mesna and Hyperhomocysteinemia

Increased plasma total homocysteine (tHcy) is a risk factor for the development of atherosclerosis and thrombosis present in over 90% of patients with end-stage renal disease (ESRD). We hypothesized that 12 mg/kg intravenous mesna administered predialysis would cause a significant decrease in plasma tHcy compared to placebo.. Patients with ESRD were recruited for 1- and 4-week placebo-controlled, cross-over studies. Intravenous 12 mg/kg mesna or placebo was administered 3 times weekly predialysis.. One week of 12 mg/kg intravenous mesna significantly decreased predialysis plasma tHcy by 12.8 +/- 7.8% (placebo 23.4 +/- 8.0 micromol/l vs. mesna 20.5 +/- 7.6 micromol/l, p = 0.0044). Four weeks of treatment yielded no significant decline in predialysis plasma tHcy (placebo 18.3 +/- 8.5 micromol/l vs. mesna 18.7 +/- 6.3 micromol/l, p = 0.41).. Although 12 mg/kg mesna significantly enhances tHcy excretion, prolonged treatment causes no change in plasma tHcy.

Topics: Adult; Aged; Cross-Over Studies; Double-Blind Method; Female; Homocysteine; Humans; Hyperhomocysteinemia; Kidney Failure, Chronic; Male; Mesna; Middle Aged; Pilot Projects; Renal Dialysis

Increased plasma total homocysteine is a graded, independent risk factor for the development of atherosclerosis and thrombosis. More than 90% of patients with end-stage renal disease have hyperhomocysteinemia despite vitamin supplementation. It was shown in previous studies that a single intravenous dose of mesna 5 mg/kg caused a drop in plasma total homocysteine that was significantly lower than predialysis levels 2 d after dosing. It was hypothesized 5 mg/kg intravenous mesna administered thrice weekly, before dialysis, for 8 wk would cause a significant decrease in plasma total homocysteine compared with placebo.. Patients with end-stage renal disease were randomly assigned to receive either intravenous mesna 5 mg/kg or placebo thrice weekly before dialysis. Predialysis plasma total homocysteine concentrations at weeks 4 and 8 were compared between groups by paired t test.. Mean total homocysteine at 8 wk in the placebo group was 24.9 micromol/L compared with 24.3 micromol/L in the mesna group (n = 22 [11 pairs]; mean difference 0.63). Interim analysis at 4 wk also showed no significant difference between mesna and placebo (n = 32 [16 pairs]; placebo 26.3 micromol/L, mesna 24.5 micromol/L; mean difference 1.88). Multivariable adjustments for baseline characteristics did not alter the analysis. Plasma mesna seemed to reach steady-state concentrations by 4 wk.. It is concluded that 5 mg/kg mesna does not lower plasma total homocysteine in hemodialysis patients and that larger dosages may be required.

Topics: Aged; Double-Blind Method; Drug Administration Schedule; Female; Homocysteine; Humans; Hyperhomocysteinemia; Injections, Intravenous; Kidney Failure, Chronic; Male; Mesna; Renal Dialysis; Treatment Outcome

In hyperhomocysteinemic patients, after reaction with homocysteine-albumin mixed disulfides (HSS-ALB), mesna (MSH) forms the mixed disulfide with Hcy (HSSM) which can be removed by renal clearance, thus reducing the plasma concentration of total homocysteine (tHcy). In order to assess the HSS-ALB dethiolation via thiol exchange reactions, the distribution of redox species of cysteine, cysteinylglycine, homocysteine and glutathione was investigated in the plasma of healthy subjects: (i) in vitro, after addition of 35 μM reduced homocysteine (HSH) to plasma for 72 h, followed by MSH addition (at the concentration range 10-600 μM) for 25 min; (ii) in vivo, after oral treatment with methionine (methionine, 200 mg/kg body weight, observation time 2-6 h). In both experiments the distribution of redox species, but not the total amount of each thiol, was modified by thiol exchange reactions of albumin and cystine, with changes thermodynamically related to the pKa values of thiols in the corresponding mixed disulfides. MSH provoked a dose-response reversal of the redox state of aged plasma, and the thiol action was confirmed by in vivo experiments. Since it was observed that the dimesna production could be detrimental for the in vivo optimization of HSSM formation, we assume that the best plasma tHcy lowering can be obtained at MSH doses producing the minimum dimesna concentration in each individual.

Topics: Adult; Antioxidants; Drug Evaluation, Preclinical; Female; Homocysteine; Humans; Hyperhomocysteinemia; Male; Mesna; Methionine; Middle Aged; Oxidation-Reduction