经不同途径区域灌注氟尿嘧啶在肝癌、肝组织及血浆中的浓度差异

背景与目的:肝动脉、肝门静脉灌注区域化疗是肝癌的重要治疗手段,本研究探讨区域性灌注化疗时氟尿嘧啶(fluorouracil,5-FU)在大鼠肝癌和肝脏组织及血浆中的分布,为临床肝脏肿瘤化疗提供参考。方法:将24只荷瘤大鼠随机分为4组,分别经外周静脉(尾静脉)、肝动脉、肝门静脉或结扎肝动脉后经肝门静脉灌注5-FU,剂量为20 mg/kg。采用高效液相色谱法测定肝癌、肝脏组织及血浆中5-FU的含量,并计算药物在血浆、肝脏和肝癌组织间的穿透比率。结果:结扎肝动脉的肝门静脉组5-FU浓度在肝脏和肝癌组织中最高,分别为(22.1±9.5)μg/g和(16.4±7.2)μg/g;其次为肝动脉组;肝门静脉组5-FU浓度在肝癌组织中的浓度较低,为(8.9±3.7)μg/g;外周静脉组5-FU浓度在肝脏和肝癌组织中的药物浓度均为最低,肝癌组织中的浓度仅为(4.3±2.2)μg/g。在血浆中的5-FU浓度正好相反,外周静脉组浓度最高(26.8±12.5)μg/m L,肝动脉组(16.4±9.7)μg/m L、结扎肝动脉的肝门静脉组(15.9±10.1)μg/m L和肝门静脉组(14.9±8.5)μg/m L等3组浓度相近,均明显低于外周静脉组(P<0.05)。5-FU的肝癌/血浆穿透比率依次为结扎肝动脉的肝门静脉组(103.47%),肝动脉组(92.94%),肝门静脉组(59.58%)和外周静脉组(16.08%)。结论:与外周静脉注射全身化疗比较,区域性灌注化疗可显著提高肝癌和肝脏组织中的药物浓度,同时减少化疗药物在外周血中的分布,其中经结扎肝动脉的肝门静脉灌注和经肝动脉灌注是肝癌区域性化疗2种较好的途径。     

比较卡铂盆腔动脉化疗栓塞与单纯动脉灌注化疗的动物实验研究

背景与目的:动脉灌注化疗与动脉栓塞可提高肿瘤组织局部药物浓度和延长药效时间,但哪一种方法在临床药代动力学上更有优势,目前尚无定论.本研究的目的是比较超液态碘油卡铂盆腔动脉化疗栓塞与卡铂单纯动脉灌注化疗后,犬子宫组织及血浆中铂(Pt)离子浓度的分布.方法:选择实验用雌犬14只,随机分为盆腔动脉化疗栓塞组(A组)7只和盆腔动脉单纯灌注组(B组)7只.A、B组分别将卡铂(12 mg/kg)溶于超液态碘油(0.2 ml/kg)和5%葡萄糖(0.2 ml/kg)中,注入双髂内动脉.然后在不同的时间点分别取子宫组织及静脉血,用原子吸收光谱法测定上述标本内的Pt离子浓度.结果:(1)A、B两组子宫组织Pt离子浓度曲线均为单峰曲线,峰值分别为(215.0±17.6)μg/g和(211.3±40.1)μg/g,两组无显著性差异(P＞0.05).(2)A、B两组子宫组织Pt离子药时曲线下面积(AUC0～240min)分别为(13.9±3.9)mg·min·g-1和(5.9±0.6)mg·min·g-1,两组有显著性差异(P＜0.01).(3)A、B两组血浆中Pt离子峰值分别为(8.7±12.5)μg/g和(16.7±3.6)μg/g,AUC0～240min分别为(0.5±0.1)mg·min·g-1和(1.2±0.4)mg·min·g-1,均有显著性差异(P＜0.01).结论:与卡铂单纯动脉灌注化疗相比,动脉化疗栓塞能有效提高并保持局部组织内的Pt浓度,降低血浆中Pt浓度,从而提高局部化疗效果、降低全身毒副作用.     

脉冲式灌注60℃盐水对兔肝VX2肿瘤血管渗透性的影响

[目的]探讨60℃盐水经脉冲式灌注肝组织及肿瘤组织对其血管渗透性的影响。[方法]建立兔VX2移植性肝癌模型30只．随机等分为3组（37℃盐水组、60℃盐水连续灌注组及60℃盐水脉冲式灌注组），各组经导管推注1％Evarls Blue（EB），2ml／kg，并分别测出3组相应的含量。[结果]灌注EB 10min后，60℃脉冲式灌注组肿瘤组织EB含量15．21±0．94μg／100mg，与60℃连续灌注组（10．71±0．84μg／100mg）相比有差异（P〈0．05）．与37℃灌注组（3．42±0．87μg／100mg）相比有差异（P〈0．01）。60℃脉冲式灌注组正常组织EB含量（8．23±0．86μg／100mg）与60℃连续灌注组（7．10±0．65μg／100mg）相比无差异（P〉0．05），但与37℃灌注组2．68±0．73μg／100mg相比有差异（P〈0．05）。60℃脉冲式灌注组肿瘤组织（43℃～45℃）持续时间12.3±3．3min，与60℃连续灌注组5．7±2．5min相比有差异（P〈0．05）。[结论]60℃脉冲式灌注热疗可以增加肝组织及肿瘤组织的血管渗透性，是一种有效的介入热疗方法。     

家兔肝动脉与耳缘静脉注入羟基喜树碱的药代动力学特征的比较

目的：探讨经耳缘静脉及肝动脉注入羟基喜树碱（10-Hydroxycamptothecine，HCPT）后，家兔血浆、肝组织中的HCPT浓度随时间变化趋势及其药代动力学特征。方法：家免84只随机分为2组，按5mg／kg分别经耳缘静脉或肝动脉注入HCPT后，于不同时间点取外周血和肝组织。血浆及肝组织匀浆经甲醇沉淀处理后，采用UV—HPLC法测定HCPT浓度，计算并比较2种途径给药后血浆及肝匀浆的HCPT药动学参数。结果：建立的测定生物样本中HCPT的UV-HPLC检测法，在80～512μg／L线性关系良好，定量下限为80μg／L，相对回收率为95．4％～103．6％，日内及日间差异RSD均〈7．5％，符合生物样本分析的有关要求。肝动脉灌注HCPT与耳缘静脉注射HCPT相比较，血浆、肝匀浆HCPT的药代动学参数Cmax、AUC（0-tn）、AUC（0-∞）、T（1/2α）、T（1/2β）、CL、MRT（0-tn）和MRT（0-∞）均差异有统计学意义，P值均〈0．01。结论：UVHPLC检测法简捷、灵敏、准确，适用于生物样本的HCPT浓度测定及药代动力学研究。经肝动脉灌注治疗原发性肝癌较静脉注入HCPT可取得更好的治疗效果，并减轻其不良反应。     

热盐水灌注对兔肝VX2肿瘤血管内皮细胞的影响

目的：研究将60℃生理盐水经肝动脉灌注兔肝VX2肿瘤对肿瘤血管内皮细胞及通透性的影响。方法：20只VX2肝荷瘤兔,随机分为2组,分别经兔肝动脉灌注37℃生理盐水60ml（对照组）、60℃生理盐水60ml（治疗组）。灌注后再经导管推注1% Evans Blue （EB）,2ml/kg。24小时后处死荷瘤兔,取小块瘤组织,称重后,放入1ml甲酰胺液中,置于50℃恒温水浴箱60h,提取液用722型光栅分光光度计测出620nm下的OD值,从标准曲线上测出相应的伊文思蓝含量,以反映该组织血管的通透性。切取肿瘤边缘血管组织包埋,行电镜检查观察肿瘤血管内皮细胞形态变化。结果：60℃生理盐水灌注组肿瘤组织EB含量［（10.71±0.84）μg/100mg］与37℃灌注组［（3.42±0.87）μg/100mg］相比有差异（P〈0.01）。电镜观察热灌注组肿瘤血管内皮细胞,细胞间隙增大。结论：60℃灌注可增大肿瘤内皮细胞间隙从而增加肝肿瘤组织的血管通透性。     

经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点

目的研究经门静脉途径灌注化疗时5-Fu在肝脏和血液中的浓度和药动学特点,并与外周静脉注射化疗相比较,探讨区域性门静脉灌注化疗的优势。方法 24只Wistar大鼠随机分组后分别经门静脉插管区域灌注及经外周静脉注射5-Fu,剂量均为20 mg/kg。采用高效液相色谱法(HPLC)测定两组给药后5、10、20、30、45、60、90、120、180 min不同时间点血浆和肝脏组织中5-Fu的浓度,对比两组5-Fu在肝脏和血浆中的药动学数据。对比两组的穿透比率、穿透指数及治疗优势度。结果经外周静脉注射5-Fu时,肝脏组织中的药物峰浓度(Cmax)和药物时量曲线下面积(AUC)分别为(13.79±4.56)μg/g及(342.20±108.20)μg·h/ml;血浆中的Cmax和AUC分别为(36.85±5.96)μg/g及(842.00±158.00)μg·h/ml。经门静脉灌注时,肝脏组织中的Cmax和AUC分别为(28.21±4.46)μg/g及(733.60±180.30)μg·h/ml;血浆中的Cmax和AUC分别为(21.02±4.06)μg/g及(529.80±111.50)μg·h/ml。门静脉灌注化疗与外周静脉注射相比的治疗优势度为3.37。结论与外周静脉注射全身化疗比较,区域性门静脉灌注5-Fu化疗可显著提高肝脏组织中的药物时-量作用强度,同时减少化疗药物在外周血中的分布,可作为肝癌化疗有效的给药途径     

CXY-001单次给药和反复给药的毒代动力学研究

背景与目的： 通过CXY-001药物在犬体内的毒代动力学的研究,探讨单次给药及反复给药的药物毒性反应与药物暴露量的相关性。 材料与方法： 分别对Beagle犬经口单次给予不同剂量的CXY-001药物,及反复给予不同剂量的CXY-001药物后,采用液相色谱-质谱-质谱(EC-MS-MS)方法检测犬血清中药物浓度,及观察犬的毒性反应。单次给药试验：给药剂量为227、511、767、1150 mg/kg,每个剂量用1只Beagle犬试验,分别于给药后0.5、1、2、3、4、5、6、8、24 h采血。反复给药试验：给药剂量分别为120、30、 7 mg/kg,连续给药90 d,停药后恢复期观察4周。首次给药后分别于0.5、1、2、3、4、5、6、8、24 h采血;给药中期(第45 d)采血点为药后0.5、5、24 h;末次给药(第90 d)后采血点分别为药后0.5、5、24、48、72和96 h,每组采血动物数为3只。 结果： 单次给药后Beagle犬主要反应为呕吐,227、511、767、1 150 mg/kg 4个剂量组单次给药AUC0-24依次为150 249、263 905、232 640和19 848 ng•h/ml;犬血清中AUCO-∞分别为151 054、 298 069、246 083和117 793 ng•h/ml;Cmax分别为13 400、19 500、29 100和6 910 ng/ml。反复给药120、30、7 mg/kg 3个剂量组首次给药后AUC0-24分别为(123 023±75 308)、(19 246±14 654)和(2 991±996) ng•h/ml,AUC0-∞分别为(200 189±106 688)、(25 145±22 443)和(4 650±1 855) ng•h/ml,Cmax分别为(10 440±5 891)、(3 653±1 776)和 (376±116) ng/ml,第45 d、第90 d相同时间点各组的血药浓度值有一定的波动,药后48 h动物体内血药浓度已低于检测线。仅30 mg/kg剂量组未见毒性作用。 结论： Beagle犬经口给予CXY-001后,在一定剂量范围内(约<600 mg)犬血清中Cmax、AUC0-24和AUC0-∞随着剂量的增加而增加;反复给药于停药后药物清除较快,提示该药连续给药后可能无蓄积作用。     

术前动脉灌注化疗对大肠癌微血管密度的影响

目的　分析评价术前动脉灌注化疗对大肠癌生物学行为的影响 ,并探讨术前动脉灌注化疗对肿瘤细胞影响的作用机制。方法　 2 8例 (同意入组研究 )大肠癌患者随机分成术前动脉灌注化疗组 (12例 )和对照组 (16例 )。术前动脉灌注化疗采用动脉造影技术 ,经肿瘤营养动脉给予 5 Fu10 0 0mg ,表阿霉素 6 0mg ,丝裂霉素 10mg。全部患者均接受手术治疗 ,切除标本分别行常规病理检查及免疫组织化学染色 (Ⅷ因子相关抗原染色 )测定大肠癌组织微血管密度 (MVD)。微血管密度计数采用Weidner方法分别计数癌中心、癌黏膜表面及癌旁组织的微血管数。结果　术前动脉灌注化疗组大肠癌组织中心、癌黏膜表面及癌旁组织的MVD分别为 40 .46± 7.0 6、5 2 .2 7± 18.40和 49.92± 8.15 ;对照组大肠癌组织中心、癌黏膜表面及癌旁组织的MVD分别为 46 .0 9± 12 .2 1、73.44± 2 2 .0 6和5 1.94± 12 .6 4。两组之间癌黏膜表面的MVD值差异有显著性 (P <0 .0 5 ) ,癌旁组织及癌中心组织MVD差异无统计学意义。结论　术前动脉灌注化疗可以降低大肠癌组织黏膜表面的微血管密度。     

孚贝联合肝动脉灌注治疗大肠癌肝转移的临床观察

为研究孚贝 (卡莫氟 )联合肝动脉灌注对大肠癌肝转移疗效及不良反应 ,对 40例不能手术切除的肝转移患者行大肠癌根治术加孚贝联合肝动脉灌注化疗和肝动脉加门静脉灌注化疗。全部患者随机分为两组 ,观察组 :孚贝联合肝动脉灌注化疗 2 0例 ;对照组 :肝动脉加门静脉灌注化疗 2 0例中 15例合格病例。观察组肝转移灶CR 1例 ,PR12例 ,近期有效率 65 0 % ( 13 /2 0 )。对照组CR 1例 ,PR 9例 ,近期有效率 66 7% ( 10 /15 )。 1、2、5年生存率观察组分别为 90 0 % ( 18/2 0 )、65 0 % ( 13 /2 0 )、2 5 0 % ( 5 /2 0 ) ;对照组为 93 3 % ( 14 /15 )、66 7% ( 10 /15 )、2 6 7% ( 4 /15 )。初步研究结果提示 ,口服孚贝联合肝动脉灌注化疗是治疗大肠癌肝转移的有效方法     

肝动脉门静脉双灌注化疗治疗晚期肝癌

对 18例不能手术切除的晚期肝癌患者 ,行肝动脉门静脉插管 ,皮下埋藏灌注器 ,经灌注器穿刺灌注化疗药物 (卡铂 40 0mg、丝裂霉素 10mg、阿霉素 3 0mg) ,其中总剂量的 3 /4行肝动脉灌注 ,1/4行门静脉灌注 ,经两次局部化疗后 ,10例(5 5 6% ,10 /18)自觉症状明显改善 ,11例 (62 5 % ,11/18)B超显示肿瘤变小或被“击碎”。结果提示肝动脉门静脉双插管灌注化疗以 1～ 2次疗效为好 ,以后再用药效果欠佳。平均生存 4 3个月 ,与未经治疗的肝癌患者生存期相比有所延长     

Effects of D-galactosamine hydrochloride and partial hepatectomy on spontaneous hepatic injury and hepatocarcinogenesis in Long-Evans Cinnamon rats.

To examine the effect of nongenotoxic chemicals on hepatocarcinogenesis in Long-Evans Cinnamon (LEC) rats, we gave 6-week-old male and female LEC rats (n = 18) weekly subcutaneous injections of D-galactosamine hydrochloride (GalN, 300 mg/kg) in 0.9% NaCl or only 0.9% NaCl for 50 weeks, and killed them in week 62. GalN-treated male rats unexpectedly showed no lethal necrotizing hepatitis. GalN treatment increased the incidence of cholangiofibrosis in males and its severity in females, but did not cause significant increases of hepatocellular tumors in either sex. GaIN treatment increased the 5-bromo-2'-deoxyuridine (BrdU)-labeling index of hepatocytes and plasma hepatocyte growth factor, and accelerated megalocytic alterations without reduction of the hepatic copper concentration. Next, male and female LEC rats were subjected to two-thirds partial hepatectomy (PH) or sham hepatectomy in week 8 (n = 12) or in week 14 (n = 9), and killed in week 62. PH in week 14 inhibited lethal hepatitis, but PH in week 8 was less effective. PH reduced the hepatic copper concentration to half that of controls. The present data suggest that induction of hepatocyte regeneration by repeated injections of GalN, or by PH just before the onset of jaundice has a significant effect in prevention of hepatic injury of LEC rats, but not enhancement of spontaneous hepatocarcinogenesis.     

维拉帕米的凋亡相关研究

第1代肿瘤耐药逆转剂维拉帕米(VER)可以单独作用或与物理、化学因素协同作用来影响肿瘤与正常细胞凋亡。VER身兼诱导凋亡与保护细胞免于凋亡的双重功能,这两种截然相反的作用因动物模型、疾病类型、细胞系及体内外环境而异。近年研究证实,VER通过影响药泵蛋白的活性或细胞内钙离子浓度等方式来发挥凋亡相关作用。     

维拉帕米的凋亡相关研究

第1代肿瘤耐药逆转剂维拉帕米（VER）可以单独作用或与物理、化学因素协同作用来影响肿瘤与正常细胞凋亡。VER身兼诱导凋亡与保护细胞免于凋亡的双重功能，这两种截然相反的作用因动物模型、疾病类型、细胞系及体内外环境而异。近年研究证实，VER通过影响药泵蛋白的活性或细胞内钙离子浓度等方式来发挥凋亡相关作用。     

Inhibition of macrophage- and neutrophil-mediated cytotoxicity by verapamil

Peripheral blood monocyte-derived macrophages and polymorphonuclear leukocytes (PMNs) obtained from normal donors kill tumor cells in vitro. However, if verapamil is added to the macrophages or neutrophil tumor cell suspensions in microgram concentrations (0.1 microgram to 0.1 mg), there is marked inhibition of tumor cell killing. The inhibitory effect for the macrophages resulted from an effect of verapamil on both the effector and target cells. When either the effector cells or target cells were preincubated with verapamil, they became resistant to the effects of the cytotoxic macrophages. Cytotoxicity was also inhibited when 0.1 mg of verapamil was added to the macrophages monolayers either at the time of addition of the tumor cells or 15-30 min after addition of the tumor cells, whereas no inhibition of cytotoxicity occurred when verapamil was added more than 30 min after the initiation of the cytotoxic reaction. For the neutrophils it was observed that the inhibitory activity resulted from an effect of verapamil on the effector cells rather than the target cells. When the effector cells were preincubated with verapamil they became incapable of killing the tumor cells, whereas preincubation of the target cells with verapamil had no effect on their ability to be killed by the neutrophils. Cytotoxicity was also inhibited when 0.1 mg of verapamil was added to the neutrophil monolayers either at the time of addition of the tumor cells or 15-60 min after addition of the tumor cells, whereas no inhibition of cytotoxicity occurred when verapamil was added more than 60 min after the initiation of the cytotoxic reaction.     

Reversal mechanism of multidrug resistance by verapamil: direct binding of verapamil to P-glycoprotein on specific sites and transport of verapamil outward across the plasma membrane of K562/ADM cells

The calcium channel blocker verapamil has been shown to reverse multidrug resistance (T. Tsuruo et al., Cancer Res. 41: 1967-1972, 1981), but the mechanism of action of this agent has not been fully elucidated. A radioactive photoactive analogue of verapamil, N-[benzoyl-3,5-3H-(+/-)-5-[(3,4-dimethoxyphenetyl)methylamino]-2- (3,4-dimethoxyphenyl)-2-isopropyl-N-p-azidobenzoylpentylamine, was used to label the plasma membranes of a human myelogenous leukemia cell line (K562), a multidrug-resistant subline selected for resistance to Adriamycin (K562/ADM) and its revertant cell (R1-3). Sodium dodecyl sulfate-polyacrylamide gel electrophoretic fluorograms revealed the presence of an intensely radiolabeled Mr 170,000-180,000 protein in the membranes from K562/ADM but not from the drug-sensitive parental K562 and revertant R1-3 cells. The Mr 170,000-180,000 verapamil acceptor was immunoprecipitated by monoclonal antibody MRK16 specific for P-glycoprotein associated with multidrug resistance, indicating that P-glycoprotein in the plasma membrane is a major target of verapamil in K562/ADM cells. The photolabeling of P-glycoprotein with N-[benzoyl-3,5-3H]-(+/-)-5-[(3,4-dimethoxyphenetyl)methylamino]-2- (3,4-dimethoxyphenyl)-2-isopropyl-N-p-azidobenzoylphentylamine was significantly blocked by other calcium channel blockers, nicardipine and diltiazem, that have been shown to overcome multidrug resistance. In addition, the photolabeling was partially blocked by Adriamycin, vincristine, and colchicine, suggesting that the specific binding sites for verapamil on P-glycoprotein are closely related to the binding sites for these calcium channel blockers and antitumor agents. To determine whether verapamil could be a substrate for P-glycoprotein, the cellular accumulation of [3H]verapamil into K562 and K562/ADM was evaluated. The accumulation of [3H]verapamil in the multidrug-resistant cells was 30% of K562 cells and increased when K562/ADM cells were treated with vincristine and nicardipine at 5 microM, indicating that the P-glycoprotein transports verapamil as well as other antitumor agents in the multidrug-resistant cells. These results suggest that verapamil enhances antitumor agent retention through competition for closely related binding sites on P-glycoprotein.     

Calcium and P-glycoprotein independent synergism between schweinfurthins and verapamil

Schweinfurthins are intriguing natural products with anti-cancer activities and as yet incompletely understood mechanisms of action. We investigated whether inhibitors of P-glycoprotein (Pgp), in a manner analogous to other natural products, might enhance schweinfurthins'' growth inhibitory actions by increasing intracellular schweinfurthin levels. Both the schweinfurthin-sensitive glioblastoma multiforme cell line SF-295 and relatively insensitive lung carcinoma cell line A549 were treated with 2 schweinfurthin analogs: 3-deoxyschweinfurthin B-p-nitro bis-stilbene (3dSB-PNBS) and 5′-methylschweinfurthin G (methyl-G). There was a synergistic enhancement of growth inhibition with the combination of the Pgp inhibitor verapamil and both analogs in SF-295 cells. Methyl-G, verapamil, and the combination did not result in alterations to intracellular calcium concentration. Verapamil increased the intracellular concentration of 3dSB-PNBS in both SF-295 and A549 cells in a Pgp-independent manner. Methyl-G, verapamil, and the combination do not result in increased ER stress. Methyl-G increased the intracellular concentration of a known Pgp substrate, Rhodamine 123 in SF-295 cells. Reduction of cellular cholesterol leads to the accumulation of Pgp substrates, as Pgp requires cholesterol for proper function. Since 3dSB enhances lovastatin-induced upregulation of the cholesterol efflux pump ABCA1, it is intriguing that co-treatment with cholesterol rescued the methyl-G-induced increase in Rhodamine 123 intracellular concentration. These studies support the hypothesis that verapamil potentiates the schweinfurthin growth inhibitory effect by increasing its intracellular concentration.     

A case of intractable hepatic encephalopathy successfully treated by oral administration of vancomycin hydrochloride, with subsequent improvement of hepatic function reserve enabling transcatheter arterial chemoembolization against hepatocellular carcinoma

We report a case of an 80-year-old male who suffered from intractable hepatic encephalopathy and hepatocellular carcinoma( HCC), associated with hepatitis type C-related liver cirrhosis. He was unable to receive HCC treatment due to the deterioration of his liver. His hepatic encephalopathy was resistant to oral administration of laxatives, lactulose, and kanamycin sulfate, etc. His blood ammonia concentration averaged about 130 mg/dL, and often exceeded 200 mg/dL(normal range: <80 mg/dL). Later, an oral administration of vancomycin hydrochloride, 0. 5 g once every 3 days, was initiated. Soon after ward, his blood ammonia concentration declined to the normal range(about 50 mg/dL), and the clinical symptoms of hepatic encephalopathy showed a remarkable improvement. By the continuation of vancomycin administration, the normalization of his state of consciousness was achieved, improving his quality of life, and his activities of daily living. Three months after beginning treatment, he was able to receive transcatheter arterial chemoembolization for the treatment of HCC, because his liver function reserve improved(Child-Pugh score decreased from 10 to 7).     

Effects of verapamil on the pharmacokinetics and metabolism of epirubicin

Summary Experimental data suggest that multidrug resistance in cancer may be overcome by using an increased dose of anticancer agent(s) in combination with a resistance-modifying agent (RMA). We studied the pharmacokinetics and metabolism of both epirubicin (EPI) and verapamil (VPL) to explore the possible pharmacokinetic interactions between these two drugs. Ten patients with advanced breast cancer were given EPI (40 mg/m² in a daily i.v. bolus for 3 consecutive days), and five of them also received VPL (4×120 mg/daily p.o. for 4 consecutive days). The data indicated a significant interaction between these two drugs that affected their metabolism. The areas under the concentration-time curves (AUC) obtained for epirubicin glucuronide, epirubicinol glucuronide, and both of the 7-deoxy-aglycones were higher in the EPI+VPL group as compared with the EPI group. The AUC, terminal half-life, mean residence time, volume of distribution at steady state, and plasma clearance of EPI alone as compared with EPI+VPL did not differ significantly. These results suggest either an induction of enzymes necessary for drug metabolism or an increase in the liver blood flow, resulting in an enhanced generation of metabolites with time or in an inhibition of excretion processes. Comparisons of the AUC values obtained for EPI and its metabolites after the first, second, and third injections of EPI revealed a cumulative effect for the metabolites that was more pronounced in the EPI+VPL group, being significant (P<0.05) for epirubicin glucuronide in both treatment groups and for epirubicinol glucuronide in the EPI+VPL group. Maximal concentrations of VPL and nor-VPL reached 705±473 and 308±122 ng/ml, respectively, with the steady-state concentrations being 265±42 ng/ml for VPL and 180±12 ng/ml for nor-VPL.This study was supported by the Erich und Gertrud Roggenbuck-Stiftung zur Förderung der Krebsforschung (Hamburg). The anthracycline metabolites were kindly provided by Dr. A. Suarato (Farmitalia, Milano, Italy); nor verapamil was provided by Dr. Traugott (Knoll, Ludwigshafen, Germany)     

盐酸哌替啶片与盐酸羟考酮控释片针对癌痛的镇痛效果对比

目的:比较盐酸哌替啶片与盐酸羟考酮控释片在癌痛镇痛中效果和不良反应.方法:43例中重度癌痛患者随机分为两组分别给予盐酸羟考酮控释片与盐酸哌替啶片,观察2周,对比两种药物的镇痛效果,不良反应等情况.结果:羟考酮组患者疼痛缓解20例,有效率90.91％.哌替啶组患者疼痛缓解16例,有效率76.19％.两组缓解率比较,有显著性差异(P＜0.05).两组患者用药后生活质量均得到明显提高(P＜0.05),两组药物的不良反应对比显示,盐酸哌替啶片的成瘾性强(P＜0.05),其余不良反应两组均未见差异(P＞0.05).结论:盐酸羟考酮控释片在治疗癌痛时镇痛效果优于盐酸哌替啶片,患者生活质量较好.