mesna and sodium-thiosulfate

Nephrotoxicity is a relatively common and potentially serious adverse effect of treatment with certain cytotoxic drugs (especially ifosfamide). The patient may develop severe chronic proximal tubular toxicity. It is therefore very important to attempt to reduce the frequency and severity of acute and chronic nephrotoxicity resulting from chemotherapy. A logical approach is described, with particular reference to ifosfamide and cisplatin, involving improved evaluation of the important clinical features of nephrotoxicity and a greater understanding of its pathogenesis. This approach will facilitate the development of logical preventive strategies, or less toxic analogues, or both. The methods used may also enable prediction of the potential nephrotoxicity of newly developed cytotoxic agents.

Topics: Adult; Antineoplastic Agents; Cell Line; Chelating Agents; Child; Child, Preschool; Cisplatin; Humans; Ifosfamide; Kidney; Kidney Diseases; Kidney Tubules; Mesna; Neoplasms; Prognosis; Risk Factors; Thiosulfates

Renal dysfunction and urinary disorders are the most troublesome adverse reaction to anticancer agents such as cisplatin (CDDP) and ifosfamide (IFM). A number of antidotes such as sodium thiosulfate (STS), WR-2721, thiourea, diethyldithiocarbamate and bismuth subnitrate have been tested to reduce the nephrotoxicity of CDDP. One notable method previously reported by Baba et al. and Pfeifle et al involves the i.v. administration of STS to prevent the nephrotoxicity of CDDP given locally. Since STS has been proven clinically effective in reducing such side effects, we initiated a study of STS in patients with advanced non-small-cell lung carcinoma who were given a combination of CDDP and vindesine (VDS) systemically. Urinary levels of beta 2-microglobulin (BMG) and N-acetyl-beta-D-glucosaminidase (NAG) were measured as an index of proximal tubular function. Analysis of both levels indicated that STS suppressed CDDP nephrotoxicity to a minimal level. Therefore, the present study clearly demonstrates that systemic administration of STS reduces the side effects of CDDP to a minimal level without impairing its antitumor activity and that STS treatment is applicable in a repeated chemotherapy using CDDP alone or in combination with other antitumor agents. Furthermore, it has been reported that urinastatin and fosfomycin may exert potent effects to reduce untoward nephrotoxicity of CDDP. IFM causes urinary disorders such as hematuria, reducing its clinical usefulness, Sodium 2-mercaptoethane sulfonate (mesna) is the thiol compound which binds specifically to the urinary toxic metabolites of IFM, and thereby decreases the undesirable effect of IFM on the lower urinary tract, especially on the bladder. Recently, it was reported by a Osaka mesna study group that mesna is useful for the prevention of IMF-induced urinary disorders. It was considered that above new treatments were required in repeating chemotherapy which induced urogenital toxicity.

Topics: Antidotes; Antineoplastic Agents; Cisplatin; Humans; Ifosfamide; Kidney Diseases; Mesna; Thiosulfates

The reactive and rapidly excreted thiol mesna (2-mercaptoethane-sulphonate sodium) has the potential to reduce the dose-limiting nephrotoxicity of cisplatin by chemical neutralisation of the latter in the kidney. The reaction kinetics of cisplatin with mesna and its disulphide, dimesna, was studied at 37 degrees C in unbuffered 0.15 mol/l NaCl (pH 5.3) and in 0.15 mol/l NaCl buffered with 0.02 mol/l Hepes (pH 7.4). The reaction mixtures were analysed for intact cisplatin. In the presence of mesna or dimesna 0.5 mol/l as anticipated in urine for conditions of renal protection, the half-life (t1/2) of 0.2 mmol/l cisplatin was less than 6 min. t1/2 of 151 and 629 min were found in the presence of mesna and dimesna concentrations of 5 mmol/l and 3 mmol/l, respectively, anticipated in plasma under conditions of renal protection. Cis-diamminemonoaquamonochloroplatinum(II) 0.2 mmol/l reacted rapidly with 50 mmol thiosulphate and 0.5 mol/l (di)mesna (t1/2 less than or equal to 1 min). This platinum species also reacted rapidly with 2.6 mmol/l thiosulphate (t1/2 less than 1 min), a concentration reached in plasma for conditions under renal protection. Reaction of the monoaquated form of cisplatin proceeded slowly in the presence of dimesna or mesna concentrations (less than 5 mmol/l), as anticipated in plasma under renal protecting conditions. It is hypothesised that renal protection by the strong nucleophiles, thiosulphate, mesna and dimesna occurs rather by neutralisation of the aquated species in the lumen of the renal tubulus than by neutralisation of intact cisplatin, and that neutralisation of these species in plasma contributes significantly to the protecting effect.

Topics: Chromatography, Ion Exchange; Cisplatin; Drug Interactions; Half-Life; Kinetics; Mesna; Thiosulfates

The effects of fractionated doses, in vivo thiol modulation, and antifibrinolytic therapy on the expression of lung damage induced by cyclophosphamide (Cy) were evaluated in C3H mice. The protein content of lung lavage samples taken 4 days after Cy treatment was used as an early indicator of damage. In fractionation studies, little difference in lung protein was observed when 200 mg of Cy/kg was administered as a single dose or as two or four equal doses given daily, suggesting that little sparing effect occurred with fractionated doses of Cy. In experiments that tested the effects of exogenous thiol administration, mice treated with WR-2721 before Cy were protected against lung damage, whereas the use of sodium thiosulfate or mesna did not give this protection. Treatment with epsilon-aminocaproic acid, which inhibits the breakdown of fibrin clots, did not result in enhanced Cy damage as measured by lung lavage or breathing rate; this suggests that the extended presence of fibrin per se did not contribute to Cy-induced pulmonary damage.

Topics: Aminocaproic Acid; Animals; Cyclophosphamide; Female; Lung; Mesna; Mice; Mice, Inbred C3H; Thiosulfates

Fosfomycin and mesna were investigated in rats and mice concerning their detoxifying effects on cisplatin toxicity in comparison to sodium thiosulfate, a known protector against cisplatin nephrotoxicity. After separate i.p. injection of cisplatin and fosfomycin (500 mg/kg) or mesna (800 mg/kg) a slight increase in the 50% lethal dose of cisplatin was found in all animals. In mice sodium thiosulfate proved to be far more effective in preventing lethal toxicity and nephrotoxicity as measured by blood urea nitrogen increase. Fosfomycin and mesna were almost without influence on cisplatin treatment of L-1210 leukemia whereas their inhibition of the antitumor effect against S-180 ascites sarcoma (increase of in cisplatin dose to cure 50% of animals from 2.0 mg/kg to 3.5/4.7 mg/kg cisplatin) was similar to thiosulfate, which showed a strong inhibiting effect in the treatment of both tumors. In rats fosfomycin distinctively reduced the antitumor efficacy of cisplatin against Yoshida ascites sarcoma. Thus the concurrent injection of fosfomycin and mesna reduced both the toxicity and the antitumor activity of cisplatin. Therefore their simultaneous administration in addition to cisplatin via the same injection route should be avoided. Due to the weak detoxifying efficacy of fosfomycin and mesna they cannot be used instead of sodium thiosulfate for renal protection against cisplatin toxicity in local i.p. treatment modalities.

Topics: Animals; Cisplatin; Female; Fosfomycin; Kidney; Lethal Dose 50; Mercaptoethanol; Mesna; Mice; Mice, Inbred DBA; Thiosulfates