Ternatin, a flavonoid, prevents cyclophosphamide and ifosfamide-induced hemorrhagic cystitis in rats

To compare the classical uroprotective efficacy of mesna (2-mercaptoethanesulfonic acid) with ternatin (flavonoid isolated from Egletes viscosa Less.) in cyclophosphamide (CYP) and ifosfamide (IFS) induced hemorrhagic cystitis (HC). Male Wistar rats received an intraperitoneal injection of saline, CYP or IFS and were treated with saline or mesna, 5 min before, 4 and 8 h after CYP or IFS administration. In other animals, 1, 2 or 3 doses of mesna were replaced with ternatin or 3 doses of mesna were replaced with dimethylsulphoxide (DMSO), ternatin diluent. In an additional group, the last 2 doses of mesna were replaced with saline. HC was evaluated 24 h after CYP or IFS administration. CYP or IFS treatment induced marked changes in macroscopic and microscopic evaluation and in bladder wet weight (BWW), and these alterations were significantly inhibited by treatment with 3 doses of mesna, as well as by the replacement of 1 or 2 doses of mesna with ternatin. The replacement of 2 doses of mesna with saline or all doses of mesna with ternatin or DMSO did not prevent HC. In conclusion, the replacement of 1 or 2 doses of mesna with ternatin efficiently blocked CYP- or IFS-induced HC, however mesna is necessary for initial uroprotection.     

Modulation of thalidomide pharmacokinetics by cyclophosphamide or 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice: the role of tumour necrosis factor

Purpose There is considerable current interest in the use of thalidomide as a single agent or in combination with drugs such as cyclophosphamide in the treatment of multiple myeloma and other cancers. Our previous work has shown that thalidomide potentiates the antitumour activity of both cyclophosphamide and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) against murine Colon 38 tumours. In both of these cases, thalidomide extends the half-life (t_1/2) of the other drug. We wished to determine whether cyclophosphamide and DMXAA altered the t_1/2 of thalidomide. Since both thalidomide and DMXAA modulate tumour necrosis factor (TNF), we also wished to determine the role of TNF in this interaction.Methods Mice with Colon 38 tumours were treated with cyclophosphamide (220 mg/kg) and/or thalidomide (20 mg/kg) or DMXAA (25 mg/kg) and thalidomide (100 mg/kg), combinations that have previously demonstrated synergistic activity. Plasma and tumour tissue drug concentrations were analysed by high-performance liquid chromatography. To determine the role of TNF, similar experiments were performed using mice defective in the TNF gene (TNF^–/–) or the TNF receptor-1 gene (TNFR1^–/–).Results Coadministration of cyclophosphamide increased the thalidomide t_1/2 by 3.9- and 3.6-fold, respectively, in plasma and tumour tissue, with a corresponding increase in the concentration-time curve (AUC). The corresponding values following coadministration of DMXAA were 3.0- and 4.6-fold, respectively. Coadministration of cyclophosphamide had similar effects on thalidomide t_1/2 in C57Bl/6, TNF^–/– and TNFR1^–/– mice, while coadministration of DMXAA did not alter the t_1/2 or AUC in TNF^–/– and TNFR1^–/– mice.Conclusions Both cyclophosphamide and DMXAA have a pharmacokinetic interaction with thalidomide, increasing t_1/2 and AUC. TNF mediates the effect of DMXAA on thalidomide pharmacokinetics but not that of cyclophosphamide.This work was supported by the Auckland Medical Research Foundation, the Marsden Fund and the Auckland Cancer Society. Francisco Chung is a recipient of an Asian Development Bank Scholarship.     

Contribution of antioxidants to preventive effect of mesna in cyclophosphamide-induced hemorrhagic cystitis in rats

Purpose The aim of this study was to evaluate whether combination of antioxidants and mesna may prevent cystitis induced by cyclophosphamide better than mesna alone.Materials and methods A total of 46 male Spraque-Dawley rats were divided into six groups. Five groups received single dose of cyclophosphamide (CP, 100 mg/kg) intraperitoneally with the same time intervals: group 2 received CP only, group 3 received mesna (21.5 mg/kg for three times), group 4 beta-carotene (20 mg/kg for two times) and mesna, group 5 received alpha-tocopherol (20 mg/kg for two times) and mesna, and group 6 received melatonin (5 mg/kg for two times) and mesna on the day of CP injection. Group 1 served as control.Results CP injection resulted in severe cystitis. Mesna has showed meaningful but not full protection against CP toxicity. Although beta-carotene did not show any additional beneficial effect when combined with mesna, alpha-tocopherol and especially melatonin with mesna resulted full protection that the pathologist, blinded to the slides, could not differ from sham control.Conclusion Oxidants may be important in the pathogenesis of CP-induced cystitis. Melatonin and alpha-tocopherol may help to ameliorate bladder damage along with other drugs such as mesna and diuretics.     

Efficacy and safety of fludarabine and cyclophosphamide combined therapy in patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL)-Polish multicentre study

The aim of this study was to investigate the efficacy of a combination of fludarabine (F) and cyclophosphamide (C) in the treatment of patients with refractory/recurrent B-cell chronic lymphocytic leukaemia (B-CLL). Between November 1999 and December 2001, 63 patients with B-CLL (median age 60 years) received a regimen that consisted of F 25 mg/m² and C 250 mg/m², days 1 - 3, intravenously, every 4 weeks, for a maximum of 6 courses. Response and toxicity were assessed according to current criteria (NCI-WG and WHO). Complete and partial remissions were achieved in 17.5% and 55.6% of patients, respectively; 19% of patients had stable disease and 7.9% of patients showed disease progression. The median follow-up was 16.5 (range 1.5 - 32) months. The median duration of progression-free survival (PFS) has not been reached among patients treated with FC regimen as second-line therapy.The median PFS was 13 (range 8 - 26) months in the 19 responding patients treated with FC regimen as third-line therapy. The most frequent side-effects were neutropenia (45%), thrombocytopenia (42%) and infections (57%). We conclude that the combination of fludarabine and cyclophosphamide demonstrated significant efficacy in pretreated, advanced B-CLL patients, with tolerable toxicity.     

环磷酰胺或足叶乙甙联合粒细胞集落刺激因子动员自体外周血造血干细胞的对照研究

背景与目的:通过动员采集获得高质量的自体外周血造血干细胞(autologousperipheralbloodstemcell,APBSC)是造血干细胞移植成功的关键,环磷酰胺(cyclophosphamide,CTX)联合重组人粒细胞集落刺激因子(recombinedhumangranulocytecolony-stimulatingfactor,rhG-CSF)是APBSC经典的动员方案,足叶乙甙(etoposide,VP-16)联合rhG-CSF是近年来应用的另一个动员方案。本研究的目的是比较上述两种动员方案对恶性淋巴瘤和生殖细胞肿瘤患者APBSC的动员效果。方法:共有52例恶性实体瘤患者,其中CTX方案组26例,剂量为CTX3.5g/m2加rhG-CSF5μg·kg-1·d-1;VP-16方案组26例,VP-16的剂量随机采用1000mg/m2或1500mg/m2加rhG-CSF5μg·kg-1·d-1。两组均在白细胞(whitebloodcell,WBC)降至最低点时开始皮下注射rhG-CSF,直至采集结束前一天。当CTX组WBC恢复到2.5×109/L、VP-16组WBC恢复到5.0×109/L以上时开始连日采集APBSC,当累计采集的单个核细胞(mononuclearcell,MNC)≥5×108/kg或CD34+细胞≥2×106/kg时停止采集。患者经预处理后回输采集到的APBSC。比较两组动员采集过程中的血液学指标变化、采集细胞数量、造血重建时间、不良反应等。结果:CTX组患者化疗后外周血中WBC和血小板(platelet,PLT)降至最低值的时间明显早于VP-     

复发性上皮性卵巢癌紫素或环磷酰胺配伍铂类治疗疗效及费用

目的比较复发性上皮性卵巢癌患者应用紫素加铂类(TP组)与环磷酰胺加铂类(PC组)方案化疗的疗效及费用。方法我院1998年1月至2003年1月收治的符合入选标准的复发性上皮性卵巢癌患者39例,其中TP方案化疗24例,PC方案化疗15例。对2组在总生存率、中位生存时间、药物反应率、不良反应、住院费用等方面进行回顾性分析。结果TP组复发后中位生存时间为28．64月,PC组中位生存时间为17．29月,2组比较,差异有统计学意义(P＜0．05);TP组及PC组复发患者化疗后有效反应持续时间中位数分别为25．02月和1．40月,2组比较,差异有统计学意义(P＜0．05);2组消化系统不良反应比较,Z=—0．422(P＜0．05),2组血液系统均无Ⅳ度不良反应发生;TP组医疗费用为62934元,PC组为22 497元,2组比较,差异有统计学意义(P＜0．05),TP组每生存1年,平均住院费用为64 641元,PC组每生存1年,平均住院费用为21 318元。结论紫素加铂类作为复发性卵巢癌的首选化疗方案,患者化疗后有效率、复发后生存时间及有效反应持续时间等方面优于环磷酰胺加铂类组,而化疗费用亦高于PC组。     

大剂量环磷酰胺冲击疗法配伍激素治疗狼疮性肾炎的临床疗效观察

目的:探讨大剂量环磷酰胺(CTX)冲击疗法配伍激素治疗狼疮性肾炎的临床疗效。方法:将26例狼疮性肾炎患者分为2组,治疗组应用大剂量CTX冲击,每次0.8~1.0g溶于100ml生理盐水中于30分钟内快速静点,每月1次,总量8~10g,同时加服强的松1mg(kg/d),6~8周后逐渐减至维持量,对照组使用强的松单药口服治疗,对照组使用强的松单药口服治疗,强的松用法及减量方法与上述相同。结果:两组多项观察指标比较具有显著性差异(P<0.05)。结论:大剂量环磷酰胺冲击疗法配伍强的松治疗狼疮性肾炎近期疗效优于单药强的松治疗。     

复方黄芪多糖拮抗环磷酰胺对小鼠毒副作用的研究

目的：探讨复方黄芪多糖拮抗环磷酰胺对小鼠毒副作用的影响。方法：对小鼠行大剂量（85mg／kg，2次）环磷酰胺（C的腹腔注射。并用复方黄芪多糖腹腔注射预防，以观察复方黄芪多糖对CY毒副作用的影响。结果：与CY组比较复方黄芪多糖注射组（10ml／kg、20ml/kg）小鼠WBC及LMY计数明显高于环磷酰胺组（P〈0．05），GRA比率低于环磷酰胺组（P〈0．05），脾脏指数明显高于CY组（P〈0．01）。结论：复方黄芪多糖具有拮抗CY对小鼠毒副作用的效应。     

养胃合剂粗多糖对小鼠免疫功能的影响

目的观察养胃合剂复方多糖提取物对小鼠免疫功能的影响。方法建立小鼠环磷酰胺(CTX)免疫抑制模型,观察养胃合剂多糖提取物对小鼠免疫功能的影响。结果养胃合剂多糖能提高CTX致免疫抑制小鼠腹腔巨噬细胞的吞噬百分率,可促进溶血素形成,促进淋巴细胞转化。结论养胃合剂多糖有免疫促进作用,可对抗环磷酰胺的免疫抑制作用。     

Comparison of conventional dose and double dose carboplatin in patients receiving cyclophosphamide plus carboplatin for advanced ovarian carcinoma: a North Central Cancer Treatment Group Study

Between March 1992 and November 1994, 91 patients with stage III and IV ovarian carcinoma were enrolled in a randomized comparative study of cyclophosphamide 600 mg/m² plus carboplatin 300 mg/m² vs. cyclophosphamide 600 mg/m² plus carboplatin 600 mg/m², each regimen given monthly for six cycles. Patients on the intensive regimen also received 10 μg/kg of granulocyte macrophage colony stimulating factor (GM-CSF) (molgramostim) daily for 14 days following each chemo-therapy treatment. The study was closed prematurely because of very poor case accrual following the preliminary announcement (in May 1993) that paclitaxel appeared superior to cyclophosphamide in the platinum-based treatment of ovarian cancer. More than 4 years after our last case entry, we analyzed the survival results for the 44 eligible patients who received the conventional dose of carboplatin and the 43 eligible patients receiving our intensified dose of carboplatin. More than 90% of the treated patients receiving the conventional dose regimen received at least 75% of the planned doses at each of the six treatment intervals, whereas the percentage of treated patients able to receive at least 75% of the assigned intensive dose regimen had declined from 95% in cycle 2 to 53% by cycle 6. Furthermore, although 32 patients received all six planned cycles of treatment in the conventional regimen group, only 15 received all six cycles of the intensified regimen. Patients receiving the intensive regimen had more fever, dermatitis, lethargy, musculoskeletal pain, and pulmonary complications than did the conventional dose patients. Median survival times for the two treatment groups were very similar (38.5 and 38.1 months, respectively, for the conventional and intensive regimens), and we saw no evidence that the distribution of survival times differed between the treatment regimens (p = 0.95).