A prospective randomized evaluation of three schedules of mesna administration in patients receiving an ifosfamide-containing chemotherapy regimen: sustained efficiency and simplified administration

Chemotherapy with oxazaphosphorines, such as ifosfamide, is often limited by unacceptable urotoxicity. Without uroprotection hemorrhagic cystitis becomes doselimiting. Mesna, a thiol compound, is a drug able to bind the toxic metabolites, forming nontoxic compounds in the urine. A total of 122 patients were enrolled in this study and 228 chemotherapy cycles with an ifosfamide-containing regimen were performed (225 evaluable). Mesna was given at the same total dose as the ifosfamide in all arms. On arm A, mesna was given i. v. in equal doses 15 min before and 4 h and 8 h following the ifosfamide dose. On arm B, mesna was given in three equivalent doses 15 min before (i.v.) and 4 h (i.v.) and 8 h (p.o., double dose) following ifosfamide. On arm C, mesna was given i.v. intwo equal doses given 15 min before and 4 h following. The incidence of urotoxicity was very low (lower than 15%) in the three arms, 0% in A, 1.36% in B and 2.70% in C. All three arms were equally efficient. Schedule C was considered superior to the others, since it was equally effective, simpler and more convenient.     

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.     

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.     

美司钠注射液有关物质及其含量测定

目的建立测定美司钠注射液有关物质及其含量的高效液相色谱法。方法采用CAPCELL PAK C18柱（4.6 mm×250 mm,5 μm）,流动相为甲醇-磷酸盐缓冲液（磷酸二氢钾、磷酸氢二钾各2.94 g,四丁基硫酸氢铵2.6 g,溶于水660 mL,用磷酸调节pH至2.3）（35：65）,流速1.0 mL•min－1,检测波长235 nm。结果美司钠和双硫化合物的线性范围分别为0.002～7.4（r＝1.000 0）和0.003～0.300 mg•mL－1（r＝1.000 0）;平均加样回收率分别为99.8%（RSD＝0.6%）和99.8%（RSD＝0.7%）。结论该方法操作简便,专属性强,定量准确,可用于该制剂的质量控制。     

In vivo mesna and amifostine do not prevent chloroacetaldehyde nephrotoxicity in vitro

Chloroacetaldehyde (CAA) is the putative metabolite responsible for ifosfamide-induced nephrotoxicity. Whereas evidence suggests that sodium 2-mercaptoethanesulfonate (mesna) and amifostine protect renal cells against CAA toxicity in vitro, their efficacy in clinical studies is controversial. To better understand the discrepancy between in vivo and in vitro results, we combined the in vivo intraperitoneal administration of either saline or mesna (100 mg/kg) or amifostine (200 mg/kg) in rats and the in vitro study of CAA toxicity to both proximal tubules and precision-cut renal cortical slices. The measured renal cortical concentrations of mesna and amifostine were 0.6±0.1 μmol/g and 1.2±0.2 μmol/g, respectively; these drugs did not cause renal toxicity. Despite this, none of the adverse effects of 0.5 mM CAA was prevented by the previous in vivo administration of mesna or amifostine. Toxicity of 0.5 mM CAA to rat proximal tubules was shown by the fall of cellular adenosine triphosphate (ATP), total glutathione and coenzyme A + acetyl-coenzyme A levels and by the altered metabolic viability of renal cells. Long-term exposure of cortical slices to CAA concentrations ≥30 μM caused severe cell toxicity (i.e. decrease in cellular ATP, total glutathione, and coenzyme A + acetyl-coenzyme A levels), which was not prevented by the in vivo administration of mesna or amifostine.     

Effect of a mucolytic agent on collagen fibres: An optical and polarized light histological study

The discovering of new substances acting on collagenic fibrous scar tissue to prevent its formation or to obtain its easier dissection during second-look surgery is, at present time, a big challenge. In this study we consider the effect of a mucolytic agent (MESNA) on collagen fibres using an experimental model of Achilles' tendon. We injected a pre-defined quantity of MESNA in the context of the tendineal fibres of Achilles' tendon of 7 sheep. Each tendon was divided in three parts and for each both longitudinal and transversal slices were obtained. We followed for 6 weeks the histological modifications of the collagen fibres by classic and polarized light analysis. The animals were divided into 3 groups. The first comprised animals killed at 1 h and 3 days after the injection. In their tendons the histological analysis didn't find out any structural alteration. Tendons of animals killed at 3 weeks showed the separation of collagen fibres with empty spaces replaced partially by mesenchimal cellular infiltrates and by an amorphous basophilic tissue. In 6 weeks killed animals there was a quite full recovery of tendineal structure evident from both classic and polarized light analysis. By the analysis of these results it is possible to say that MESNA exerts an effect on collagen fibres that results in modification of the tendineal structure with infiltration and proliferation of mesenchinal cells. Considering its biochemical and pharmacodinamic characteristics and its absent toxicity on cellular structures, MESNA represents a good possibility for studies about fibrosis also in human models.     

Interaction between cisplatin and mesna in mice

Summary The uroprotectant thiol mesna was found to protect adult CD-1 mice from high-dose cisplatin lethality. Mesna doses of 50 mg/kg were given with cisplatin, or 5 min after cisplatin (25 or 30 mg/kg) and acute survival was increased in non-tumor-bearing mice. In contrast, mesna mixed directly with cisplatin significantly reduced cisplatin antitumor effects in DBA/2J mice given 10⁶ P-388 leukemia i.p. Mesna administered i.p. 5 min after cisplatin (6,8 or 10 mg/kg) did not reduce cisplatins' antitumor efficacy in this same tumor model. Mesna appears to inactivate cisplatin directly in vitro but possibly not in vivo if separate injections are used.     

Attenuation of bleomycin-induced lung fibrosis in rats by mesna

Lung fibrosis is a common side effect of the chemotherapeutic agent, bleomycin. Current evidence suggests that reactive oxygen species may play a key role in the development of lung fibrosis. The present study examined the effect of mesna on bleomycin-induced lung fibrosis in rats. Animals were divided into three groups: (1) saline control group; (2) Bleomycin group in which rats were injected with bleomycin (15 mg/kg, i.p.) three times a week for four weeks; (3) Bleomycin and mesna group, in which mesna was given to rats (180 mg/kg/day, i.p.) a week prior to bleomycin and daily during bleomycin injections for 4 weeks until the end of the treatment. Bleomycin treatment resulted in a pronounced fall in the average body weight of animals. Bleomycin-induced pulmonary injury and lung fibrosis was indicated by increased lung hydroxyproline content, and elevated nitric oxide synthase, myeoloperoxidase, platelet activating factor, and tumor necrosis factor-alpha in lung tissues. On the other hand, bleomycin induced a reduction in reduced glutathione concentration and angiotensin converting enzyme activity in lung tissues. Moreover, bleomycin-induced severe histological changes in lung tissues revealed as lymphocytes and neutrophils infiltration, increased collagen deposition and fibrosis. Co-administration of bleomycin and mesna reduced bleomycin-induced weight loss and attenuated lung injury as evaluated by the significant reduction in hydroxyproline content, nitric oxide synthase activity, and concentrations of myeoloperoxidase, platelet activating factor, and tumor necrosis factor-alpha in lung tissues. Furthermore, mesna ameliorated bleomycin-induced reduction in reduced glutathione concentration and angiotensin activity in lung tissues. Finally, histological evidence supported the ability of mesna to attenuate bleomycin-induced lung fibrosis and consolidation. Thus, the findings of the present study provide evidence that mesna may serve as a novel target for potential therapeutic treatment of lung fibrosis.     

美司钠联合水化、强迫利尿、碱化预防造血干细胞移植后出血性膀胱炎

 目的　分析美司钠联合水化、强迫利尿、碱化对造血干细胞移植（HSCT）出血性膀胱炎（HC）的预防效果。方法　32例接受HSCT的患者,2例重型再生障碍性贫血（SAA）采用全身照射+环磷酰胺（TBI-CTX）预处理方案,其余30例均采用经典的白消安+CTX（BU-CTX）预处理方案,所有患者均采用美司钠联合水化、强迫利尿、碱化预防HC,并给予更昔洛韦和阿昔洛韦预防巨细胞病毒（CMV）和其他病毒感染,监测移植前后血CMV-IgM水平。鼓励患者每小时排尿,检测尿pH值并计算尿量,每6 h复查一次尿常规并测中心静脉压（CVP）,每8 h检测血电解质。结果　仅1例患者移植后6个月出现迟发型Ⅱ级HC,经过水化、碱化、利尿、止血、抗移植物抗宿主病（GVHD）及更昔洛韦抗病毒治疗,35 d后患者HC治愈,其余31例均未出现HC。患者均未出现循环负荷过重造成的不良后果,未出现明显的水电解质及酸碱平衡紊乱。结论　美司钠联合水化、强迫利尿、碱化预防HC是安全、有效的。     

Ifosfamide and mesna in the treatment of malignant disease mesna as urothelial protector

Summary One hundred and forty-six patients with advanced malignant disease were treated with 6 different dosage schedules of ifosfamide (IFX). Mesna was used as urothelial protector. With mesna, urothelial toxicity was moderate, and single doses of up to 7 g/m² could be administered without intolerable urotoxicity. Leukopenia was the dose-limiting factor in this study. Unexpected pulmonary edema occurred in 3 patients. Therapeutic results were disappointing. A malignancy identified in this study that warrants further investigation with IFX and mesna, is malignant mesothelioma.