Fertility in patients with multiple sclerosis: current knowledge and future perspectives

Abstract The issue of fertility in patients with multiple sclerosis (MS) has not been exhaustively studied. Epidemiological data have suggested that spontaneous fecundity might be reduced; several endocrine and sexual disturbances potentially interfering with reproduction have been evidenced in MS patients of both sexes. Moreover, some medical treatments used in MS (e. g., mitoxantrone, cyclophosphamide) may exert detrimental effects on spermatozoa as well as on oocytes, leading to early impairment of fertility. This review illustrates the factors potentially interfering with fertility in MS and discusses the therapeutic tools that may be used to promote fertility in these patients. The safety of hormonal therapies in MS is also examined. The current applications of assisted reproductive technology (ART) are discussed, including in vitro fertilisation (IVF) techniques. Currently available methods to preserve fertility in patients that undergo cytotoxic treatments by means of sperm/oocyte cryostorage or by ovarian fragment cryopreservation and autografting are considered.     

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.     

灌注米托蒽醌预防膀胱癌术后复发的临床观察

目的探讨膀胱灌注米托蒽醌(MTZ)预防膀胱癌术后复发的疗效及安全性。方法对116例浅表性膀胱癌患者行TURBT或膀胱部分切除术,术后1周用MTZ10mg进行膀胱内定期灌注,并随访5~72月。结果116例患者均未见全身性药物不良反应,仅7例出现轻微膀胱刺激症状;复发12例,复发率10.34%。结论膀胱灌注MTZ预防膀胱癌术后复发的疗效确切,不良反应少,安全性好。     

中剂量阿糖胞苷联合米托蒽醌及依托泊甙巩固治疗对难治复发性AML患儿的疗效及安全性

【摘要】目的 探讨中剂量阿糖胞苷联合米托蒽醌及依托泊甙巩固治疗对难治复发性急性髓系白血病（AML）患儿的疗效及安全性。方法 选取2008年12月～2012年12月我院收治的行阿糖胞苷联合米托蒽醌、依托泊甙巩固治疗的难治复发性AML患儿96例作为研究对象,采用回顾性分析法分析所有患儿的临床及随访资料,根据阿糖胞苷使用剂量的不同将其分为低剂量组、中剂量组和高剂量组3组,每组各32例,治疗结束后分析并比较3组患儿近期和远期临床疗效,并记录3组患儿治疗过程中不良反应的发生情况。结果 近期临床总有效率3组相比较差异均无统计学意义（P＞0.05）,且所有部分缓解的患儿中8例患儿进行骨髓移植治疗后治愈,余42例继续采用药物进行治疗;3组患儿5年总生存率（OS）比较差异有统计学意义（P＞0.05）,中剂量组和高剂量组患儿5年OS均高于低剂量组（P＞0.05）,但中剂量和高剂量组5年OS比较差异无统计学意义（P＞0.05）,3组患儿其5年无事件生存年率（EFS）比较差异均无统计学意义（P＞0.05）;3组患儿在骨髓抑制和心脏毒性的不良反应方面比较差异无统计学意义（P＞0.05）,但中剂量组和高剂量组患儿其感染、胃肠道反应以及肝肾功能损伤的不良反应发生率均显著高于低剂量组,且高剂量组患儿胃肠道和肝肾功能损伤的不良反应发生率均高于中剂量组患儿,组间比较差异均有统计学意（P＞0.05）。结论 中剂量阿糖胞苷联合米托蒽醌及依托泊甙巩固治疗对难治复发性AML患儿具有较好的临床疗效和较低的毒副反应,存在一定的安全性,可作为临床上治疗AML患儿的首选治疗方案。     

Intensive chemotherapy with mitoxantrone administered as a single injection in patients with high-risk acute myeloid leukemia: results of the EMA 2000 trial

Following a dose-escalation study performed to assess the maximally tolerated dose of high-dose mitoxantrone in a single injection combined with chemotherapy, a phase II trial (EMA 2000 regimen) was performed in patients with refractory or relapsed acute myelogenous leukemia (AML) between October 2000 and December 2003. Sixty-two patients entered the study and received mitoxantrone 45 mg/m² on day 1 in combination with cytarabine and etoposide. Overall, 39 patients (63%) achieved complete remission (CR). Four patients died during remission induction, and 19 patients had resistant disease. Median time to granulocyte and platelet recovery was 34 and 39 days, respectively. The predominant non-hematologic toxicity was infection, with 53% severe infections. Thirty-three of the 39 remitters received subsequent treatment consisting of maintenance chemotherapy courses in 17 patients, allogeneic stem cell transplantation (SCT) in 7 patients, and autologous SCT in 9 patients. The median overall survival of the entire cohort was 8.1 months, with 18% at 2.5 years. EMA chemotherapy using a single injection of mitoxantrone is effective in the treatment of high-risk AML. CR proportion was significantly higher in patients with a first CR duration 6 months when compared with those from a control trial using standard-dose mitoxantrone (90 vs 70%, p=0.03).     

盐酸米托蒽醌治疗恶性肿瘤的近期疗效

应用国产盐酸米托蒽醌注射液单药和组成联合化疗方案治疗各类恶性肿瘤230例,在可评定疗效的218例中,白血病单药有效率43.8％,联合化疗有效率81.8％;恶性淋巴瘤单药有效率61％,联合化疗有效率65.5％;乳腺癌单药有效率34.6％,联合化疗有效率50％。主要毒副作用是白细胞减少,未见严重的心脏毒性。我们认为米托蒽醌是一有效的、值得临床推广应用的抗肿瘤药。     

不同四种方案治疗骨髓增生异常综合征临床研究

目的 研究不同四种方案治疗骨髓增生异常综合征(MDS)疗效,寻求有效的治疗的策略.方法 经FAB标准确诊的MDS患者39例在积极支持治疗下,按个体差异采取不同的化疗方案进行诱导化疗.结果 小剂量阿糖胞苷(LD-Ara-C)组治疗10例,完全缓解(CR)率13.5%;MA组治疗8例,CR率45.0%;DA组治疗6例,CR率40.5%;CAG组治疗15例,CR率60.5%,PR者经2个疗程治疗后,余改用其它方案治疗.结论 CAC方案治疗MDS,CR率高.不良反应小,为MDS患者延长生存期,改善生活质量,提供一种可行的方案.     

Rationale for the use of mitoxantrone in multiple sclerosis

Mitoxantrone is a member of the anthracendione family developed to treat malignancies and increasingly used to treat multiple sclerosis (MS). It has been studied as a treatment for MS since the late 1980s, and is licensed in a number of countries for progressive and worsening MS. Review of the published earlier open-label, and more recently of controlled trials suggests that mitoxantrone is efficacious in cases of worsening MS that have an inflammatory component as evidenced by progression with or without superimposed relapses and/or gadolinium (Gd) enhancing magnetic resonance (MR) lesions. Today there is no robust evidence of efficacy in primary progressive MS or in later stages of secondary progressive MS beyond an EDSS score of 6. Relevant immunomodulatory mechanisms act both on T- and B-cell function, and mitoxantrone has selective immune effects in MS by decreasing levels of TNF-alpha, IL-2, IL-2R-beta1, IL-10 and IFN-gamma. Adverse events include nausea, alopecia, infections, menstrual disorders, risk of cardiotoxicity and malignancy. Different regimens are used according to different regulatory demands in different countries. The two most commonly used regimens are every 3 months intravenous (i.v.) 12 mg/m2 for 2 years or 20 mg mitoxantrone (i.v.) combined with 1 g methylprednisolone (i.v.) every 4 weeks for 6 months. The cumulative life dose in MS patients is 140 mg/m2. Mitoxantrone is currently used as a second line drug in MS patients whose disease is not controlled by beta-interferon or glatiramer acetate. In this review, we will discuss the clinical disease patterns of MS patients who are most likely to benefit from mitoxantrone, its magnitude of clinical effect, and limitations of using mitoxantrone in MS. Mitoxantrone as a second line therapy in non-responders of beta-interferon and glatiramer acetate will be assessed. Recent strategies of combination therapy, and the optimal dose regimen will also be discussed.     

Bendamustine plus mitoxantrone--a new effective treatment for advanced chronic lymphocytic leukaemia: results of a phase I/II study

The toxicity and efficacy of the combination bendamustine plus mitoxantrone (BM) was evaluated in 22 patients with advanced chronic lymphocytic leukaemia (CLL). Twenty out of twenty-two patients had received at least one prior regimen. Median age was 71 years (range 53-86). Six out of twenty-two patients were Binet stage B and 16/22 Binet stage C. Bendamustine was given in escalating doses from 80 up to 240 mg/m₂ divided in two to three doses per course, mitoxantrone was given as short infusion with 8 up to 10 mg/m₂ per course. The number of courses was limited to six and chemotherapy stopped when a complete remission (CR) or partial remission (PR) according to NCI-Criteria was achieved. Haematotoxicity and infection were dose limiting with 4/6 patients suffering from grade 3 infectious complication in the bendamustine level with 240 mg/m₂. Six out of twenty-two patients achieved a CR and 13/22 patients a PR resulting in an overall response rate of 86% (19/22 patients). Median time to progression was 10 months (range 4-22) and median survival 39 months (range 6-50). For further studies we recommend a bendamustine dose of 150 mg/m₂ combined with 10 mg/m₂ mitoxantrone.     

Synthesis of 2-Fluoro N10-Substituted Acridones and Their Cytotoxicity Studies in Sensitive and Resistant Cancer Cell Lines and Their DNA Intercalation Studies

A series of 2-fluoro N¹⁰-substituted acridone derivatives with varying alkyl side chain length with propyl, butyl substitution, and a tertiary amine group at the terminal end of the alkyl side chain were synthesized and screened against cancer cell lines SW 1573, SW 1573 2R 160 (P-gp substrate) which are non-small lung cancer cell lines, MCF-7, MCF-7/MR (BCRP substrate) are breast cancer cell lines, 2008 WT, 2008MRP1, 2008MRP2, 2008MRP3 are ovarian cancer cell lines, and human embryo kidney cell lines like HEK293, HEK293 MRP4, and HEK293 MRP5i. The propyl-series compounds showed lipophilicity in the range of 1.93 to 4.40 and the butyl series in the range of 2.37 to 4.78. The compounds 4 , 7 , and 8 showed good cytotoxicity against the 60 human cancer cell line panel of the National Cancer Institute, USA. The compounds 14 and 15 showed a better cytotoxicity in most of the cancer cell lines compared to other compounds tested. The DNA-binding properties of the compounds were evaluated based on their affinity or intercalation with CT-DNA measured with absorption titration. The compound 11 bearing planar tricyclic ring linked with a butyl methylpiperazino side chain showed the highest binding affinity with a binding constant (K_i) of 10.38×10 M^–1. Evaluation of the compounds in cell lines with an overexpression of various multidrug resistance-related protein (MRP), P-glycoprotein (P-gp), or Breast Cancer Resistance Protein (BCRP) showed that all compounds are not substrates for any of these transporters.