柔红霉素在白血病患儿体内的药代动力学与疗效和毒副反应的相关性研究

目的 研究柔红霉素(DNR)在急性白血病(AL)患儿体内的药代动力学,探讨DNR药代动力学与化疗疗效和毒副反应的相关性.方法 (1)采用高效液相色谱-荧光检测法(HPLC-FR),测定20例AL患儿开始静脉滴注DNR后24 h内不同时点DNR血药浓度,研究其药代动力学.(2)在化疗不同阶段监测骨髓象、外周血白细胞、心电图、超声心动图、心肌酶谱、肝肾功能等指标.结果 (1)DNR在血中以二房室模型衰减,静脉滴注DNR后,血药浓度1～3 h达高峰,峰浓度(Cmax)为63.50 ug/L,平均血浆峰值时间(Tmax)为1.45 h,静脉滴注结束后又迅速降至11.52 ug/L,并维持这一低水平.DNR药代动力学在AL患儿体内个体间差异非常大.清除率(CL)最高值为最低值的9倍,曲线下面积(AUC)为8倍,Cmax为5倍.(2)①CL:男性为57.99 L/(h·m2),女性为93.71L/(h·m2),男性明显低于女性(P<0.05).②Tmax:>6岁组为1.1 h,≤6岁组为1.8 h(P<0.05);Cmax:>6岁组为90.77 ug/L,≤6岁组为57.44 ug/L(P<0.05).结论 (1)DNR在儿童体内的药代动力学个体差异很大,提示治疗效应也可能存在个体差异,需要药物监测.(2)男性及>6岁组对DNR的生物利用度高,代谢清除慢,提示男性及>6岁组可能更易出现毒副反应,可适当减少用量.     

柔红霉素诱导治疗急性白血病患儿前后血浆脑钠素变化的意义

目的观察柔红霉素(DNR)化疗后急性白血病(AL)患儿血浆脑钠素(BNP)水平及心脏功能指标改变,以探讨BNP水平变化早期评价DNR对心脏功能影响的意义。方法选择急性淋巴细胞性白血病(ALL)患儿,应用DNR 长春新碱 左旋门冬酰胺酶 泼尼松(DVLP)方案诱导化疗31例,应用DNR前后采用酶联免疫吸附试验(ELISA)测定其血浆BNP水平,采用彩色多普勒超声测定左心室舒张末期直径(LVEDD),常规检测化疗前后心电图(ECG)及心肌酶谱(LDH1、CK-MB)。结果ALL患儿应用DNR化疗后血浆BNP水平从(3.97±2.41)ng/L升高至(18.25±7.63)ng/L(P<0.01)。LVEDD也从(50.1±1.9)mm增加至(53.9±2.3)mm(P<0.05)。BNP水平升高和LVEDD增加呈正相关(r=0.61 P=0.005)。而ECG、心肌酶谱治疗前后均无显著改变。结论血浆BNP水平可作为早期监测DNR对ALL患儿心脏功能影响指标之一。     

柔红霉素与扩张型心肌病(附四例报告)

急性白血病是小儿时期较常见的恶性疾病,病势凶险,病死率高。近来由于联合化疗方案的改进,尤其是柔红霉素(DNR)及左旋门冬酰胺酶是近年推荐的化疗方案中关键药物,对于减少白血病的复发,延长无病生存时间至关重要。但随着DNR等蒽醌类抗生素的应用,其毒副作用,尤其是心脏毒性日渐被人们认识。心肌毒性主要表现为心肌损害,导致充血性心力衰竭,最终形成扩张型心肌病,造成不可逆的毒性改变。我院近年来先后接诊了4例小儿急性白血病应用含有DNR化疗方案后发生扩张型心肌病伴重度心力衰竭的病例,其中3例为外院转诊患儿。1　临床资料4例患儿均通…     

铁剥夺对 DNR诱导 K562细胞多药耐药基因表达的影响

目的 探讨铁剥夺对柔红霉素（DNR）诱导多药耐药基因MDR1表达的影响。方法 以柔红霉素单用或联合应用去铁胺（DFO）或二氯化铁（FeCl3）为处理因素作用于人红白血病细胞株K562,应用RT—PCR法、流式细胞分析技术,检测K562细胞多药耐药基因信使核糖核酸（MDR1mRNA）和P-糖蛋白（Pgp）表达的情况。结果 ①与空白对照组相比,柔红霉素（1μmol／L）作用24h可使MDR1／Pgp表达增加（P〈0．05）;②与单用DNR组相比,DFO可显著抑制柔红霉素诱导的MDR1／Pgp的表达,而FeCl3的作用相反（P〈0．05）。结论 柔红霉素短期作用可诱导MDR1表达,提示化疗药本身的诱导作用在肿瘤多药耐药产生中发挥重要作用。铁剥夺可减少柔红霉素诱导的MDRI／PgP表达,而FeCl3的作用相反,提示铁剥夺有可能成为阻止或降低白血病化疗耐药的新的措施之一,而白血病化疗患者补铁应慎重。     

柔红霉素与扩张型心肌病（附四例报告）

急性白血病是小儿时期较常见的恶性疾病，病势凶险，病死率高。近来由于联合化疗方案的改进，尤其是柔红霉素(DNR)及左旋门冬酰胺酶是近年推荐的化疗方案中关键药物，对于减少白血病的复发，延长无病生存时间至关重要。但随着DNR等蒽醌类抗生素的应用，其毒副作用，尤其是心脏毒性日渐被人们认识。心肌毒性主要表现为心肌     

去铁胺对K562细胞多药耐药基因MDR1及核因子κB表达的影响

目的 探讨去铁胺对柔红霉素（DNR）诱导多药耐药基因MDR1及核因子KB（NFκB）表达的影响，初步了解NFKB与MDR1表达、细胞内铁代谢的关系。方法 以DNR单用或联合应用25μmol／L去铁胺（DFO）为处理因素作用于人红白血病细胞株K562，应用RT-PCR法、流式细胞分析技术分别检测对照组、DNR组和DNR＋DFO组K562细胞MDRlmRNA和P糖蛋白（PgP）的表达情况，同时采用免疫组织化学染色法检测NFKBκB表达及活性情况。结果 与对照组相比，DNR可同时诱导MDRlmRNA、Pgp表达和NFgB活化（P〈0．05）；25μmol／LDFO联合DNR可显著抑制DNR诱导的MDRlmRNA、Pgp的表达及NFKB的活化（P〈0．05）。结论 去铁胺可减少柔红霉素诱导的MDRl、PgP表达，其机制可能与铁剥夺后降低了柔红霉索诱导的K562细胞的氧化应激反应，进而影响NFκB的活化有关。     

应用二维斑点追踪成像技术监测急性淋巴细胞白血病柔红霉素化疗患儿左室扭转功能探讨

探讨应用二维斑点追踪成像技术监测柔红霉素化疗对急性淋巴细胞白血病（急淋）患儿左心室短轴心肌扭转功能的影响,分析心脏功能损伤与柔红霉素不同累积剂量的关系。方法　研究对象为2007年1月至2009年12月深圳市儿童医院诊断的急淋患儿60例,均接受柔红霉素化疗,按治疗程序分为A组（化疗前）、B组（柔红霉素化疗累积剂量达120 mg/m2）和C组（柔红霉素化疗累积剂量达240 mg/m2）。对照组为同期体检正常儿童60名。检测每组常规超声心动图指标左室射血分数（EF）、二尖瓣口舒张期血流比值（E/A）,并应用超声二维斑点追踪成像技术（two-dimensional speckle tracking imaging,2DSI）检测对照组及A、B、C组的左室短轴基底段和心尖段的心肌节段收缩期峰值旋转度,计算左室心肌收缩期峰值扭转角度。结果　心率、EF、二尖瓣口舒张期E/A比值在对照组、A、B、C各组间比较,差别无统计学意义（P > 0.05）。A、B组与对照组比较,基底段和心尖段的峰值旋转角度差异无统计学意义（P > 0.05）;C组与对照组比较心尖段峰值旋转角度,差异无统计学意义（P > 0.05）; C组与对照组、A组、B组比较,基底段峰值旋转角度差异有统计学意义（F＝5.23, P < 0.05）。A、B组与对照组比较,左室扭转角度差异无统计学意义（P > 0.05）,但C组小于对照组、A组、B组,差异有统计学意义（F＝4.51, P < 0.05）。结论　急淋患儿柔红霉素化疗累积剂量达120 mg/m2时未发现心脏扭转功能损伤,当达到240 mg/m2时,心脏扭转功能出现显著损伤,2DSI可无创性定量监测患儿心脏功能的变化,对临床评价柔红霉素的心脏毒性、预防化疗后遗症的发生有重要意义。     

柔红霉素对白血病儿童心脏毒性的研究进展

白血病是小儿时期最常见的恶性肿瘤 ,柔红霉素是小儿白血病联合化疗中的基本药物。由于柔红霉素易诱发不可逆性心脏毒性 ,因而限制了它的临床应用。 30多年来国内外学者对此进行了大量的临床观察和实验研究 ,对心脏毒性进行分类 ,对相关危险因素进行了研究 ,从细胞水平和分子水平阐述其发病机制 ,提出有效的防治措施 ,从各个环节减少心脏毒性发生 ,提高生存质量 ,延长患儿生命。     

急性白血病患儿柔红霉素化疗致心肌损害时血清硫化氢水平的变化

目的 探讨急性白血病(AL)患儿柔红霉素(DNR)化疗致心肌损害时血清硫化氢(H2S)水平变化.方法 2008年10月-2011年6月本院儿童血液科住院的AL患儿共159例,中位年龄7岁.均行禽DNR方案化疗,采用敏感硫电极法测定其化疗前后血清H2S水平变化,分析在不同DNR累积剂量时心肌细胞损害与H2S的关系.结果 随着DNR累积剂量的增加,心肌损害的发生率亦随之增高(Pa＜0.05),血清H2S水平亦随之增加.中剂量组患儿血清H2S水平较低剂量组升高,差异有统计学意义(P＜0.05)；而高剂量组血清H2S水平较中剂量组进一步升高,差异有统计学意义(P＜0.01).心肌损害组血清H2S水平较无心肌损害组显著升高,差异有统计学意义(P＜0.01).对心肌损害组和无心肌损害组血清H2S水平进行ROC曲线分析,ROC曲线下面积为0.929 (95％ CI0.857 ～ 1.000).以假阳性率(1-特异性)2.8％为诊断点,血清H2S诊断心肌损害的诊断点为128.09 μmol·L-1,以此诊断的敏感性为83.3％,特异性为97.2％.对心肌损害患儿进行回顾性分析发现,DNR剂量达中剂量以上心肌细胞尚未受损时,其血清H2S水平已显著升高.以128.09 μmol·L-1为临界点,血清H2S水平升高的患儿其进一步化疗心肌损害的发生率亦显著升高.结论 血清H2S水平可反映心肌细胞的损害程度,是早期监测心肌细胞受损的有效指标.     

超声检查评价柔红霉素对急性白血病患儿左心室功能的影响

采用彩色超声诊断仪对以柔红霉素（DNR）为主要药物治疗的53例急性白血病（AL）患儿和30例健康儿童的左心室功能（LVF）进行测定，发现AL患儿治疗前的LVF与健康儿童无差异（P＞0．1），DNR治疗后，当DNR累积剂量达到（120～20）mg／m2时，AL患儿的左心室舒张功能（LVDF）较治疗前明显受损（P＜0．05）。当DNR累积剂量达到360mg／m2以上时，LVDF受损进一步加重，并伴有左心室收缩功能（LVSF）受损（P＜0．01〕。结果提示：DNR可影响AL患儿的LVF，且LVDF受损较LVSF受损为早，彩色超声检查可作为DNR治疗AL时心脏毒性监测的可靠方法。     

雷公藤、盐酸小檗碱及柔红霉素在MOLT-4细胞中的药物作用及不同噻唑蓝法比较

目的研究雷公藤多甙、盐酸小檗碱及柔红霉素(DNR)对急性T淋巴细胞白血病细胞株MOLT-4细胞的细胞毒性作用,比较传统MTT法及改良MTT法在检测药物对悬浮细胞细胞毒性方面差异。方法分别用传统MTT法、改良MTT法检测不同药物浓度作用时MOLT-4细胞的存活率。结果改良MTT法组内变异指数在0~0.2,而传统MTT法在0.2~0.6,改良法同组内差异明显小于传统法;药物作用24h后细胞存活率:单独DNR(1mg/L)为36.36%,DNR与雷公藤(10mg/L)合用时为14.81%,DNR与盐酸小檗碱(10mg/L)合用时为21.56%。雷公藤单独作用时为95.32%,盐酸小檗碱单独作用时为61.56%。结论改良MTT法在研究悬浮细胞增殖及药物毒性方面明显优于传统方法。DNR和盐酸小檗碱均对MOLT-4细胞增殖有抑制作用,雷公藤、盐酸小檗碱可以增强DNR抗肿瘤作用。     

Pharmacokinetics and toxicity of methotrexate in children with Down syndrome and acute lymphocytic leukemia

Children with Down syndrome and acute lymphocytic leukemia (ALL) have poor tolerance to antineoplastic drugs, including methotrexate (MTX). We evaluated MTX pharmacokinetics and toxicity in five patients with Down syndrome and ALL who had received multiple high doses of MTX (1 g/m2). Three control patients without Down syndrome were matched to each case according to sex, race, age, and initial leukocyte count. Median MTX plasma concentrations, measured 42 hours after infusion, were significantly higher in patients with Down syndrome versus control patients (average 0.47 vs 0.24 mumol/L, respectively, P = 0.03). When a 42-hour MTX concentration of 0.5 mumol/L was used to identify patients at risk for toxicity, more courses were considered at high risk for toxicity among patients with Down syndrome (31 of 62, 50%) than in control patients (13 of 214, 6.1%, P less than 0.0001). The average MTX clearance was 64.1 mL/min/m2 in Down syndrome vs an average control value of 80.6 mL/min/m2 (P = 0.13). Toxicity after each high-dose MTX course was graded according to standardized criteria. Grades 2 through 4 gastrointestinal toxicity and grades 3 and 4 hematologic toxicity occurred more frequently in the patients with Down syndrome (36% and 13.4% of courses, respectively) vs the control patients (3.6% and 0.9% respectively, P less than 0.0001 for both). This higher frequency of toxicity occurred despite higher doses and prolonged duration of leucovorin given to all patients with Down syndrome. We conclude that altered MTX pharmacokinetics may contribute to the higher incidence of MTX-induced toxicity seen in patients with Down syndrome.     

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??Objective??To assess the left ventricular torsion in children with acute leukemia after induced therapy by daunorubicin??DNR??. Methods??A total of 60 healthy volunteers served as controls??60 children with acute leukemia before and after induced therapy by DNR were enrolled. All the child patients were divided into three groups according to course of therapy by DNR. Group A?? patients before induced therapy by DNR?? Group B?? patients undergoing induced DNR with accumulated dose of 120 mg/m2?? Group C?? patients induced DNR withaccumulated dose of 240 mg/m2. The left ventricular short-axis images at the levels of mitral annulus and apex were acquired. Using 2-dimensional strain software?? the peak systolic rotations were measured in the left ventricular short-axis images and the peak systolic torsions were calculated. Results??There was no significant difference between control group and group?? A??B and C in EF and E/A. In healthy volunteers?? the left ventricular performed a systolic torsion?? with a counterclockwise rotation at the apex and a clockwise rotation at the mitral annulus. In the children with acute leukemia receiving induced therapy by DNR with accumulated dose of 240 mg/m2?? the peak systolic rotations of the level of mitral annulus and the peak systolic torsion were decreased. Conclusion??The early changes of left ventricular regional myocardial systolic function in children with acute leukemia after induced therapy by DNR with accumulated dose of 240mg/m2 can be measured by two- imensional speckle tracking imaging.     

Altered prednisolone pharmacokinetics in patients with cystic fibrosis.

Prednisolone pharmacokinetics were evaluated in eight patients with cystic fibrosis (CF) (aged 1.8 to 20 years) by assessing absorption of orally administered prednisone (in its active form, prednisolone) and elimination of prednisolone after intravenous administration. After an overnight fast, subjects received intravenously administered doses of prednisolone or orally administered doses of prednisone, 40 mg/1.73 m2 body surface area, before a standardized breakfast. Serial blood samples were collected for 12 hours and analyzed for prednisolone concentration. Prednisolone pharmacokinetics were compared in eight age-matched patients with asthma who required steroids after intravenous administration of prednisolone. The prednisolone pharmacokinetic parameters derived demonstrated an increased total clearance (by 60%), an increased volume of distribution (by 46%), a lower peak concentration (by 35%), and no difference in elimination half-life in patients with CF compared with those with asthma. Bioavailability averaged 88.4% +/- 20.1% of the administered dose. Prednisolone clearance was markedly increased in those with CF. There was a proportional increase in nonrenal clearance, with no difference in renal clearance in those with asthma or CF. The plasma protein binding of prednisolone was only slightly decreased in patients with CF and did not account for the observed pharmacokinetic alteration. The marked increase in prednisolone clearance may necessitate the use of more frequent or higher doses of this steroid in the treatment of patients with CF, leading to a potentially less favorable benefit/risk ratio.     

Continuous infusion of ceftazidime in the empiric treatment of febrile neutropenic children with cancer

PURPOSE: Infection remains one of the most important complications in cancer therapy. The choice of antibiotics and the method of administration can affect results. Beta-lactam antibiotics can be administered by several short injections per day or by continuous infusion. The latter modality may provide superior pharmacokinetics. PATIENTS AND METHODS: The authors studied the pharmacokinetics of ceftazidime in children treated for malignancy and in febrile aplasia after chemotherapy. They received a continuous infusion of ceftazidime (200 mg/kg/day) after a loading dose (65 mg/kg/day) administered with amikacin (25 mg/kg/day) and vancomycin (50 mg/kg/day).RESULTS Twenty-three pharmacokinetic studies were performed. Mean ceftazidime serum levels were 31.1 +/- 11.9, 31.2 +/- 10, 32.4 +/- 11.6, 33 +/- 11.6, and 30.4 +/- 12.1 mg/L at 25, 27, 30, 36, and 43 hours, respectively. Treatment was tolerated well. There were no toxic or infectious deaths. CONCLUSIONS: Ceftazidime's time-dependent pharmacokinetics shows the advantage of continuous infusion. This study confirmed the feasibility and safety of this administration schedule in the empiric treatment of febrile neutropenic children with cancer.     

Single-dose pharmacokinetics of imipenem in children

The single-dose pharmacokinetics of imipenem (N-formimidoyl thienamycin) was evaluated in 13 pediatric patients (mean age 5.2 +/- 3.5 years). Imipenem was administered in combination with cilastatin as either a 10 mg/kg or 25 mg/kg dose (not to exceed 500 mg) over 15 minutes. Plasma disposition in children was best described by a two-compartment open model. The distribution phase was rapid (t1/2 lambda 1 = 0.18 hours) and was followed by a monoexponential elimination phase (t1/2 lambda 2 = 1.2 hours). The calculated value for the apparent volume of distribution (0.66 L/kg) was similar to that of total body water. The total plasma clearance was rapid (0.36 L/hr/kg). Direct proportionality was exhibited between administered dose and either resultant plasma concentration or area under the plasma concentration versus time curve. Comparison of imipenem plasma pharmacokinetic data derived from these children with data reported from adult subjects revealed disparities for both the apparent volume of distribution and plasma clearance. Based on preliminary pharmacokinetic simulations using parameters generated from our study, a 25.0 mg/kg dose of imipenem administered every 6 hours appears adequate for initiation of therapy in children.     

Pharmacokinetic determination of ranitidine pharmacodynamics in pediatric ulcer disease

The pharmacokinetics and pharmacodynamics of ranitidine were evaluated during three methods of administration in 12 children ranging in age from 3.5 to 16 years with documented gastric or duodenal ulcer disease. First, a continuous intravenous infusion of ranitidine was administered to determine the serum concentration necessary to suppress gastric acid secretion by at least 90%. From these data a therapeutic dose of ranitidine was calculated and administered on separate days via the intravenous bolus and oral routes. Half-life, volume of distribution, and clearance values for ranitidine were the same after intravenous bolus and oral doses (1.8 vs 2.0 hours, 2.3 vs 2.5 L/kg, and 794.7 vs 788.0 ml/min/1.73 m2, respectively). The bioavailability of ranitidine given orally averaged 48%. Serum ranitidine concentrations necessary to inhibit gastric acid secretion by at least 90% ranged between 40 and 60 ng/ml for all children studied. No adverse clinical or biochemical effects were observed in any child during the 6 weeks of orally administered treatment. Endoscopic reevaluation after 6 weeks indicated complete healing of initial ulcers.     

Induction toxicity in childhood acute lymphoblastic leukemia: A comparison of two schedules of daunorubicin administration

The haematological toxicity of the induction phase of chemotherapy for acute lymphoblastic leukaemia (ALL) was compared in two cohorts of patients. The principal difference between these two cohorts was the mode of administration of the anthracycline, daunorubicin (DNR). Both groups received four-drug induction chemotherapy, which produced a high remission rate. Those receiving DNR on days 1 and 2 experienced a profound but shorter period of neutropenia and more severe thrombocytopenia than those who received the DNR weekly. The pattern of hospitalisation and support facilities in the individual unit may determine which regimen is to be preferred. These observations are relevant for the newly diagnosed patient in whom an anthracycline is retained in the induction therapy for ALL. © 1995 Wiley-Liss, Inc.