰化物和氧化物对小鼠的LD50分别为14.39，14.47，18.41，23.21，9.98 mg·kg^-1 ， 均大于浙贝乙素对小鼠的LD50。结论浙贝乙素乙酰化物、丙酰化物、丁酰化物、苯甲酰化物和氧化物的毒性均较小，有望从中筛选出高效、低毒的镇咳药物。     

Preclinical factors affecting the interindividual variability in the clearance of the investigational anti-cancer drug 5,6-dimethylxanthenone-4-acetic acid

Cancer chemotherapy is characterized by significant interindividual variations in systemic clearance, therapeutic response, and toxicity. These variations are due mainly to genetic factors, leading to alterations in drug metabolism and/or target proteins. The aim of this study was to determine, using a human liver bank (N=14), the interindividual variations in the expression and activity of liver enzymes that metabolize the investigational anticancer drug 5,6-dimethylxanthenone-4-acetic acid (DMXAA), i.e cytochrome P450 (CYP1A2) and uridine diphosphate glucuronosyltransferase (UGT1A9/2B7). In addition, interindividual variations in enzyme inhibition, hydrolysis of DMXAA acyl glucuronide (DMXAA-G) by plasma and hepatic microsomes, and the binding of DMXAA by plasma proteins also were examined. The results indicated that there was approximately one order of magnitude of interindividual variation in the expression of CYP1A2 and UGT2B7, activity of the enzymes toward DMXAA, and inhibition potency (IC(50)) by diclofenac, cyproheptadine, and alpha-naphthoflavone. The enzyme activities toward DMXAA and IC(50) values were closely correlated with enzyme expression. There was a smaller (2- to 3-fold) variation in the enzyme-catalyzed hydrolysis of DMXAA acyl glucuronide in human plasma and liver microsomes (N=6) and in the binding of DMXAA by plasma proteins in humans. In conclusion, the interindividual variability of DMXAA disposition observed in vitro might reflect the greater elimination variability (>one order of magnitude) in Phase I cancer patients. The variability in DMXAA clearance in these cancer patients would be due mainly to differences in its metabolism and its metabolic inhibition by co-administered drugs. To a lesser extent, variability in the clearance of DMXAA could be due to the hydrolysis of its acyl glucuronide and/or its binding to plasma proteins. Further study is needed to examine the genotype-phenotype relationship, and the result, together with therapeutic drug monitoring may provide a useful strategy for optimizing DMXAA treatment.     

中药仙鹤复方提取物急性毒性试验及对小鼠移植性肿瘤H22的抗肿瘤作用研究

目的 研究中药仙鹤复方乙醇提取物的急性毒性,以及中药仙鹤复方乙醇提取物和水提取多糖对小鼠移植性肿瘤H22的抑瘤作用,进而对中药仙鹤复方进行抗肿瘤活性研究.方法 测定中药仙鹤复方乙醇提取物的LD50,建立荷实体型肝癌H22小鼠模型,观察中药仙鹤复方乙醇提取物和水提取多糖的抑瘤作用.结果 中药仙鹤复方乙醇提取物的LD50为26.95g·kg-1,95%可信区间为21.99～33.01g·kg-1;中药仙鹤复方乙醇提取物9.25g·kg-1·d-1剂量组与中药仙鹤复方水提取多糖8.05g·kg-1·d-1剂量组时小鼠移植性肿瘤H22均有明显的抑制作用,其抑瘤率分别为49.2%(P＜0.01)和33.7%(P＜0.01).结论 中药鹤复方乙醇提取物和水提取多糖对小鼠移植性肿瘤H22有抑制作用.     

3种肿瘤标志物的联合检测在恶性肿瘤诊断中的价值

目的探讨肿瘤标志物癌胚抗原（CEA）、糖类抗原CA125、糖类抗原CA199在各种人群中的表达及其在恶性肿瘤诊断中的价值．．方法收集可供分析的31025例肿瘤标志物检测结果,分析CEA、CA125、CA199在各种人群、各类型肿瘤中表达情况。结果在恶性肿瘤患者中,CEA、CA125、CA199表达升高的比例明显高于良性病变患者及健康体检者,差异有统计学意义（P〈O．01）。各类型肿瘤中,CEA升高率在肠癌中最高（42．63％）;CA125升高率在卵巢癌中最高（53．17％）,其次为胰腺癌（50．08％）和肝癌（42．81％）;CA199升高率在胰腺癌中最高（62．32％）;CEA／CA125表达伴随升高最常出现于胰腺癌,其次也常见于卵巢癌、肝癌、肺癌、乳腺癌;CEA／CA199表达伴随升高最常出现于胰腺癌,其次为肝癌、卵巢癌：CA125／CA199表达伴随升高最常出现于肠癌,其次为胰腺癌、肝癌、卵巢癌;CEMCA125／CA199表达联合升高最常出现于胰腺癌。其次为肝癌、卵巢癌。结论联合检测肿瘤标志物CEA、CA125、CA199可显著提高胰腺癌、肝癌、卵巢癌等恶性肿瘤诊断的敏感性。     

喹唑啉和嘧啶类66个化合物体外的抗肿瘤活性

试验了四类66个喹唑啉和嘧啶类化合物对L1210白血病细胞株的增殖抑制作用,结果显示2,4-二氨基-6-取代苄氨基喹唑啉优于双(2,4-二氨基喹唑啉6-基-取代氨基)烷烃或芳烷烃及其它2,4-二氨基喹唑啉和2,4-二氨基-5-取代嘧啶。其中以2,4-二氨基-6-(N-甲基-N-对氯苄基氨基)喹唑啉(24)的抑瘤活性最为显著,并强于阳性对照药甲氨蝶呤。     

洛美沙星体内外抗菌活性研究

洛美沙星对革兰氏阴性菌具有强的抑菌活力。对克氏肺炎杆菌的抗菌活性最强,MIC_(50)为0.12mg/L;对痢疾杆菌、产气杆菌、粘质沙雷氏菌、不动杆菌和枸椽酸杆菌的MIC_(50)分别为1和4mg/L。洛美沙星对肠细菌科细菌的活力比诺氟沙星和依诺沙星强2～16倍,明显地比丁胺卡那霉素、庆大霉素强。对金葡球菌MIC_(50)为1mg/L, MRSA对洛美沙星同样敏感。洛美沙星对表葡球菌、链球菌、粪链球菌及肺炎双球菌等的抗菌活性与地氟沙星相似,比诺氟沙星、依诺沙星、丁胺卡那霉素、庆大霉素和头孢三嗪分别强2～4倍。 洛美沙星对小鼠全身感染的疗效优于诺氟沙星。对大肠杆菌、克氏肺炎杆菌和绿脓杆菌感染小鼠iv的ED_(50)分别是0.74、0.13和3.45mg/kg, po的ED_(50)分别是0.94、1.46和6.20mg/kg。     

GBE50对大鼠生理/心理应激模型的应激缓解作用

目的 研究银杏叶提取物制剂GBE50的应激缓解作用.方法 应用大鼠生理/心理应激模型(PS/ES Model),大鼠分组后被安置在特制的二室电击笼中,经受足部电刺激(生理应激,PS)或旁观电击(心理应激,ES).每天10 min、为期6 d的刺激完成后,进行旷场试验测定行为学指标,其后测定大鼠血浆皮质酮水平和全血黏度数据.结果 GBE50可恢复PS组大鼠的活动性,显示有改善ES大鼠血液流变学的趋势,对PS/ES大鼠血浆皮质酮水平的影响似乎不大.结论 GBE50可从不同方面提供一定的应激缓解作用.     

依托咪酯对布比卡因致惊厥作用的影响

目的 观察依托咪酯(etomidate,Eto)对布比卡因(bupivacaine,Bup)致惊厥作用及半数有效量(ED50)、半数致死量(LD50)的影响.方法 皮下注射3种不同剂量的依托咪酯20min后,腹腔注射致惊厥作用的布比卡因,观察小鼠惊厥潜伏期、持续时间、未惊厥数和死亡数;并以序贯法测定预先给予依托咪酯20min后布比卡因的致惊厥ED50和LD50.结果 依托咪酯2、4mg/kg可延长布比卡因致小鼠惊厥的潜伏期(P＜0.01),缩短持续时间(P＜0.01),减少惊厥发生数和死亡数;增大布比卡因致惊厥的ED50(P＜0.05,P＜0.01),增大布比卡因的LD50(P＜0.01).结论 依托咪酯能够拮抗布比卡因的致惊厥作用,降低布比卡因的毒性.     

丙泊酚镇静下瑞芬太尼对不同年龄患者抑制气管插管反应的半数有效浓度

目的 测定丙泊酚镇静深度下瑞芬太尼抑制不同年龄患者插管反应的半数有效血浆靶控浓度(Cp50)、半数有效实测浓度(Cm50)值、半数有效效应室浓度(EC50)值.方法 60例上腹部手术患者,男37例、女23例,年龄22岁～82岁,分为:青年组(n=20),22岁～44岁,中年组(n=20),45岁～64岁,老年组(n=20),65岁～82岁.所有患者靶控输注丙泊酚、调节丙泊酚靶控输注血浆浓度将脑电双频指数(bispectral index,BIS)目标值定为45～55,待BIS目标值稳定5 min,靶控输注瑞芬太尼.瑞芬太尼的血浆靶控浓度按序贯法确定,输注5 min给予维库溴铵0.1 mg/kg行气管插管,记录血流动力学变化和计算瑞芬太尼Cp50、Cm50、EC50值.结果 3组患者瑞芬太尼抑制插管反应的Cp50和95%CI分别是5.77 μg/L.,4.76 μg/L～7.01 μg/L;4.80 μg/L,3.56 μg/L～6.48 μg/L;4.06 μg,/L,3.52 μg,/L～4.92 μg/L.青年组与中年组、老年组差异有统计学意义(P<0.01),中年组与老年组差异有统计学意义(P<0.05).EC50和95%CI分别是5.90μg/L,4.47 μg/L～7.68 μg/L;4.60 μg/L,3.03 μg/L～5.90 μg/L;4.06 μg/L,2.97 μg/L～5.42 μg/L.青年组与中年组、老年组差异有统计学意义(P<0.05),中年组与老年组差异有统计学意义(P<0.01).Cm50和95%CI分别是4.25 μg/L,2.04 μg/L～6.47 μg/L;3.62 μg/L,1.70 μg/L～5.54 μg/L;3.09 μg/L,1.3μ/L～4.89 μg/L.青年组与老年组差异有统计学意义(P<0.01).3组患者在达到目标BIS值时丙泊酚靶控浓度分别为(3.6±0.6)mg/L、(3.4±0.8)mg/L、(2.7±0.8)mg/L,青年组与老年组差异有统计学意义(P<0.05).结论 丙泊酚复合瑞芬太尼用于抑制气管插管反应,在维持BIS值为45～55时,各年龄组之间的丙泊酚靶控输注血浆浓度、瑞芬太尼的Cp50、Cm50、EC50差异有统计学意义.