Induction of chromosmal aberrations in the syrian hamster by insecticides tested in vivo

The insecticides demeton, dimetoat, dichlorovos, endosulfan, trichlorofon, carbaryl, lindane, methoxychlor, propoxur and malathion were examined for their ability to induce chromosomal aberrations in the bone marrow cells of the Syrian hamster (Mesocricetus auratus) treated in vivo. Mutagenicity of commercial preparations was examined at four doses: LD₅₀; 1/2, 1/5 and 1/10 LD₅₀. The positive control was an IP injection of cyclophosphamide to hamsters at a dose of 40 mg/kg body wt. Demeton, dichlorovos and endosulfan gave positive results. Malathion, dimethoate and the mixture of methoxychlor and propoxur were weakly clastogenic; at some doses these compounds induced statistically significant increases in the number of aberrations. Trichlorfon and the mixture of carbaryl and lindane were negative in this test.This work was supported by the Polish Academy of Sciences within the projet 09.7.3.4.3     

两种环磷酰胺冲击方案对狼疮性肾炎的疗效和肿瘤坏死因子的影响

目的：探讨大剂量环磷酰胺静脉冲击治疗狼疮性肾炎（LN）的合理方案及对肿瘤坏死因子（TNF）水平的影响,方法：将51例LN患者分为A,B两组,分别给予2周（A组）和4周（B组）一次环磷酰胺静脉冲击治疗（IV－CYC）,每次用量0．5－1．0g/m2,同时口服强的松1mg.kg^-1.d^-1。用ELISA双抗体夹心法检测LN患者血清和尿TNF水平。结果：A组病情缓解率显著高于B组（P＜0．05）,活动期LN患者血清和尿TNF水平显著高于稳定期,轻度肾功不全患者血清TNF水平显著高于肾功正常者（P＜0．05）,结论：IV－CYC加强的松治疗能显著降低LN患者TNF水平且2周方案优于4周方案,治疗中应根据病情,外周白细胞数和肾功能调整,重症和急进期LN每2周1次,病情轻者可每4周1次,血清和尿TNF的变化有助于监测狼疮活动和肾损害程度。     

64例狼疮性肾炎大剂量环磷酰胺冲击治疗的研究

目的　观察大剂量环磷酰胺冲击治疗狼疮性肾炎的疗效。方法　对 6 4例狼疮肾炎 ( L N ,其尿红细胞 >10个 /高倍视野 ,2 4小时尿蛋白 >1g,血肌酐 >133μmol/ L )进行大剂量环磷酰胺 ( CTX)冲击治疗 (每月 1次 ,共 6次 ,其后每 3月 1次 ,共 6次 )。结果　 49例 L N患者达到肾脏损害缓解 ( 2 4小时尿蛋白 <1g;血肌酐 <133μmol/ L ;尿沉渣内红细胞 <10个 /高倍视野 ;尿管型消失 )。达到肾脏病变缓解所需冲击次数平均为 3.6次 ( 1～8次 )。每次用 CTX剂量均数 1.1g( 0 .6～ 1.6 g)。副作用有闭经 (发生率 33% ) ;带状疱疹 (发生率 13% ) ;出血性膀胱炎 1例。结论　此治疗方案治疗 L N有效 ,安全 ,副作用小     

鹿茸醇提物对白细胞减少小鼠模型腹腔吞噬细胞吞噬功能的影响

目的 :探讨鹿茸醇提物对由于环磷酰胺所致白细胞减少小鼠模型免疫功能的影响。方法 :用鹿茸醇提物对该动物模型进行灌胃 ,然后测定该小鼠腹腔吞噬细胞的吞噬功能。结果 :鹿茸醇提物组 (即实验组 )小鼠腹腔吞噬细胞吞噬鸡红细胞的吞噬百分率为 8.41± 0 .0 8,吞噬指数为 0 .10 0± 0 .0 0 4;而对照组的吞噬百分率为 3.40± 0 .0 8,吞噬指数为 0 .0 44± 0 .0 0 2 ,两组相比较 ,两项指标差异极显著 (P<0 .0 1)。结论 :鹿茸醇提物可提高因环磷酰胺所致白细胞减少、免疫功能低下动物模型的非特异性免疫功能 ,即鹿茸醇提物对环磷酰胺的副作用具有一定的对抗作用。     

皮质激素和间断环磷酰胺冲击治疗局灶节段性肾小球硬化疗效观察

目的 观察激素及同断环磷酰胺(CTX)冲击治疗局灶节段性肾小球硬化-肾病综合征(FSGS-NS)的疗效。方法回顾性分析1993～1997年间,63例FSGS-NS患者对激素治疗的反应,疗效与病理的关系及随访结果。结果以NS为表现的]SGS占同期肾活检FSGS的43.45％,平均发病年龄(31±14)岁,男女之比为2.15∶1,平均随访43个月。对初治疗有反应的患者(Ⅰ组)完全缓解率(CR)高,为65.79％,无进展至慢性肾功能衰竭(CRF)者;对初始治疗无反应者(Ⅱ组)CR低,为12％,延长激素及CTX治疗可使CR或部分缓解率(PR)增加至48％,进展至CRF者为6.35％。治疗的反应及CR的高低与肾小球病变范围及肾小管间质病变严重程度有关,肾小球病变范围大,小管间质病变严重者,对初始治疗反应差,CR低。药物不良反应以感染和肝损为主。结论延长皮质激素及间断CTX冲击治疗FSGS-NS使NS的治疗缓解率增加(总CR44.44％),进展至CRF少(6.35％),患者预后改善,临床上应根据肾脏病理,在严密监测药物不良反应的情况下,对其积极治疗。     

Cancer risk assessment for health care workers occupationally exposed to cyclophosphamide

In the present study a cancer risk assessment of occupational exposure to cyclophosphamide (CP), a genotoxic carcinogenic antineoplastic agent, was carried out following two approaches based on (1) data from an animal study and (2) data on primary and secondary tumors in CP-treated patients. Data on the urinary excretion of CP in health care workers were used to estimate the uptake of CP, which ranged from 3.6 to 18 g/day. Based on data from an animal study, cancer risks were calculated for a health care worker with a body weight of 70 kg and a working period of 40 years, 200 days a year (linear extrapolation). The lifetime risks (70 years) of urinary bladder cancer in men and leukemias in men and women were found to be nearly the same and ranged from 95 to 600 per million. Based on the patient studies, cancer risks were calculated by multiplication of the 10-year cumulative incidence per gram of CP in patients by the estimated mean total uptake in health care workers over 10 years, 200 days a year. The risk of leukemias in women over 10 years ranged from 17 to 100 per million using the secondary tumor data (linear extrapolation). Comparable results were obtained for the risk of urinary bladder tumors and leukemias in men and women when primary tumor data were used. Thus, on an annual basis, cancer risks obtained from both the animal and the patient study were nearly the same and ranged from about 1.4 to 10 per million. In The Netherlands it is proposed that, for workers, a cancer risk per compound of one extra cancer case per million a year should be striven for (target risk) and that no risk higher than 100 per million a year (prohibitory risk) should be tolerated. From the animal and the patient study it appears that the target risk is exceeded but that the risk is still below the prohibitory risk.     

蒲公英水煎液对环磷酰胺诱导的实验性小鼠精子畸形的影响

目的 :研究蒲公英水煎液对实验性小鼠生殖细胞遗传物质的影响。方法 :应用小鼠精子畸形实验 ,观察蒲公英水煎液本身能否诱发雄性生殖细胞遗物质的损伤 ;以及对环磷酰胺诱导的雄性生殖遗传物质损伤是否具有抑制作用。结果 :蒲公英水煎液本身不能诱发实验性小鼠精子畸形 ;对环磷酰胺诱导实验性小鼠精子畸形具有明显抑制作用。结论 :蒲公英水煎液具有一定的抗突变作用 ,可安全应于临床肿瘤治疗。     

Metabolism-based anticancer drug design

Many conventional anticancer drugs display relatively poor selectivity for neoplastic cells, in particular for solid tumors. Furthermore, expression or development of drug resistance, increased glutathione transferases as well as enhanced DNA repair decrease the efficacy of these drugs. Research efforts continue to overcome these problems by understanding these mechanisms and by developing more effective anticancer drugs. Cyclophosphamide is one of the most widely used alkylating anticancer agents. Because of its unique activation mechanism, numerous bioreversible prodrugs of phosphoramide mustard, the active species of cyclophosphamide, have been investigated in an attempt to improve the therapeutic index. Solid tumors are particularly resistant to radiation and chemotherapy. There has been considerable interest in designing drugs selective for hypoxic environments prevalent in solid tumors. Much of the work had been centered on nitroheterocyclics that utilize nitroreductase enzyme systems for their activation. In this article, recent developments of anticancer prodrug design are described with a particular emphasis on exploitation of selective metabolic processes for their activation.     

高剂量表阿霉素治疗进展期和晚期乳腺癌

目的评价高剂量表阿霉素（ＨＤ－ＥＰＩ）合并环磷酰胺（ＣＴＸ）、氟脲嘧啶（５－Ｆｕ）治疗进展期和晚期乳腺癌的安全性和有效性。方法对３２例可评价的Ⅲ、Ⅳ期乳腺癌患者静脉给予ＣＴＸ６００ｍｇ／ｍ２、ＥＰＩ９０ｍｇ／ｍ２～１１０ｍｇ／ｍ２、５－Ｆｕ９００ｍｇ／ｍ２,每２１天重复。并与３０例非同期低剂量组比较（ＥＰＩ为５０ｍｇ／ｍ２）。结果高剂量组的总有效率为７１．９％,完全缓解率为１２．５％,明显高于低剂量组（５６．７％和６．７％）;初治的有效率（８０．０％）略高于复治者（６８．２％）。全组中位缓解期７．４个月,中位生存期１２．５个月。白细胞减少为主要的毒副反应,发生率为８９．５％（６８／７６）,Ⅲ、Ⅳ度分别为２７．６％和１８．４％;胃肠道毒性为轻、中度,未见明显的心肝肾毒性。结论ＨＤ－ＥＰＩ＋ＣＴＸ＋５－Ｆｕ方案治疗晚期乳腺癌安全有效,可在临床进一步试用     

Occupational exposure to antineoplastic agents at several departments in a hospital

Summary The occupational exposure to cyclophosphamide (CP), ifosfamide (IF), 5-fluorouracil (5FU), and methotrexate (MTX) of 25 pharmacy technicians and nurses from four departments of a hospital was investigated. Previously developed methods for the detection of exposure to some antineoplastic agents were validated. Exposure to CP, IF, 5FU, and MTX was measured by the analysis of these compounds in the environment (air samples and wipe samples from possible contaminated surfaces and objects). Contamination of the work environment was found not only on the working trays of the hoods and on the floors of the different rooms but also on other objects like tables, the sink unit, cleaned urinals and chamber pots, and drug vials and ampules used for preparation and packing of drugs. The gloves used during preparation of the drugs and during cleaning of the hoods were always contaminated. The uptake of CP or IF was determined by the analysis of both compounds in urine. CP or IF was detected in the urine of eight pharmacy technicians and nurses. The amounts ranged from < 0.01 to 0.5 g (median: 0.1 g). CP and IF were found not only in the urine of pharmacy technicians and nurses actively handling these compounds (n = 2) but also in the urine of pharmacy technicians and nurses not directly involved in the preparation and administration of these two drugs (n = 6). CP and IF were excreted during different periods ranging from 1.40 to 24.15 h after the beginning of the working day, suggesting different times of exposure, different exposure routes, and/or interindividual differences in biotransformation and excretion rate for these compounds. The urinary CP and IF determination method seems to be sensitive and suitable for monitoring the exposure to and measuring the uptake of these toxic compounds by pharmacy technicians and nurses during occupational activities.