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Mizoribine: a new approach in the treatment of renal disease.

Kawasaki Y - Clin. Dev. Immunol. (2009)

Bottom Line: The immunosuppressive effect of MZB has been reported to be due to the inhibition of DNA synthesis in the S phase of the cell cycle.Because of its relative lack of toxicity, during the past decade MZB has been frequently used instead of azathioprine as a component of immunosuppressive drug regimens.This review summarizes the published findings on the efficacy of MZB for renal disease including IgA nephropathy, lupus nephritis, and NS, as well as of oral MZB pulse therapy for severe lupus nephritis and NS, and also the mechanism of the effect of oral MZB pulse therapy on the lymphocyte cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima City, Fukushima 960-1295, Japan. kyuki@fmu.ac.jp

ABSTRACT
Mizoribine (MZB) is an imidazole nucleoside and an immunosuppressive agent. The immunosuppressive effect of MZB has been reported to be due to the inhibition of DNA synthesis in the S phase of the cell cycle. Because of its relative lack of toxicity, during the past decade MZB has been frequently used instead of azathioprine as a component of immunosuppressive drug regimens. MZB is being used to treat renal transplantation patients, IgA nephropathy, lupus erythematosus, and childhood nephrotic syndrome (NS), and some recent studies have assessed the efficacy of oral MZB pulse therapy for severe lupus nephritis, steroid-resistant NS, and frequently relapsing-steroid-dependent NS. This review summarizes the published findings on the efficacy of MZB for renal disease including IgA nephropathy, lupus nephritis, and NS, as well as of oral MZB pulse therapy for severe lupus nephritis and NS, and also the mechanism of the effect of oral MZB pulse therapy on the lymphocyte cell cycle.

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Related in: MedlinePlus

Change in the serum MZB concentration of each patient on the days when MZB was administered.
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Related In: Results  -  Collection


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fig1: Change in the serum MZB concentration of each patient on the days when MZB was administered.

Mentions: The peak blood level of MZB, during regular MZB therapy, that is, 3 mg/kg daily in three divided, the peak levels of the drug has been reported to be approximately 0.5 μg/mL [5]. It has recently been reported that peak blood MZB levels in the 3.0–6.0 μg/dL are sufficient to inhibit the human MLR [6]. Thus, the higher serum MZB concentrations achieved by pulse therapy are needed to inhibit disease activity. Stypinski et al. [23] reported that higher doses than the current clinical dosage of 2–5 mg/kg day may be needed to maintain the efficacy of MZB. The safety, tolerability and pharmacokinetics of MZB in two clinical trials of higher-dose MZB administration to healthy male volunteers have been reported. Forty-eight healthy White male nonsmokers participated in two randomized, double-blind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9, and 12 mg/kg) and 16 in a multiple-dose study (6 mg/kg/day once daily for 5 days or twice daily for 7 days), and standard assessments of safety, tolerability, and pharmacokinetics were performed. The safety profiles in both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg/kg/day) in the multiple-dose study. After oral MZB reached its peak serum concentrations within 2-3 hours and was eliminated mostly via the kidney (65–100% of dose), its serum half-life was 3 hours. Only the 12 mg/kg/day group had trough concentrations that were within the therapeutic window (trough concentrations >0.5 but <3 μg/mL). Based on the safety profile of MZB and current pharmacokinetic information, a new starting dose in the 6–12 mg/kg/day range is recommended for kidney transplant patients in the up to 3-month acute phase following transplantation. Kawasaki et al. reported a peak serum MZB concentration of 1.4–4.8 μg/mL and a morning trough serum MZB concentration of 0–0.3 in 8 patients with NS when MZB was given orally in a dose of 10 mg/kg body weight daily (maximum total daily dose 500 mg) in three divided doses, 2 days a week (Figure 1) [24, 25]. In addition, Kawasaki et al. found that the peak serum concentration was 3.0–5.1 μg/mL, the AUC 0–4 of MZB was 7.0–16.0 μg · h/mL and the morning trough serum MZB concentration was 0 μg/mL (Table 1), when MZB was given orally in a dose of 6 mg/kg body weight daily (maximum total dose 300 mg) twice a week in 11 patients with frequently relapsing NS [26].


Mizoribine: a new approach in the treatment of renal disease.

Kawasaki Y - Clin. Dev. Immunol. (2009)

Change in the serum MZB concentration of each patient on the days when MZB was administered.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2801010&req=5

fig1: Change in the serum MZB concentration of each patient on the days when MZB was administered.
Mentions: The peak blood level of MZB, during regular MZB therapy, that is, 3 mg/kg daily in three divided, the peak levels of the drug has been reported to be approximately 0.5 μg/mL [5]. It has recently been reported that peak blood MZB levels in the 3.0–6.0 μg/dL are sufficient to inhibit the human MLR [6]. Thus, the higher serum MZB concentrations achieved by pulse therapy are needed to inhibit disease activity. Stypinski et al. [23] reported that higher doses than the current clinical dosage of 2–5 mg/kg day may be needed to maintain the efficacy of MZB. The safety, tolerability and pharmacokinetics of MZB in two clinical trials of higher-dose MZB administration to healthy male volunteers have been reported. Forty-eight healthy White male nonsmokers participated in two randomized, double-blind, placebo-controlled trials: 32 in a single-dose study (3, 6, 9, and 12 mg/kg) and 16 in a multiple-dose study (6 mg/kg/day once daily for 5 days or twice daily for 7 days), and standard assessments of safety, tolerability, and pharmacokinetics were performed. The safety profiles in both studies were generally unremarkable, except for elevated serum uric acid concentrations at the highest dose (12 mg/kg/day) in the multiple-dose study. After oral MZB reached its peak serum concentrations within 2-3 hours and was eliminated mostly via the kidney (65–100% of dose), its serum half-life was 3 hours. Only the 12 mg/kg/day group had trough concentrations that were within the therapeutic window (trough concentrations >0.5 but <3 μg/mL). Based on the safety profile of MZB and current pharmacokinetic information, a new starting dose in the 6–12 mg/kg/day range is recommended for kidney transplant patients in the up to 3-month acute phase following transplantation. Kawasaki et al. reported a peak serum MZB concentration of 1.4–4.8 μg/mL and a morning trough serum MZB concentration of 0–0.3 in 8 patients with NS when MZB was given orally in a dose of 10 mg/kg body weight daily (maximum total daily dose 500 mg) in three divided doses, 2 days a week (Figure 1) [24, 25]. In addition, Kawasaki et al. found that the peak serum concentration was 3.0–5.1 μg/mL, the AUC 0–4 of MZB was 7.0–16.0 μg · h/mL and the morning trough serum MZB concentration was 0 μg/mL (Table 1), when MZB was given orally in a dose of 6 mg/kg body weight daily (maximum total dose 300 mg) twice a week in 11 patients with frequently relapsing NS [26].

Bottom Line: The immunosuppressive effect of MZB has been reported to be due to the inhibition of DNA synthesis in the S phase of the cell cycle.Because of its relative lack of toxicity, during the past decade MZB has been frequently used instead of azathioprine as a component of immunosuppressive drug regimens.This review summarizes the published findings on the efficacy of MZB for renal disease including IgA nephropathy, lupus nephritis, and NS, as well as of oral MZB pulse therapy for severe lupus nephritis and NS, and also the mechanism of the effect of oral MZB pulse therapy on the lymphocyte cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Fukushima Medical University School of Medicine, 1 Hikariga-oka, Fukushima City, Fukushima 960-1295, Japan. kyuki@fmu.ac.jp

ABSTRACT
Mizoribine (MZB) is an imidazole nucleoside and an immunosuppressive agent. The immunosuppressive effect of MZB has been reported to be due to the inhibition of DNA synthesis in the S phase of the cell cycle. Because of its relative lack of toxicity, during the past decade MZB has been frequently used instead of azathioprine as a component of immunosuppressive drug regimens. MZB is being used to treat renal transplantation patients, IgA nephropathy, lupus erythematosus, and childhood nephrotic syndrome (NS), and some recent studies have assessed the efficacy of oral MZB pulse therapy for severe lupus nephritis, steroid-resistant NS, and frequently relapsing-steroid-dependent NS. This review summarizes the published findings on the efficacy of MZB for renal disease including IgA nephropathy, lupus nephritis, and NS, as well as of oral MZB pulse therapy for severe lupus nephritis and NS, and also the mechanism of the effect of oral MZB pulse therapy on the lymphocyte cell cycle.

Show MeSH
Related in: MedlinePlus