急性白血病诱导缓解治疗期间残留白血病检测的重要意义

现代联合化疗方案使急性白血病 (ＡＬ)的诱导缓解率得到了显著的提高 ,儿童急性淋巴细胞白血病 (ＡＬＬ)的完全缓解 (ＣＲ)率已达 95 %,成人ＡＬＬＣＲ率超过 75 %,急性髓系白血病 (ＡＭＬ)的ＣＲ率 70 %～ 80 %,但达骨髓ＣＲ(ｍＣＲ)后患者白血病复发仍是阻碍长期无病生存 (ＤＦＳ)的主要原因。采取个体化缓解后治疗策略提高ｍＣＲ患者残留白血病的根除率 ,使患者获得真正治愈是当前努力探索的方向。最近研究发现ＡＬ在诱导缓解期白血病细胞的清除速度 (ＣＳ)和清除程度 (ＣＤ)是制定个体化缓解后治疗策略的一个独立的重要参数。在儿童ＡＬ…     

Oral acyclovir as prophylaxis for bacterial infections during induction therapy for acute leukaemia in adults

We prospectively tested the hypothesis that prevention of herpes simplex virus infection with acyclovir might also reduce the incidence of bacterial infections in adult patients with acute leukaemia. During the first induction therapy a double-blind, randomized and placebo-controlled study was undertaken. Fifty-two patients were treated with 200 mg acyclovir orally four times daily throughout the induction period, whereas 55 patients received placebo. The groups were comparable with regard to age, cytotoxic chemotherapy and duration of neutropenia. Bacteraemias were significantly fewer in the acyclovir group (20 versus 41 episodes; P=0.007). The number of isolated microorganisms causing bacterial or fungal infections was also lower during acyclovir prophylaxis (52 isolates, versus 93 isolates; P=0.02). There was no significant differenc between the groups with regard to the number of clinically documented infections or fevers of unknown origin. Herpes simplex virus isolations occurred only in the placebo group (P=0.001). Thus, oral acyclovir prophylaxis was associated with reductions of all microbiologically documented infections suggesting that prevention of herpes simplex virus reactivation in acute leukaemia patients may reduce the occurrence of other infections. The following investigators participated in this study: Magnus Björkholm, Karl Merk, Anders Åhre, Department of Medicine, Danderyd Hospital, Danderyd; Lars Engstedt, Ann-Maria Udén, Department of Medicine, Stockholm Söder Hospital, Stockholm; Gösta Gahrton, Ragnhild Lindquist, Dieter Lockner, Christer Paul, Department of Medicine, Huddinge Hospital, Huddinge; Andreas Killander, Bengt Simonsson, Department of Medicine, University Hospital, Uppsala; Bengt Wadman, Ann-Marie Stalfelt, Department of Medicine, Medical Centre Hospital, Örebro; Christer Sundström, Department of Pathology, University Hospital, Uppsala; Åke Öst, Department of Pathology, Karolinska Hospital, Stockholm; Bo Johansson, Christina Simonsson-Lindemalm, Håkan Mellstedt, Christina Wedelin, Radiumhemmet, Karolinska Hospital, Stockholm     

Comparison of azithromycin pharmacokinetics following single oral doses of extended-release and immediate-release formulations in children with acute otitis media

An azithromycin extended-release (ER) oral suspension was developed to improve the gastrointestinal tolerability profile without substantially compromising systemic exposure. A single dose of 30 mg/kg azithromycin immediate-release (IR) oral suspension has been used in children to treat acute otitis media (AOM). This study was conducted to compare the pharmacokinetics of a 60-mg/kg azithromycin ER single dose with a 30-mg/kg azithromycin IR single dose in children with AOM aged 6 months to 6 years (n = 19 per treatment). Serum samples were collected at 1, 2, 3, 4, 8, 24, 48, and 72 h after dosing. The area under the curve from time zero to 72 h postdosing (AUC(0-72)) was calculated based on a noncompartmental method. One-way analysis of variance (ANOVA) was used to compare exposure parameters (e.g., AUC(0-72) and peak concentration) as well as concentrations at each time point. The adjusted geometric mean ratio of the ER/IR AUC(0-72) was 157.98% (90% confidence interval [CI], 98.87%, 252.44%), which met the predefined criterion of the lower boundary of the 90% CI of ≥ 80%. As expected, due to the slower-release profile of the ER formulation, the concentrations of the ER formulation during the first 3 h were lower than those of the IR formulation. After 3 h postdosing, the lower boundaries of the 90% CI for the ER/IR concentration ratios were greater than 100%. These results indicated that a 60-mg/kg single dose of ER azithromycin provides similar or greater systemic exposure in children than the 30-mg/kg single dose of IR azithromycin.     

Vascular access for daunorubicin during childhood acute lymphoblastic leukaemia induction treatment: A UKCCSG supportive care group and MRC childhood leukaemia working party survey

Daunorubicin was reintroduced into induction chemotherapy in UK protocols for intermediate- and high-risk childhood acute lymphoblastic leukaemia in 1999. Concern about the risk of central venous catheter-associated venous thromboembolism led to a recommendation that induction treatment should be given by peripheral venous access wherever possible, whilst recognising anxieties concerning the risk of daunorubicin extravasation. A survey performed to determine how these conflicting concerns influenced practice in the administration of daunorubicin revealed considerable variation. The results highlight that recommendations were not being followed and that local practice and guidance were being utilised in this area of practice. However, there is a need to identify patients at higher risk of venous thromboembolism during induction treatment and better strategies to prevent this complication.     

Generation of autologous immunity to acute myeloid leukaemia and maintenance of complete remission following interferon-alpha treatment.

Interferon-alpha (IFN-alpha) is established as part of the treatment for chronic myeloid leukaemia, although its precise mode of action remains largely unknown. Its use in acute myeloid leukaemia (AML) has been limited. We have previously documented autologous cytolytic activity against AML blasts in patients after autologous bone marrow transplantation. Here we present a patient with poor-risk AML who relapsed from first complete remission (CR) and was unwilling to undergo high-dose chemotherapy with stem cell rescue. In second chemotherapy-induced CR, the patient had no evidence of antileukaemia cytolytic activity in an in vitro assay, and she commenced IFN-alpha (Roferon). She subsequently developed high levels of leukaemia-specific cytotoxicity, and has remained in second CR for two years. These findings support the use of IFN-alpha in patients with poor-risk AML, and suggest that one mechanism of action may be immunological.     

三种用于急性早幼粒细胞白血病完全缓解后维持治疗的治疗方案比较——附72例报告

１引言 自我国首创的全反式维Ａ酸（ＡＴＲＡ）诱导治疗急性早幼粒细胞白血病（Ｍ３）以来,该病的缓解率明显提高,完全缓解率达８０％至９０％［１］,但完全缓解后用哪一种巩固维持治疗方案各家意见不一,也是目前研究的要点。为总结经验,我们对７２例经ＡＴＲＡ诱导完全缓解后用不同治疗方案作巩固维持治疗的Ｍ３病例的临床资料跟踪随访,分析如下。２对象和方法２．１一般资料 ７２例均为１９９０年１月至１９９８年１月的住院病人。根据１９７６年法美英协作组分类标准诊断为Ｍ３。男４３例,女２９例,年龄１７岁至５８岁,中位年龄…     

Placebo-controlled trial of itraconazole for treatment of acute vaginal candidiasis.

Itraconazole is a new orally active triazole antifungal agent with enhanced activity against Candida species. In the clinical trial described in this paper, we compared the efficacy and safety of itraconazole capsules with those of clotrimazole vaginal tablets and placebo oral capsules for women with acute vulvovaginal candidiasis. Ninety-five patients were randomized in a 2:1:1 fashion to receive itraconazole (200 mg/day), clotrimazole (200 mg/day), or placebo (two capsules per day) for 3 consecutive days. Clinical success rates (cure and improvement) were similar for women who received itraconazole (96%) and clotrimazole (100%) 1 week posttreatment. These response rates were statistically superior to those obtained with placebo treatment (77%, P < 0.05). Negative mycological cultures were found in 95, 73, and 32% of the patients treated with clotrimazole, itraconazole, and placebo, respectively (P < 0.005) [active treatments versus placebo]). By 4 weeks posttreatment, the clinical failure rate for itraconazole was less than that observed for clotrimazole (17 versus 30%), but this difference did not reach statistical significance (P > 0.05; beta = 0.81). Mycological response rates for itraconazole and clotrimazole were also similar. No patients enrolled in this study discontinued treatment because of an adverse event. Minor side effects were reported by 35, 4, and 41% of patients who received itraconazole, clotrimazole, and placebo, respectively. The most common side effects associated with itraconazole therapy were nausea and headache. In summary, itraconazole was found to be as effective and safe as clotrimazole in women with acute candida vaginitis. Moreover, oral therapy was highly favored over intravaginal treatment in our survey of patients.     

Single oral dose pharmacokinetics of the two main components of pristinamycin in humans

A preliminary study of the pharmacokinetics of the two main components of pristinamycin, PIA and PIIA is reported. A single oral dose of 2 g of pristinamycin was administered to six patients with normal renal and hepatic function. The samples were withdrawn during 9.5 h and assayed by HPLC. PIA and PIIA plasma levels evolved in parallel in each subject and their kinetic parameters were comparable: Tmax of 3.25 +/- 1.80 h and 3.08 +/- 1.98 h, Cmax of 0.760 +/- 0.427 mg/l and 0.581 +/- 0.285 mg/l, elimination half-life of 4.03 +/- 2.77 h-1 and 2.83 +/- 0.75 h-1, respectively. The relative proportions of PIA and PIIA, which govern the antibacterial activity of the mixture, were maintained during the study in the range of values leading to 90-100% of optimal activity against Staphylococcus aureus. The sum of the plasma concentrations of PIA and PIIA, which can be considered to be equivalent to the concentration of total pristinamycin, was superior to the MICs for the most susceptible staphylococcal strains during the entire period of study. On the other hand, the sum of PIA and PIIA concentrations exceeded the MICs for the less susceptible strains for only 4 h. These results differ from the scanty pharmacokinetic data presently available, which were obtained by microbiological methods.     

Effect of multiple dose oral ciprofloxacin on the pharmacokinetics of theophylline and indocyanine green

Interaction between ciprofloxacin and theophylline was studied in eight male volunteers, who were randomly divided into two groups. All subjects were given intravenous theophylline and indocyanine green (ICG) on study days 0, 7 and 14. Group I subjects received ciprofloxacin 750 mg orally every 12 h on days 1-7. Group II subjects received ciprofloxacin 750 mg every 12 h on days 6-14. No significant changes in ICG clearance or half-life were noted. A significant increase in theophylline half-life and volume of distribution was observed (P less than 0.05); however, clearance was not significantly decreased (P = 0.1). A potentially clinically significant interaction was detected in three subjects whose theophylline clearance decreased by 42-113%. Until further clinical experience is gained, we advise caution when these agents are coadministered. Some adjustment in theophylline dosage may be required; therefore, these patients should have serum theophylline concentration measurements and careful clinical assessment for theophylline toxicity.     

Survivors of acute leukaemia and highly malignant lymphoma—retrospective views of daily life problems during treatment and when in remission

Fifty-four former patients, in remission after acute leukaemia or highly malignant lymphoma, responded to a questionnaire covering their physical problems, their view of the help they received, who was most helpful to them during the treatment phase, and the impact of the disease and treatment on their current life. Energy loss and nutritional problems were most troublesome during the treatment phase, signifying many other physical problems. Patients with acute leukaemia had more problems, and thought the care was worse than did patients with highly malignant lymphoma. Serious physical problems correlated with low satisfaction with practical help received, indicating that the nurses failed to meet the needs of those suffering the most. Reduced psychological and sexual energy persisted in remission, showed no correlation with the extent of physical problems during the treatment phase, but correlated with co-existing problems and sensitivity to infections, with a great need for intimate help and counseling and with a low sense of coherence. Family relationships were said to have improved, while work and finances were negatively affected. The results indicate that nursing care should actively focus on physical problems, especially on energy loss and nutritional problems. The overwhelming fatigue hinders patients in taking physical care of themselves, and may be overlooked by the nurse since their motor capability seems intact. The long-term effect of the illness means a reduced psychological and sexual energy and a high degree of existential problems and sensitivity to infections, which indicates the importance of follow-up care, and perhaps especially o counseling for the long-term reactions and disturbance of equilibrium.     

Comparison of steady-state pharmacokinetics of two dosage regimens of vancomycin in normal volunteers.

A pharmacokinetic comparison of the two recommended dosages of vancomycin given as multiple doses has not been previously performed. Eleven adult subjects with normal renal function randomly received 500 mg every 6 h (five doses) and, later, 1,000 mg every 12 h (three doses). Each dose was infused over 1 h, and regimens were separated by 1 week. Compared with the two-compartment fit, a three-compartment fit significantly reduced the residual weighted sums of squares. Accumulation occurred for both regimens after repeated dosing and was independent of dose. At steady state, concentrations in serum at 1 h showed little variation for the 1,000- or the 500-mg dose regimen (33.7 +/- 3.8 versus 22.6 +/- 3.2 micrograms/ml); trough concentrations were 7.9 +/- 1.7 versus 11.2 +/- 2.2 micrograms/ml, respectively. With the 1,000-mg dose, the terminal half-life was 7.7 +/- 1.8 h, steady-state area under the curve for the dose interval was 227 +/- 28.3 micrograms X h/ml, and total body clearance was 86.1 +/- 8.9 ml/min per 1.73 m2. The red-man syndrome occurred in 9 of 11 volunteers who received 1,000-mg doses and in none of those who received 500-mg doses. We concluded that vancomycin disposition in healthy adults with normal renal function is best described by a three-compartment model, there is relatively little variation in vancomycin disposition in normal volunteers, significant accumulation occurs with multiple dosing, it is inappropriate to use the same therapeutic window for both regimens, and the pharmacokinetics of vancomycin justify a 12-h dose interval; however, a 1-g dose is associated with a significantly greater incidence of the red-man syndrome.     

不同剂量丙种球蛋白对急性吉兰-巴雷综合征疗效的比较

目的观察静脉滴注不同荆量丙种球蛋白治疗吉兰-巴雷综合征的临床疗效。方法123例吉兰-巴雷患者分成3组：低剂量丙种球蛋白组（0．2g·kg^-1·d^-1）、大剂量丙种球蛋白组（0．4g·kg^-1·d^-1）和单独应用糖皮质激素治疗组．记录其临床症状的改善状况,并进行比较。结果低剂量和大剂量丙种球蛋白对于轻度和中度的格林-巴利患者效果好于激素组（P分别为0．004,0．008,0．012,0．022）,且不良反应少,对重度患者疗效差异无统计学意义（P=0．788）。低剂量和大剂量两组患者在临床疗效上没有区别。结论丙种球蛋白治疗效果明显好于激素组,且低剂量和大剂量组差异无统计学意义。     

Rituximab pharmacokinetics during the management of acute idiopathic thrombotic thrombocytopenic purpura

Summary. Background: Increasingly, patients with acute, idiopathic, antibody mediated thrombotic thrombocytopenic purpura (TTP) are being treated with rituximab to achieve a durable remission, however, there is the potential that it is removed by plasma exchange (PEX). Objectives: To look at the pharmacokinetics and pharmacodynamics of rituximab in patients with acute idiopathic TTP undergoing PEX. Patients and methods: Patients who received rituximab for acute idiopathic TTP (group 1, n = 30) and a control group (group 2, n = 3) of TTP patients in remission receiving rituximab electively as maintenance were included. Rituximab levels were measured before/after each infusion, before/after PEX and in follow‐up. ADAMTS‐13 activity, anti‐ADAMTS‐13 IgG and CD19% were measured to assess response. Results: The median number of PEX to remission after rituximab was 10 (range 4–25). In group 1 there was no significant incremental rise in the peak serum rituximab level until dose 4. Trough levels were lower in patients who had had PEX since their last rituximab infusion. In the control group, there was an incremental rise in the peak serum rituximab level and all patients had detectable trough levels. The median fall in rituximab per PEX was 65%. All patients achieved CD19 < 1%. In group 1, the median time to undetectable rituximab was 5 months (range 0–12 months) and to B cell return was 7 months (range 3–24 months). ADAMTS‐13 increased and anti‐ADAMTS‐13 fell after therapy. There were three deaths and two relapses in group 1. Relapse was not temporally related to B cell return.     

Comparison of itraconazole and ketoconazole in the treatment of experimental candidal vaginitis.

Comparison of itraconazole (R51,211) and ketoconazole in the treatment of experimental candidal vaginitis in rats on schedules of 3 and 5 days revealed significantly superior results with itraconazole at all dosages (1.0 to 7.5 mg/kg) studied, but was particularly evident at 1.0 and 2.5 mg/kg. A single 25-mg/kg dose of itraconazole was as effective as 5 daily 5-mg/kg doses of itraconazole.     

Open-label crossover study to determine pharmacokinetics and penetration of two dose regimens of levofloxacin into inflammatory fluid.

Two levofloxacin administration regimens were used for six healthy male volunteers. They received either 500 mg of levofloxacin orally every 12 h for five doses or 500 mg every 24 h for three doses, and then 6 weeks later they received the other course. The concentrations of the drug in plasma, cantharidin-induced inflammatory fluid, and urine were measured with a microbiological assay following administration of the final dose. Mean peak concentrations in plasma of 9.3 and 6.6 micrograms/ml were attained 1.1 and 1.2 h after the 12- and 24-h regimens, respectively. Mean peak concentrations is inflammatory fluid of 6.8 and 4.3 micrograms/ml were attained at 2.3 and 3.7 h, respectively. The average steady-state concentrations were 5.0 and 2.2 micrograms/ml in plasma and 4.7 and 2.3 micrograms/ml in inflammatory fluid, respectively. The mean terminal elimination half-lives for plasma were 7.9 and 8.0 h for the two regimens, respectively, and the same values were noted for inflammatory fluid. The overall penetration into inflammatory fluid ranged from 88 to 101% with the 12-h regimen and 83 to 112% with the 24-h regimen. Mean urinary recoveries were 87 and 86% over the corresponding interval of the 12- and 24-h regimens, respectively. These results suggest that administration of levofloxacin once and twice daily should be efficacious for infections caused by the majority of pathogens.     

黄芪注射液对急性淋巴细胞白血病患儿诱导缓解化疗期间感染的影响

目的分析黄芪注射液对急性淋巴细胞白血病(ALL)患儿诱导缓解化疗期间感染的影响。方法选取ALL患儿100例,将其随机分为观察组和对照组各50例,2组患儿均应用诱导缓解化疗方案治疗,观察组患儿同时加用黄芪注射液静脉滴注,对2组患儿化疗期间的医院感染发生率、发生部位及化疗前、后外周血白细胞(WBC)和中性粒细胞(NE)计数进行观察和比较。结果观察组患儿化疗期间感染的总发生率显著低于对照组,观察组中各危险度分型患儿的感染发生率亦显著低于对照组中的同种分型患儿(χ~2=13.000、4.250、3.895、5.106,P0.05),观察组患儿化疗期间呼吸道、泌尿道、皮肤软组织感染的发生率显著高于对照组(χ~2=11.602、4.960、6.112,P0.05),化疗后观察组中各危险度分型患儿的外周血NE计数均显著高于对照组中的同种分型患儿(t=5.265、3.795、4.286,P0.05)。结论在ALL患儿的诱导缓解化疗期间,加用黄芪注射液能够缓解患儿的骨髓抑制,降低ALL患儿的感染发生率。