异环磷酰胺的合成

氮杂环丙烷和3-氯丙醇经缩合、与三氯氧磷反应制得2-氯-3-（2-氯乙基）-1，3，2-氧氮磷杂环己烷-2-氧化物，再与2-氯乙胺盐酸盐缩合得到异环磷酰胺，总收率22．7％（以3-氯丙醇计）。     

异环磷酰胺有关物质的合成

目的合成异环磷酰胺原料药中的一种有关物质。方法以3-氨基丙醇为原料,与三氯氧磷环合制得2-氯-1-氧杂-3-氮杂-2-磷杂环己烷-2-氧化物(3);以1-氨基-2-丙醇为原料,与氯化亚砜反应制得2-氯丙胺盐酸盐(5);化合物3与5经取代、酰化、还原得到有关物质3-(2-氯乙基)-2-[(2-氯丙基)氨基]-1-氧杂-3-氮杂-2-磷杂环己烷-2-氧化物。结果与结论合成了异环磷酰胺原料药中的一种有关物质,其结构经1H-NM R、13C-NM R和M S谱确证,纯度在99%以上。该有关物质可作为异环磷酰胺原料药质量控制的对照品。     

异环磷酰胺引起心房颤动

患者女性,49岁,因“四肢近端肌肉疼痛无力,进行性加重1月”,于2006年11月6日入院。既往史:24年前怀孕体检时发现心脏杂音,诊断为“风湿性心脏病,二尖     

异环磷酰胺与头孢噻肟钠的配伍稳定性

目的:考察不同温度下,注射用异环磷酰胺与头孢噻肟钠在0.9 %氯化钠注射液中配伍的稳定性.方法:采用反相高效液相色谱法测定异环磷酰胺与头孢噻肟钠配伍后24 h内各时间的含量,同时观察外观变化并测定pH值.结果:两药在0.9%氯化钠注射液中配伍后,异环磷酰胺在不同温度下24 h内的含量在97.48%以上.头孢噻肟钠随着时间的推移有水解,呈一级反应规律0 ℃～4 ℃,T0.9=76.85 h,25 ℃ T0.9=21.96 h,37 ℃ T 0.9=3.96 h. 结论:两药配伍后异环磷酰胺比较稳定.     

环磷酰胺与异环磷酰胺致肝毒性机制的比较

目的　为阐明环磷酰胺 (CP)和异环磷酰胺 (IFO)肝脏毒作用机制。方法　给大鼠腹腔注射CP或IFO 40mg·kg-1·d-1连续 5d ,观察停药后 1、4、7、10d血清生化指标、肝组织中丙二醛含量、巯基状态和细胞色素P45 0含量的变化。结果　两组动物血浆生化指标和肝组织丙二醛含量没有显著变化 ,而肝组织总巯基、非蛋白巯基、蛋白结合巯基和细胞色素P45 0含量下降 ,蛋白巯基的消耗与总巯基含量下降相关。但两药引起上述变化的程度不同。肝微粒体总P45 0含量的变化趋势与巯基相似 ,CP组细胞色素P45 0含量给药结束后 1、4、7、10d分别下降了 19 2 %、2 6 8%、6 1 1%、15 2 % ,IFO组细胞色素P45 0仅在 1、7d分别下降 2 0 7%和 40 2 %。结论　CP引起肝脏巯基和细胞色素P45 0含量下降程度明显强于 1FO ,表明这两种药物的差异可能与其毒性不同有关。     

家兔体内异环磷酰胺的药动学

目的:研究异环磷酰胺在兔体内的药动学。方法:随机选用家兔6只,根据体质量予相应剂量的异环磷酰胺静脉注射,在5,10,20,30,45min及1,1.5,2,2.5,3,5,7h取血1mL。血清样品用C18固体萃取小柱处理,用高效液相测定药物浓度。所测定数据用3P97程序处理,以获得相关的药动学参数。结果:异环磷酰胺在2.5~200mg.L-1(r=0.999)范围内线性良好;绝对回收率在89.3%~93.6%之间。拟合的最佳房室模型为二室模型;测定的药动学参数为:tα/2=0.44±0.12h,tβ/2=5.3±3.1h,k21=0.25±0.43h-1,k10=1.2±0.4h-1,k12=0.39±0.50h-1,V=1.44±0.25L,CL=1.7±0.8L.h-1,AUC0-∞=140.5±39.3mg.L-1.h,AUC0-t=128.4±34.3mg.L-1.h。结论:异环磷酰胺在兔体内的代谢符合二室房室模型。     

环磷酰胺与异环磷酰胺对离体大鼠肝细胞毒性机制

目的 探讨环磷酰胺（CP）与异环磷酰胺（Ifo)对混悬培养大鼠肝细胞的毒性效应及其可能机制。方法 以两步灌流法消化成年大鼠肝细胞,并进行混悬培养。CP与Ifo分别以20mmol/L染毒,观察染毒后30、60、120和180min肝细胞的存活率、胞内酶泄漏以及肝细胞巯基、MDA含量的变化,并对肝细胞表面形态和超微结构进行观察。结果 随着染毒时间的延长,两药均引起肝细胞存活率逐渐下降,胞内酶泄漏加重,增养液中乳酸脱氢酶（LDH）、天冬氨酸转移酶（AST）活性增高,同时肝细胞总巯基（TSH）、非蛋白巯基（NPSH）、蛋白巯基（PSH）也逐渐下降,其中PSH下降在TSH耗竭中起主要作用。两药引起的这些改变CP有比Ifo重的趋势,肝细胞MDA含量未发现有显著增遍,形态学检查发现CP与Ifo20mmol/L染毒180min均使肝细胞表面出现“大疱”,胞内线粒体肿胀,空泡化,粗面内质网扩张,部分脱颗粒,内腔模糊。结论 CP与Ifo对混悬培养大鼠肝细胞有损伤作用。巯基物质的降低在两药肝细胞毒性中起重要作用。     

环磷酰胺的HPLC测定

环磷酰胺的ＨＰＬＣ测定朱耀华，陈桂良，赵蔚君，张顺妹（上海市药品检验所，上海２００２３３）ＨＰＬＣＤＥＴＥＲＭＩＮＡＴＩＯＮＯＦＣＹＣＬＯＰＨＯＳＰＨＡＭＩＤＥ￥ＺＨＵＹａｏ－Ｈｕａ；ＣＨＥＮＧｕｉ－Ｌｉａｎｇ；ＺＨＡＯＷｅｉ－Ｊｕｎ；ＺＨＡＮＧＳｈ...     

Ifosfamide pharmacokinetics

This review examines and details the pharmacokinetics of ifosfamide (a congener of cyclophosphamide) when administered by a number of commonly used chemotherapeutic regimes. The influence of route of administration, schedule of administration and dose on the pharmacokinetics of ifosfamide and its metabolites are discussed. Oral fractionated ifosfamide therapy, which causes an excessively high incidence of neurotoxicity, is similar to intravenous fractionated therapy in that it exhibits a time dependent increase in ifosfamide metabolic clearance. Five g/m² ifosfamide given intravenously as a short (half hour) or long (24 hr) infusion does not exhibit dose dependent (zero-order) pharmacokinetics. In patients who develop ifosfamide/mesna associated CNS toxicity the pharmacokinetics of parent ifosfamide are not aberrant. This implies that ifosfamide metabolites are more likely to be responsible for the neurotoxicity rather than the parent drug. The development of simple and more specific analytical methodology, will allow further studies of the pharmacokinetics of the active ifosfamide metabolite(s). This may lead to further optimisation of the therapeutic index of ifosfamide treatment.     

Ifosfamide encephalopathy

We describe a case of reversible encephalopathy caused by the recently released anticancer drug Ifosfamide. The clinical course, role of EEG in monitoring and predicting encephalopathy, and putative mechanism of neurotoxicity is discussed. Short infusion times and/or prior CNS disease may increase the risk of encephalopathy.     

Ifosfamide and mesna

The chemistry, pharmacology, pharmacokinetics, and adverse effects of ifosfamide and mesna are described separately, followed by a discussion of the adverse effects of concurrent ifosfamide and mesna, the clinical spectrum of ifosfamide, and the dosage and administration of the two drugs. Ifosfamide, an active analogue of cyclophosphamide, differs from other direct alkylating substances in that it requires biotransformation in the liver before it can exert its alkylating effects. The bioavailability of ifosfamide after oral administration exceeds 95%. The adverse effects of ifosfamide include hematologic, urinary tract, GI tract, and CNS toxicity. Mesna is a thiol compound designed to function as a regional detoxificant of urotoxic oxazaphosphorine cytostatics such as ifosfamide. The drug is rapidly oxidized in the plasma to its dimeric form, dimesna, one third of which is converted back to mesna by glutathione reductase. The mean total urinary availability of mesna administered orally is 76%. Mesna may produce gastrointestinal and allergic reactions. The adverse effects of concurrent ifosfamide and mesna include urinary tract and renal toxicity. Although current FDA-approved labeling is limited to refractory germ cell testicular cancer, ifosfamide has also shown efficacy in the treatment of lymphoma, lung cancer, and sarcomas. Optimum dosage and scheduling remain to be determined; studies suggest that a fractionated dosage schedule provides antineoplastic activity with tolerable toxicity. Ifosfamide, used in combination with mesna for uroprotection, provides a useful therapeutic option for the management of patients with testicular cancer, soft tissue sarcomas, or high-grade malignant lymphomas.     

Ifosfamide in pediatric oncology.

Since the number of patients seen in a pediatric oncology center is relatively small, it is difficult to perform single drug phase two studies, even on a national base. This also probably explains the lack of information on ifosfamide, despite the fact that it has now been used for more than 10 years in pediatrics. As long as chemotherapy plays such an important role in childhood cancer it remains of the utmost importance to determine the role of ifosfamide in the treatment of young cancer patients.     

Separation and pharmaco-toxicological studies of the enantiomers of Ifosfamide

The enantiomers of ifosfamide were isolated chromatographically by the use of an optically active adsorbent. The biological activities of the racemic product and of the enantiomers (+)- and (-)-ifosfamide were compared as to the acute toxicity after single intraperitoneal administration on mice. Futhermore, the antitumor activity has been compared with regard to the rat leukemia L 5222 and the haematotoxicological effect. Under the conditions given, no biological differences between these 3 ifosfamide preparations were observed.     

Ifosfamide: new idications-new dose strength. Limited evidence of effectiveness

In three new approved indications (non Hodgkin's lymphoma, Hodgkin's lymphoma and acute lymphoblastic leukaemia) and in three previously existing indications (ovarian cancer, soft tissue sarcomas and osteogenic sarcomas), non comparative trials show that ifosfamide can induce tumour regression in patients who relapse after a first course of chemotherapy (sometimes containing cyclophosphamide). But clinical assessment has not yet formally demonstrated that this leads to a significant increase in survival time and/or quality of life, mainly because of toxicity. In cervical cancer, a new indication, a comparative trial shows higher tumour response rates with the ifosfamide + cisplatin combination than with cisplatin alone. However, the greater toxicity of the combination and the lack of any increase in survival must both be taken into account. In breast cancer and lung cancer comparative trials show no difference in efficacy between cyclophosphamide and ifosfamide, while toxicity may be worse with ifosfamide. Ifosfamide has no specific value in these approved indications. The same applied to ENT cancer, against which ifosfamide seems to have little activity.     

顶空气相色谱法测定异环磷酰胺中多种有机溶剂残留量

目的建立分离测定异环磷酰胺原料中残留的多种有机溶剂的方法。方法采用顶空气相色谱法,色谱柱为HP—INNOWax毛细管柱,栽气为氮气,FID检测器,柱温采用程序升温,外标法测定异环磷酰胺中乙醚、丙酮、四氢呋喃、二氯甲烷、甲醇、乙醇的残留量。结果6种有机溶剂能完全分离,质量浓度在所考察的范围内与峰面积线性关系良好,r为0．9996～1．0000,平均回收率为94．6％～100．5％,精密度的RSD均不大于10％,检测限为20～2350ng／mL。结论顶空气相色谱法快速、灵敏、准确,适用于异环磷酰胺中多种有机溶剂残留量的测定。     

Ifosfamide nephrotoxicity in children: a mechanistic base for pharmacological prevention

The antineoplastic drug ifosfamide (IFO) in the treatment of solid tumors, particularly in children, is the cause of severe nephrotoxicity. Although it is a potent and effective chemotherapeutic agent, the associated nephrotoxicity has a serious impact on the health and the quality of life of exposed children. The toxic metabolite of IFO thought to be responsible for IFO-induced kidney damage is chloroacetaldehyde (CAA). Those suffering from nephrotoxicity typically develop tubular and glomerular toxicities, with the most severe form being Fanconi's syndrome. As the mode of toxicity of CAA seems to be primarily owing to oxidative stress, the use of antioxidants as a protective measure for the kidneys is a promising strategy. In this review, we highlight recent research that supports the local renal production of CAA as the proximate cause of IFO-induced nephrotoxicity with age as an important risk factor, those under the age of three being the most vulnerable. Most importantly, we focus on the potential advantages of the antioxidant N-acetylcysteine owing to both its antioxidant properties and its current use clinically in pediatrics.     

Ifosfamide. Metabolic studies, new therapeutic approaches and new analogs

Ifosfamide (IFO), an oxazaphosphorine-type anticancer alkylating agent, was found to be particularly useful in the treatment of a wide variety of neoplasm in adults and children. IFO is a positional isomer of cyclophosphamide (CPA) and was introduced into clinical practice in the 80s and has recently attracted much attention. Therapeutic application of high-dose IFO is limited by several side-effects; among them neurotoxicity and nephrotoxicity give the greatest concern. The presence of these side-effects is likely to be connected with the metabolism of this drug. In recent years there have been many studies aiming better understanding metabolism of this drug, employing new therapeutic approaches and preparing new analogs.