Detection of contamination with antineoplastic agents in a hospital pharmacy department

The contamination with fluorouracil, cyclophosphamide and methotrexate was studied in a hospital pharmacy department where these drugs were prepared. In the preparation room, air samples were taken before and during preparation of the drugs. Methotrexate was detected in one sample which was collected during preparation (0.3g/m³). Spot samples were taken in the vertical laminar airflow safety hood before and after preparation of the drugs and after cleaning of the hood. Contamination of the laminar airflow hood was: cyclophosphamide: 1–160 ng/cm²; fluorouracil: 10–62 ng/cm² and methotrexate: 2–633 ng/cm². Spot samples from the floor in front of and beneath the laminar airflow hood showed contamination with especially fluorouracil (48–236g/m²). The gloves used during preparation of the drugs were contaminated mainly with fluorouracil (5–980 ng/cm²). Urine samples from two workers involved in the preparation of the drugs were analysed for unmetabolized cyclophosphamide; it was not detected. Although no uptake of cyclophosphamide was established, it is shown that the methods for measurement of cyclophosphamide, fluorouracil and methotrexate in the preparation room are applicable for the control of occupational exposure to these drugs.     

Pharmacokinetics of trofosfamide and its dechloroethylated metabolites

 To contribute to effective and safe outpatient treatment, we investigated the metabolism of trofosfamide (Trofo) after oral administration. We analyzed Trofo metabolism in 15 patients aged from 3 to 73 years who were treated with 150 or 250 mg/m² Trofo in combination with etoposide. Serum samples were collected with 13 patients after oral administration, and Trofo and its dechloroethylated metabolites were quantified by gas chromatography. Urine samples were collected from five patients and analyzed by same method. Ifosfamide (Ifo) was the main metabolite in serum and urine (AUC_Trofo:AUC_Ifo 1:13), whereas cyclophosphamide (Cyclo) was formed in smaller amounts (AUC_Ifo:AUC_Cyclo 18:1). Ifo and Cyclo were further oxidized in the chloroethyl side chains to form 2- and 3-dechloroethylifosfamide in varying quantities. The urinary excretion of Trofo and its dechloroethylated metabolites amounted to about 10% of the total dose. Our results confirm former in vitro observations about the metabolism of Trofo. The main side-chain metabolites Ifo and Cyclo can be further activated by oxidation and formation of their respective phosphoramide mustards. Hence, Trofo is an interesting agent for oral chemotherapy. Received 21 July 1996 / Accepted: 11 November 1996     

TCMP方案治疗对常规化疗耐药的复发转移性乳腺癌

目的:为评估由三苯氧胺、环磷酰胺、氨甲喋呤和顺铂组成的TCMP方案对常规化疗耐药后复发转移性乳腺癌的疗效.方法:25例对常规化疗耐药的复发转移性乳腺癌患者接受TCMP方案化疗.给药方法是三苯氧胺,10mg,口服,每天2次;环磷酸胺,0.8～1.0,静推,第1天;氨甲喋呤,40mg,肌注,第1、8天;顺铂40mm,静滴,第1～4天.23例患者有客观评价指标,均接受TCMP方案化疗最小2周期.结果:23例可评价患者中,总客观有效率为52.17%(95%可信区间31～73%),其中2例CR,10例PR.经Ridit检验治疗效果与雌激素受体状态无关.结论:以上提示TCMP方案对常规治疗耐药后复发转移性乳腺癌有较好疗效,三苯氧胺与以顺铂为主化疗方案在乳腺癌的治疗中有协同作用.     

Pharmacokinetic interaction between ondansetron and cyclophosphamide during high-dose chemotherapy for breast cancer

Purpose: Both ondansetron and cyclophosphamide are thought to be metabolized by hepatic microsomal processes. The purpose of this study was to evaluate the potential pharmacokinetic interactions between ondansetron and high-dose alkylating agent chemotherapy. Methods: A total of 54 breast cancer patients receiving high-dose cyclophosphamide, cisplatin and carmustine were treated prospectively in four sequential cohorts. Cohorts I and II received continuous infusions of both ondansetron and prochlorperazine, and cohorts III and IV received a continuous infusion of ondansetron alone at the same doses. All patients received lorazepam every 4 h. A group of 75 matched historical controls had received a continuous infusion of prochlorperazine with lorazepam. Pharmacokinetic monitoring of each drug used in the high-dose chemotherapy regimen was conducted. Results: Median AUCs of cyclophosphamide in patients receiving ondansetron (73.6 mg/ml · min) were lower than those of the control patients (88.3 mg/ml · min, n = 75, P = 0.0004), but the median cisplatin AUC was approximately 10% higher and no difference in the disposition of carmustine was demonstrated. Patients treated with ondansetron displayed a higher frequency of headaches than the controls. The frequency of achieving complete emetic control was greater in the ondansetron + prochlorperazine groups compared to the ondansetron alone groups and was greater in both these groups than in the prochlorperazine alone group on the first day of therapy only. Conclusion: Ondansetron altered the systemic exposure to cyclophosphamide when these agents were administered concomitantly. Ondansetron did not substantially improve overall emetic control when used alone but may improve control in combination with prochlorperazine. Future randomized studies are needed to delineate the effect of ondansetron on the disposition of the active cyclophosphamide metabolites so that clinical implications can be addressed. Received: 28 October 1997 / Accepted: 9 March 1998     

马利兰和环磷酰胺预处理方案的非亲缘异基因骨髓移植治疗骨髓增生异常综合征

目的:评估以马利兰和环磷酰胺(Bu-CY2)为预处理方案的非亲缘异基因骨髓移植治疗骨髓增生异常综合征(MDS)的临床疗效。方法:对6例MDS患者进行非亲缘异基因骨髓移植术,以Bu-CY2为预处理方案,Bu 4 m g.k-g 1.d-1,-7 d~-4 d,CY 60 m g.k-g 1.-d 1,-3 d~-2 d。输入单个核细胞数(MNC)为3.38×108/kg(2.4×108/kg~4.6×108/kg),CD 34+细胞数5.81×106/kg(1.2×106/kg~8.5×106/kg),粒-巨噬细胞集落形成单位(CFU-GM)数2.88×105/kg(1.61×105/kg~4.56×105/kg)。以霉酚酸酯加环孢素A(C sA)和短程氨甲蝶呤(MTX)预防移植物抗宿主病,前列腺素E1脂质微球预防肝静脉阻塞病。结果:6例患者中性粒细胞≥0.5×109/L的中位时间为18 d(13~21 d),血小板≥20×109/L的中位时间为21 d(13~24 d)。经DNA短串联重复序列多态性分析和染色体检查,均为供者骨髓植活。早期死亡率为0,移植后随访时间为27个月(6~60个月)。目前实际无病生存6例,缓解期实际生存率100%。结论:以Bu-CY2为预处理方案的非亲缘异基因骨髓移植是治疗MDS的有效方法。     

Protective effect of Pumpkin seed extract on sperm characteristics,biochemical parameters and epididymal histology in adult male rats treated with Cyclophosphamide

Cancer treatment with cyclophosphamide (CP) may result in reproductive toxicity as one of its side effects. The pumpkin seed is a rich natural source of antioxidant. We have assessed the possible protective efficacy of pumpkin seed extract on sperm characteristics, biochemical parameters and epididymal histology of CP‐treated rats. Male adult Wistar rats were categorised into four groups. Group 1 served as control and received intraperitoneal (IP) injection of isotonic saline solution. Group 2 rats were treated with CP by IP injection in a single dose of 100 mg/kg body weight, only once. Group 3 and 4 received CP plus 300 and 600 mg/kg pumpkin seed extract respectively. Six weeks after treatment, sperm characteristics, biochemical parameters and histopathological changes were examined. Results showed that, sperm characteristics in CP‐treated rats were significantly decreased. Biochemical analysis results showed that the co‐administration of 300 mg pumpkin seed extract could increase the total antioxidant capacity (TAC) level significantly. In CP‐treated rats, histopathological changes such as vacuolisation, disorganisation and separation of epididymal epithelium were observed as well. Interestingly, pumpkin seed extract could improve the above‐mentioned parameters remarkably in CP‐treated rats. Our findings indicated that pumpkin seed extract might be used as protective agent against CP‐induced reproductive toxicity.     

Protective effects of betulinic acid on intestinal mucosal injury induced by cyclophosphamide in mice

BackgroundBetulinic acid (BA) is a plant-derived pentacyclic triterpenoid with a variety of biological activities. The purpose of this study was to assess the potential protective role of BA against intestinal mucosal injury induced by cyclophosphamide (CYP) treatment.MethodsMice were pretreated with BA daily (0.05, 0.5, and 5.0 mg/kg) for 14 days, then injected intraperitoneally with CYP (50 mg/kg) for 2 days.ResultsBA pretreatment reduced the contents of malondialdehyde (MDA) and glutathione (GSH), decreased the activity of superoxide dismutase (SOD) in small intestine, increased villus hight/crypt depth ratio and restored the morphology of intestinal villi in CYP-induced mice. Moreover, BA pretreatment could significantly down-regulate the levels of pro-inflammatory cytokines interleukin-5 (IL-5), IL-17, IL-12 (P70) and tumor necrosis factor α (TNF-α), reduced production of chemokines macrophage inflammatory protein-1α (MIP-1α), macrophage inflammatory protein-1β (MIP-1β) and regulated upon activation, normal T-cell expressed and secreted (RANTES), and enhanced the levels of anti-inflammatory such as IL-2 and IL-10 in serum, and decreased the mRNA expressions of IL-1β and TNF-α in intestine of CYP-induced mice. Furthermore, RT-PCR demonstrated that BA improved intestinal physical and immunological barrier in CYP-stimulated mice by enhancing the mRNA expressions of zonula occluden 1 (ZO-1) and Claudin-1.ConclusionsBA might be considered as an effective agent in the amelioration of the intestinal mucosal resulting from CYP treatment.     

环磷酰胺与泼尼松联合治疗狼疮性肾炎的疗效观察

目的：探讨环磷酰胺（ cytoxan，CTX）与泼尼松（ methylprednisolone，MP）联合治疗狼疮性肾炎（ lupus nephritis，LN）的临床疗效与安全性。方法：随机抽取2013年1月—2014年1月于汕头潮南民生医院就诊的LN患者90例，以随机数字表法分为观察组和对照组各45例。观察组患者给予CTX与MP联合治疗，对照组给予MP单药治疗，比较2组患者的临床疗效与安全性。结果：观察组患者的总有效率为93．33％（42／45），显著高于对照组的73．33％（33／45）（P＜0．05）；治疗后，观察组患者的尿蛋白、血沉以及血清肌酐水平均显著低于对照组（P＜0．05），血红蛋白及补体C3水平均显著高于对照组（P＜0．05）；观察组患者不良反应发生率为13．33％（6／45），与对照组的6．67％（3／45）比较，差异无统计学意义（P＞0．05）。结论：CTX与MP联合治疗LN，可改善患者临床症状及肾功能，减少蛋白尿，提高临床疗效，且不良反应较少，值得临床推广。     

The effect of intravenous cyclophosphamide pulse on peripheral blood lymphocytes in lupus erythematosus patients

In the present study we investigated the long-term effect of intravenous pulse cyclophosphamide (CY) on lymphocyte surface antigens in systemic lupus erythematosus (SLE) patients. Blood samples derived from 17 lupus erythematosus patients were analysed using two- and three-colour flow cytometry. During the CY therapy, the total number of T lymphocytes (CD3+) was reduced by 31.4%, B lymphocytes (CD19+) by 67.4% and NK cells (CD16+) by 27.4%. Six months after the end of the CY regimen, these values recovered to entry levels. At the onset of the study we observed increased percentages of CD3+ CD25+, CD3+ CD4– CD8–, CD4+ CD29+, CD19+ and CD19+ CD5+ cells. The CY treatment regimen decreased the CD3+ CD25+, CD3+ CD4– CD8–, CD19+ and CD19+ CD5+ cells, but increased the CD3+ CD8+ subpopulation. Taken together, a deficiency of CD8+ T cells associated with CD4+ CD29+ predominance may imply an immune regulatory imbalance leading to abnormal CD4+ cell activation and in consequence to autoimmunity. Depletion of CD19+ cells combined with an enlargement of CD8 cells as a result of CY therapy may reduce the enhanced immune response in SLE patients. Received: 13 December 1996 / Accepted: 10 March 1997     

促性腺释放激素类似物联合环磷酰胺治疗系统性红斑狼疮的安全性

目的：探讨促性腺释放激素类似物(GnRHa)联合环磷酰胺(CTX)治疗对系统性红斑狼疮(SLE)患者病情的影响,以及GnRHa作为CTX治疗的SLE患者卵巢保护剂的安全性。方法选取2013年3月~2014年12月在北京大学深圳医院风湿科确诊为SLE的育龄女性24例,根据是否使用GnRHa分为CTX+GnRHa组和CTX组,每组各12例。采用双能X线骨密度仪检测两组患者腰椎(L1~L4正位)骨密度;比较两组患者治疗前后病情、CTX的累积治疗量、骨密度及治疗后副作用。结果①SLE病情：治疗后两组SLE患者临床症状均消失,两组治疗前后系统性红斑狼疮疾病活动指数(SLEDAI)评分组内比较,差异均有高度统计学意义(t=23.534、19.187,均P=0.000);治疗后两组SLEDAI评分比较,差异有高度统计学意义(t=3.425,P=0.002)。②CTX的累积治疗量：CTX+GnRHa组与CTX组的CTX的累积治疗量分别为(6.9±2.0)、(7.0±1.5)g,两组比较差异无统计学意义(t=0.217,均P=0.830)。③骨密度：两组SLE患者治疗前后腰椎(L1~L4正位)骨密度值比较,差异均无统计学意义(t=0.126、0.175,P=0.901、0.863)。④治疗后的副作用、围绝经期症状及月经改变：CTX+GnRHa组在使用第2次GnRHa后均出现闭经,并伴有不同程度的潮热、多汗、睡眠困难等低雌激素症状,而停用GnRHa、月经恢复后上述症状缓解消失。CTX组有7例出现月经不规则,其中3例月经淋漓不尽,4例月经稀发,但均无低雌激素症状。结论 GnRHa联合CTX治疗对SLE患者的病情无明显的负面影响,GnRHa具有保护CTX治疗中SLE患者卵巢的功能,但其作为CTX治疗的SLE患者的卵巢功能保护剂的安全性及有效性仍有待进一步证实。