Mizoribine Group Research Articles

Efficacy and Safety of Mizoribine in comparison with Cyclophosphamide for Treatment of Refractory Nephrotic Syndrome: Protocol for a Multi-center, Controlled, Open-label, Randomized Controlled Trial.

Nephrotic syndrome that is resistant to steroidal therapy is termed refractory nephrotic syndrome (RNS), a condition that is associated with an increased risk of end-stage renal disease (ESRD). Immunosuppressants are utilized to treat RNS, however prolonged may lead to significant adverse effects. Mizoribine (MZR) is a novel agent used in long-term immunosuppressive therapy that has few adverse effects, but data on its long-term use in patients with RNS are unavailable. We propose a trial to examine the efficacy and safety of MZR compared to cyclophosphamide (CYC) in Chinese adult patients with RNS. This is a multi-center, randomized, controlled interventional study with a screening phase (1 week) and a treatment phase (52 weeks). This study was reviewed and approved by the Medical Ethics Committees of all 34 medical centers. Patients with RNS consented to participation, and were enrolled and randomized into an MZR group or a CYC group (1:1 ratio), with each group receiving tapering doses of oral corticosteroids. Participants were assessed for adverse effects and collection of laboratory results at 8 visits during the treatment phase on week-4, week-8, week-12, week-16, week-20, week-32, week-44, and week-52 (exit visit). Participants were able to withdraw voluntarily and investigators were required to remove patients when there were safety concerns or deviations from protocol. The study started in November 2014, and was completed in March 2019. A total of 239 participants from 34 hospitals in China were enrolled. Data analysis is completed. The results are waiting to be finalized by Center for Drug Evaluation. The purpose of the current study is to evaluate the efficacy and safety of MZR in comparison with CYC for treatment of RNS in Chinese adult patients with glomerular diseases. It is the longest lasting and largest randomized controlled trial to examine MZR in Chinese patients. The results can help determine whether RNS should be considered as an additional indication for MZR treatment in China. ClinicalTrials.gov Register, NCT02257697. Registered 2014-10-01, https://clinicaltrials.gov/ct2/show/NCT02257697?term=MZR&rank=2.

Efficacy and safety of mizoribine in comparison with cyclophosphamide for treatment of lupus nephritis: Protocol for a multi-center, open-label, randomized controlled trial

Background: Monthly intravenous cyclophosphamide (IVCY) is a widely accepted induction therapy for lupus nephritis (LN) because this regimen balances the time needed for renal remission with the risk of adverse events. However, IVCY is associated with numerous severe toxicities. Mizoribine (MZR) was originally used as an antibiotic against Candida albicans, but researchers found it had strong immunosuppressive activity in various animal models. Previous clinical trials also examined the efficacy of MZR as an immunosuppressant, and it has been used for treatment of LN in Japan since 1990. We will conduct a phase 3 study in China to evaluate the efficacy and safety of oral MZR in comparison with standard IVCY in patients with LN. Methods: This study will be a multi-center, randomized, controlled, open-label clinical trial that consists of a screening period (seven days) followed by a treatment period (52 weeks). After screening, all eligible subjects will be randomized to an MZR or IVCY group in a 1:1 ratio. Then, subjects will initially receive methylprednisolone pulse therapy (0.5 g/day) for three days, followed by the study drug (MZR or CY) with oral corticosteroid therapy from visit two (day four). The efficacy and safety of oral MZR in comparison with standard IVCY will be determined. Discussion: This paper describes the protocol of a multi-center, open-label, randomized controlled trial that compares the efficacy and safety of MZR with IVCY for treatment of LN. The results may help determine whether LN should be considered an indication for this drug in China. Trial registration: ClinicalTrials.gov register, NCT02256150. Registered 2014-10-01. The protocol version number is 1.3 (2016-08-30).

Mizoribine combined with steroids and dietary sodium restriction on the treatment of primary membranous nephropathy: a prospective study.

We aimed to initially explore the efficiency and safety of mizoribine (MZR) combined with steroids and dietary sodium restriction on the treatment of primary membranous nephropathy (MN) compared with cyclophosphamide (CPM)-based steroids. Patients with primary MN were enrolled. According to the therapy, they were divided into theMZR combined with steroids and dietary sodium restriction group (N = 30) and CPM-based steroids group (N = 30). Both groups were followed up for 1year to monitor safety and efficacy. Compared with the CPM-based steroids group, theMZR combined with steroids and dietary sodium restriction group had significantly lower daily sodium intake, serum sodium, blood pressure (BP), and 24h urine protein (all P < 0.05). Conversely, plasma albumin and complete remission rate in the MZR group were higher at the 12th follow-up (40.39 ± 5.14g/L vs. 37.63 ± 5.40g/L; 86.67% vs. 66.67%; all P < 0.05). These two groups showed similar adverse events rates (20.00% vs. 26.67%, P = 0.54). This study demonstrates that MZR combined with steroids and dietary sodium restriction is superior to CPM-based steroids in terms of completeremission and 24h urine protein in patients with primary MN.

The Efficacy and Safety of Mizoribine versus Mycophenolate Mofetil for the Treatment of Renal Transplantation: A Systematic Review and Meta-Analysis.

Background Mizoribine (MZR) is widely used in Asia due to its high safety and low cost, and comparative studies of its safety and efficacy with the first-line drug mycophenolate mofetil (MMF) have been carried out. This paper aimed to compare the efficacy and safety of MZR and MMF in immunosuppressive therapy of renal transplantation by meta-analysis. Methods We searched randomized controlled trials (RCTs) comparing MZR versus MMF for renal transplantation in PubMed, Excerpta Medica Database (EMBASE), Cochrane Library, Web of Science, WanFang Database, China National Knowledge Infrastructure (CNKI), and Chinese Biomedical Database (CBM). Articles were assessed for their risk of bias using the Cochrane Collaboration. Forest plots and funnel plots were also performed on the included articles. Results A total of twelve studies with 1103 patients were selected in the analysis. No significant difference were observed between the MZR group and the MMF group for the rate of acute rejection (RR = 1.50, 95% CI 1.11 to 2.01, P = 0.008), patient survival (RR = 1.01, 95% CI 0.99 to 1.03, P = 0.56), graft survival (RR = 1.02, 95% CI 1.00 to 1.04, P = 0.12), leucopenia (RR = 0.69, 95% CI 0.44 to 1.10, P = 0.12), and liver damage (RR = 0.72, 95% CI 0.46 to 1.13, P = 0.15). The MZR group was associated with a lower risk of gastrointestinal disorder (RR = 0.28, 95% CI 0.13 to 0.62, P = 0.002) and cytomegalovirus infection (RR = 0.59, 95% CI 0.42 to 0.84, P = 0.003) but had a higher risk of hyperuricemia (RR 1.79, 95% CI 1.17 to 2.75, P = 0.007). No significant publication bias was observed among included studies. Discussion. MZR is similar to MMF in efficacy, and in terms of safety, MZR has a lower risk of gastrointestinal disorder and cytomegalovirus infection but a higher risk of hyperuricemia.

Comparative efficacy and safety of mizoribine and mycophenolate mofetil for treating systemic lupus erythematosus: a retrospective cohort study.

Background:Mizoribine (MZR) is an immunosuppressive agent that selectively inhibits inosine monophosphate dehydrogenase; its actions are considerably similar to those of mycophenolate mofetil (MMF). This study aimed to clarify whether MZR can be a good treatment option for systemic lupus erythematosus (SLE) and to compare the efficacy and safety of MZR and MMF in patients with active SLE.Methods:We retrospectively compared the efficacy, continuation rate, and safety of MZR (52 patients) and MMF (31 patients) after adjusting for stabilized inverse probability of treatment weighting based on propensity scores. The efficacy endpoints were as follows: cumulative incidence of lupus low disease activity state (LLDAS) or remission attainment and flares and change in prednisolone dose over 2 years. Drug continuation rates were defined as the time from drug initiation to discontinuation for any cause, owing to the lack of efficacy, or owing to adverse events. The safety endpoint was the frequency of adverse events.Results:Overall, 25 (48.1%) and 13 (25.0%) patients in the MZR group and 18 (58.1%) and 15 (48.3%) in the MMF group achieved LLDAS and remission during the follow-up period, respectively; thus, the cumulative incidence of LLDAS and remission attainment of the two groups was similar after adjustment. Prednisolone dose was steadily reduced in both the groups, and the change in prednisolone dose was nearly identical between the two groups. Drug discontinuation rate due to adverse events and the frequency of all adverse events and infections were higher in the MMF group than in the MZR group, albeit without significance after adjustment.Conclusion:MZR is as effective as MMF in controlling SLE activity. The adverse events of MZR, whose profile differs from MMF, are comparable to or less than those of MMF. MZR may be a valuable option as an immunosuppressive agent for SLE, as well as MMF.

Effectiveness and safety of mizoribine for the treatment of IgG4-related disease: a retrospective cohort study

Abstract Objective Patients with IgG4-related disease (IgG4RD) usually require steroid-sparing agents due to relapse with tapering glucocorticoids (GC). We aimed to determine the efficacy and safety of mizoribine (MZR) among IgG4RD patients. Methods We retrospectively reviewed records of IgG4RD patients at Immuno-Rheumatology Center in St. Luke’s International Hospital, Tokyo, Japan. Patients treated with MZR were classified into the MZR group, and those treated with GC alone or with other immunosuppressants were included in the control group. Disease exacerbation, GC dose, IgG-IgG4 titre and adverse events were evaluated using univariate analyses, including the Kaplan–Meier method. The Cox proportional hazard model was used to evaluate risk factors for disease exacerbation. Results A total of 14 and 29 cases were included in the MZR and control group. Multiple organ involvement (three or more organs) was significantly more frequent in the MZR group [10 (71.4%) vs 9 (31.0%), P= 0.021]. Kaplan–Meier analysis revealed a significant reduction inexacerbation in patients with multiple organ involvement (P&amp;lt; 0.001) but not in total (P= 0.42). The adjusted hazard ratios of MZR use and multiple organ involvement for exacerbation were 0.34 (95%CI 0.12–1.01; P = 0.052) and 3.51 (95%CI 1.29–9.51; P= 0.014). The cumulative GC dose (mg per year, interquartile range) tended to be lower in the MZR group [1448 (1003–1642) vs 2179 (1264–3425); P= 0.09]. Conclusion MZR decreased disease exacerbation among IgG4RD patients with multi-organ involvement and showed a steroid-sparing effect. MZR could be a treatment option for IgG4RD.

Effect of mizoribine pulse therapy in adult membranous nephropathy.

Membraneous nephropathy (MN) is one of the complicated kidney diseases associated with proteinuria. Mizoribine (MZR) is an emerging treatment option for nephrotic syndrome; however, its dosage and administration are yet lack of consensus. This study aims to evaluate the efficacy and safety of high-dose MZR pulse therapy for adult membraneous nephropathy. Sixty patients with membraneous nephropathy were recruited, and assigned to two treatment groups. One group received conventional treatment of steroid combining with cyclophosphamide (CPM), the other group received steroid combining with high-dose MZR pulse administration. Both groups were followed up for 1 year. Treatment efficacy and side effects were measured regularly. Fifty-nine patients completed the treatment courses. There was no significant difference in demographic and disease conditions prior to treatment between two treatment groups. Both groups showed significant decrease of urine proteins and increase of serum albumin levels after treatments with no severe side effects. After 6months of treatment, MZR group has 71% reduction (compared to 74.4% reduction in CPM group) in urine protein compared to baseline after adjusting for age and gender. 89.7% of patients in CPM and 93.3% in MZR groups had partial/ complete remission after 12months. This study demonstrated satisfactory safety and efficacy of high-dose mizoribine pulse administration combining with steroid treatment for adult patients with membranous nephropathy.

Efficacy and Safety of a Quadruple Regimen Compared with Triple Regimens in Patients with Mycophenolic Acid-Related Gastrointestinal Complications After Renal Transplantation: A Short-Term Single-Center Study

BackgroundAt present, there is no ideal conventional triple regimen that can effectively treat gastrointestinal (GI) complications in patients after kidney transplantation. We aimed to investigate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids, compared with regimens containing standard-dose tacrolimus, corticosteroids, plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after renal transplantation.Material/MethodsBetween August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplant recipients with MPA-related GI complications were enlisted in a single-center, prospective, randomized, control study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group, 37 recipients were assigned to the low-dose EC-MPS group, and 39 recipients were assigned to the standard-dose MZR group. We analyzed the Gastrointestinal Symptom Rating Scale (GSRS), estimated glomerular filtration rate (eGFR), graft rejection, serum creatinine, human leukocyte antigen (HLA) antibody, and the occurrence of adverse events among the 3 groups.ResultsCompared with baseline, gastrointestinal symptoms improved significantly in all 3 groups. The reduction in mean subscale scores from baseline to month 3 was more significant in the standard-dose MZR group compared with the other 2 groups. The low-dose EC-MPS plus low-dose MZR group had better renal function. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection, as well as the incidence of hyperuricemia, in the low-dose EC-MPS plus low-dose MZR group were all significantly reduced.ConclusionsThis quadruple regimen may be equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplant, and is also advantageous for kidney function, graft rejection, and the rates of adverse events.

Efficacy and Safety of a Quadruple Regimen in Patients with Gastrointestinal Complications after Renal Transplantation

Objectives: The aim of this study was to evaluate the efficacy and safety of a quadruple regimen including standard-dose tacrolimus, low-dose enteric-coated mycophenolate sodium (EC-MPS), low-dose mizoribine (MZR), and corticosteroids compared with regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in patients with mycophenolic acid (MPA)-related GI complications after kidney transplantation. Methods: Between August 2016 and October 2018 in Qilu Hospital of Shandong University, 115 living donor kidney transplantations with MPA-related GI complications were enrolled in a single-center, prospective study. Thirty-six recipients were assigned to the low-dose EC-MPS plus low-dose MZR group. Thirty-seven recipients were assigned to the low-dose EC-MPS group, and thirty-nine recipients were assigned to the standard-dose MZR group. The three groups were compared with the Gastrointestinal Symptom Rating Scale (GSRS), graft rejection, human leukocyte antigen (HLA) antibody, serum creatinine levels, estimated glomerular filtration rate (eGFR), and incidence of adverse effects. Results: A significant improvement in GI symptoms was observed in all three groups compared with baseline. Renal function was better in the low-dose EC-MPS plus low-dose MZR group. The incidence of graft rejection and cytomegalovirus (CMV) and polyomavirus BK (BKV) infection with the incidence of hyperuricemia were all significantly lower in the low-dose EC-MPS plus low-dose MZR group. Conclusions: The quadruple regimen may be not only equivalent to regimens containing standard-dose tacrolimus, corticosteroids plus either low-dose EC-MPS or standard-dose MZR in improving GI symptoms after kidney transplantation but also advantageous for renal function, graft rejection rates, and the incidence of adverse effects. Funding: This study was funded by the Provincial Key Technologies R & D Program of Shandong Province (Grant No. 26010104011025), National Natural Science Foundation of China (Grant No. 81600092), Key Research and Development Plan of Shandong Province (Grant No. 2017GSF218003). Declaration of Interest: The authors declare no competing interests. Ethical Approval: Patients gave their informed consent to be in the study, and the study protocol was approved by the ethics committee of Qilu Hospital of Shandong University, China (2016Qilu Hospital of Shandong University IRB Approval No. 2016041).

Study protocol: high-dose mizoribine with prednisolone therapy in short-term relapsing steroid-sensitive nephrotic syndrome to prevent frequent relapse (JSKDC05 trial)

BackgroundEighty percent of children with steroid-sensitive nephrotic syndrome (SSNS) relapse within 2 years and 40–50% patients show frequently-relapsing nephrotic syndrome (FRNS). Patients showing a relapse within 6 months after initial remission are at high risk of FRNS. Since frequent prednisolone treatment for FRNS induces severe prednisolone side effects, development of a treatment to prevent patients from shifting to FRNS is desirable. Mizoribine is an immunosuppressive drug with fewer side effects than prednisolone. Recent studies reported the efficacy of high-dose mizoribine in children with FRNS.Methods/designWe conduct a multicenter, open, randomized controlled trial to investigate the efficacy and safety of standard prednisolone plus high-dose mizoribine therapy in children with SSNS showing a relapse within 6 months after an initial remission. Patients are allocated to either standard prednisolone alone treatment group, or standard prednisolone plus high-dose mizoribine group. For the former group, mizoribine is administered at a dose of 10 mg/kg/day once daily and continued for 2 years. The primary endpoint is the duration to frequent relapse.DiscussionThe results provide important data on use of high-dose mizoribine to prevent SSNS patients from shifting to FRNS. Since blood concentrations of mizoribine have not been investigated in detail until now, there is a possibility that mizoribine is underestimated in favor of other immunosuppressive drugs. In future, high-dose mizoribine therapy may lead to prevention of relapse in children at high risk of FRNS, and to decreased total dose of prednisolone.Trial registrationUMIN000005103, (Prospectively registered 1st March 2011).

Mizoribine is as Effective as Methotrexate for the Treatment of Polymyalgia Rheumatica: A Retrospective Case Series Analysis.

This study aims to evaluate the efficacy and safety of mizoribine (MZR) as a steroid-sparing agent compared to methotrexate (MTX) in the treatment of polymyalgia rheumatica in elderly patients. Twenty-four patients (9 males, 15 females; mean age 71.7 years; range 50 to 86 years) diagnosed with polymyalgia rheumatica between April 1998 and August 2014, who received prednisone in combination with either MTX or MZR, were included. We collected the data on the cumulative prednisone dose that patients received within 48 weeks after MTX or MZR and its side effect profile. There were 10 patients in the MTX group and 14 in the MZR group. The cumulative prednisone dose over 0-48 weeks was 2272±396 mg in the MTX group and 1907±241 mg in the MZR group, which was not significantly different (p=0.41). In terms of side effects, in the MTX group, three patients experienced a transient elevation in liver enzymes, and one patient developed gastrointestinal symptoms that led to MTX withdrawal. In the MZR group, one patient was hospitalized due to pneumonia that led to MZR withdrawal. Mizoribine was non-inferior to MTX in terms of steroid-sparing effects on polymyalgia rheumatica. Also, MZR tended to have fewer side effects than MTX.

A Prospective Randomized, Comparative Trial of High-Dose Mizoribine Versus Mycophenolate Mofetil in Combination With Tacrolimus and Basiliximab for Living Donor Renal Transplant: A Multicenter Trial.

Our objectives were to compare the clinical outcomes of mizoribine (12 mg/kg/d) and mycophenolate mofetil (2000 mg/d) in combination with tacrolimus, basiliximab, and corticosteroids. We enrolled 83 recipients of living-donor renal transplant (performed between 2008 and 2013) in this study. This prospective multi-institutional randomized comparative study compared mizoribine (n = 41) and mycophenolate mofetil (n = 42) in combination with tacrolimus, basiliximab, and corticosteroids for living-donor renal transplant recipients. We compared the acute rejection and graft survival rates and adverse event rates within 1 year of renal transplant between the 2 groups using intention-to-treat analyses. During the 1-year observation period, patient and graft survival rates were 100%. The acute rejection rate was 17.1% in the mizoribine group and 19% in the mycophenolate mofetil group. The incidence rate of cytomegalovirus infection seropositivity (recipient and donor with positive cytomegalovirus antibody status) was higher in the mycophenolate mofetil group than in the mizoribine group, although the difference in these rates was not statistically significant. The incidence of leukopenia was higher in the mizoribine group than in the mycophenolate mofetil group. High-dose mizoribine at 12 mg/kg/day was a safe and efficacious immunosuppressive alternative to mycophenolate mofetil in living-donor renal transplant recipients. Leukopenia should be closely monitored in the initial period of insufficient kidney function after renal transplant.

Treatment of membranous nephropathy with mizoribine: A control trial

AimMembranous nephropathy remains the most common form of the nephrotic syndrome in adults. The combination therapy of steroid and cyclophosphamide has routinely been used. Although satisfactory therapeutic efficacy can be achieved, its side effect on reproductive system has been a concern. Mizoribine is an imidazole nucleoside and a novel immunosuppressant that has been used to treat other immune-related diseases. In this study we examine if the combined regimen of mizoribine and steroid would be advantageous over the use of cyclophosphamide and steroid in treating adult membranous nephropathy. MethodsThere were total of fifty-five patients completed the study. These patients had membranous nephropathy with presentation of proteinuria. They were treated with combined regimen of mizoribine and steroid or cyclophosphamide and steroid, and were followed up for one year to monitor safety and efficacy. ResultsWe found the condition of proteinuria was significantly improved in the mizoribine group and the improvement was comparable to the patients treated with cyclophosphamide. These patients also exhibited an increase of serum albumin. There was no significant increase of adverse events with the use of mizoribine-based therapy, suggesting the tolerability of mizoribine in adult patients with membranous nephropathy. ConclusionIn conclusion, the results indicated the satisfactory safety and efficacy of the combination regiment of mizoribine and steroid in treating adult patients with membranous nephropathy.

Efficacy and Safety of High-Dose Mizoribine Combined With Cyclosporine, Basiliximab, and Corticosteroids in Renal Transplantation: A Japanese Multicenter Study

Mizoribine (MZR) is an immunosuppressive agent that exhibits a less potent immunosuppressive effect at doses up to 3 mg/kg/d. We investigated whether high-dose MZR is effective and safe for renal transplant patients in conjunction with cyclosporine (CsA), basiliximab, and corticosteroids. Ninety Japanese renal transplant patients were administered MZR (6 mg/kg/d), CsA (7 mg/kg/d), prednisolone (maintenance dose, 10 mg/d), and basiliximab (20 mg/body). They were compared with a control group of 81 renal transplant patients who received mycophenolate mofetil (MMF; 1500 mg/d), CsA, prednisolone, and basiliximab. The 2-year patient and graft survival rates were 98.9% and 97.8% in the MZR group and 98.8% and 97.5% in the MMF group, respectively. The rejection rate within 2 years after transplantation was 21.1% in the MZR group and 16.0% in the MMF group; the difference was nonsignificant. None of the MZR group developed cytomegalovirus (CMV) disease, whereas 12.3% of the MMF group contracted CMV (P < .0001). CMV viremia developed in 28.9% of the MZR group vs 46.9% of the MMF group (P < .0001); their peak antigen levels were 20.4 ± 44.1 and 252.8 ± 527.0 (P < .01). Furthermore, the incidence of gastrointestinal disorder, hyperlipidemia, and blood disorder was significantly lower in the MZR group than in the MMF group. The combination of high-dose MZR with CsA, basiliximab, and corticosteroids not only provides satisfactory immunosuppression but is also associated with a low incidence of CMV infection and gastrointestinal and blood disorders.

Influence of cyclosporine A on glomerular growth and the effect of mizoribine and losartan on cyclosporine nephrotoxicity in young rats.

The aim of this study was to evaluate the influence of cyclosporine A (CsA) on glomerular growth and the effect of mizoribine (MZR) and losartan (LSAR) on CsA-induced nephropathy in young rats. Six-week-old male Sprague-Dawley rats maintained on a low salt diet were given CsA (15 mg/kg), CsA and LSRT (30 mg/kg/day), CsA and MZR (5 mg/kg), or a combination of CsA, LSRT, and MZR for 4 and 7 weeks (two experiments) and compared with control group (olive oil-treated). Histopathology and glomerular size, inflammatory and fibrotic factors were studied. The score of acute CsA toxicity significantly decreased in the CsA + MZR group compared to the CsA group (p < 0.01). MZR and MZR + LSRT reduced tubulointerstitial fibrosis and TGF-β1 mRNA expression at 7 weeks. Osteopontin (OPN) mRNA expression was decreased at 7 weeks in MZR + LSRT (p < 0.01). Glomerular area decreased CsA group and recovered in MZR (p < 0.01) and MZR + LSRT (p < 0.01) at 7weeks. This study demonstrated that MZR and LSRT had suppressive effects on inflammatory process in chronic CsA nephropathy and led to improvement of tubular damage, tubulointerstitial fibrosis and arteriolopathy by down regulation of OPN and TGF-β1 and glomerular size contraction.

Bezafibrate–mizoribine interaction: Involvement of organic anion transporters OAT1 and OAT3 in rats

A patient with rheumatoid arthritis developed rhabdomyolysis while undergoing treatment with mizoribine concomitantly with bezafibrate. The symptoms rapidly disappeared and laboratory test results normalized when she discontinued the two drugs. The purpose of the present study was to elucidate the transporter-mediated molecular pharmacokinetic mechanisms of drug–drug interactions between bezafibrate and mizoribine. Comparing bezafibrate–mizoribine group with bezafibrate group, the Tmax and Cmax of bezafibrate were essentially unchanged in rats. The AUC of bezafibrate was significantly increased and t1/2β was prolonged markedly with an obviously reduction in plasma clearance and cumulative urinary excretion. The changes were similar to oral studies following intravenous co-administration. In rat kidney slices, the uptake of bezafibrate was markedly inhibited by p-aminohippurate, benzylpenicillin and probenecid but not by tetraethyl ammonium. Mizoribine not only decreased the uptake of bezafibrate, but also inhibited the uptake of p-aminohippurate and benzylpenicillin. The uptakes of bezafibrate and mizoribine were significantly higher compared to vector-HEK293 cells. The uptakes of bezafibrate and mizoribine in highest concentration were increased 1.63 and 1.46 folds in hOAT1-transfected cells, 1.43 and 1.24 folds in hOAT3-transfected cells, respectively. The Km values of bezafibrate uptake by hOAT1/3hOAT1-/hOAT3-HEK293 K293 cells were increased 1.68 fold in hOAT1-HEK293 cell and 2.12 fold in hOAT3-HEK293 cell in the presence of mizoribine with no change of Vmax. It indicated that mizoribine could inhibit the uptake of bezafibrate by hOAT1/3-HEK293 cells in a competitive way. In conclusion, OAT1 and OAT3 are the target transporters of drug–drug interactions between bezafibrate and mizoribine in pharmacokinetic aspects.

Mizoribine versus mycophenolate mofetil or intravenous cyclophosphamide for induction treatment of active lupus nephritis

Background Lupus nephritis (LN) is one of the most serious manifestations of systemic lupus erythematosus. Although there have been substantial improvements in LN treatment over the last decade, the outcome remains unoptimistic in a considerable percentage of patients. The aim of this study was to evaluate the efficacy and safety of mizoribine (MZR), a novel selective inhibitor of inosine monophosphate dehydrogenase, as induction treatment for active LN in comparison with mycophenolate mofetil (MMF) and intravenous cyclophosphamide (CYC). Methods Ninety patients with active LN were observed. Thirty patients were given MZR orally at the dose of 300 mg every other day. Thirty patients took MMF at 2 g per day in two divided doses. Thirty patients received CYC intravenously 0.5 g every 2 weeks. Therapeutic effects and adverse events (AEs) were evaluated at the end of 24-week treatment. One-way analysis of variance (ANOVA) followed by Dunn's test was applied to compare the difference among the groups. For comparing categorical data between two groups, χ2 test was employed. Results Early responses at week 12 were achieved by 73.3%, 90.0%, and 96.7% in MZR, MMF, and CYC groups, respectively. There was no significant difference in the complete remission rates (22.7%, 24.0%, and 25.0%, respectively) or overall response rates (68.2%, 72.0%, and 75.0%, respectively) among the three groups at week 24. The most prominent drop-down of Systemic Lupus Erythematosus Disease Activity Index scores was observed in MMF or CYC group, and the decline of health assessment questionnaire scores in MZR or MMF group was more prominent than that in the CYC group at week 12. Serum complement 3 (C3) or C4 levels were elevated in all groups after the treatments. CYC was more effective in inhibiting anti-double-stranded DNA antibody, while MZR was more effective in inhibiting antinuclear antibody. The incidences of AEs in patients treated with CYC were significantly higher than those in patients treated with MZR or MMF (24.2% for CYC vs. 3.3% for MZR, and 2.6% for MMF, P=0.01). Conclusions MZR is well tolerated and has an effect similar to MMF in the induction therapy of active LN. MZR may serve as an alternative approach for LN patients.

Mizoribine Ameliorates Renal Injury and Hypertension along with the Attenuation of Renal Caspase-1 Expression in Aldosterone-Salt-Treated Rats

Aldosterone-salt treatment induces not only hypertension but also extensive inflammation that contributes to fibrosis in the rat kidney. However, the mechanism underlying aldosterone-salt-induced renal inflammation remains unclear. Pyroptosis has recently been identified as a new type of cell death that is accompanied by the activation of inflammatory cytokines. We hypothesized that aldosterone-salt treatment could induce inflammation through pyroptosis and that mizoribine, an effective immunosuppressant, would ameliorate the renal inflammation that would otherwise cause renal fibrosis. Ten days after recovery from left uninephrectomy, rats were given drinking water with 1% sodium chloride. The animals were divided into three groups (n = 7 per group): (1) vehicle infusion group, (2) aldosterone infusion group, or (3) aldosterone infusion plus oral mizoribine group. Aldosterone-salt treatment increased the expression of the nucleotide-binding oligomerization domain, leucine-rich repeat and pyrin domain containing 3 and caspase-1, and also increased the number of terminal deoxynucleotidyl transferase dUTP nick end labeling-positive cells. However, the oral administration of mizoribine attenuated these alterations. Furthermore, mizoribine inhibited hypertension and renal fibrosis, and also attenuated the aldosterone-induced expression of serum/glucocorticoid-regulated kinase and α epithelial sodium channel. These results suggest that caspase-1 activation plays an important role in the development of inflammation induced by aldosterone-salt treatment and that it functions as an anti-inflammatory strategy that protects against renal injury and hypertension.

Mizoribine Versus Mycophenolate Mofetil in Combination Therapy With Tacrolimus for De Novo Kidney Transplantation: Evaluation of Efficacy and Safety

The present study compared the efficacy and safety of mizoribine (MZR) with mycophenolate mofetil (MMF) in kidney transplantation. This multicenter, randomized clinical trial. Employed doses of study drug tailored to the immunosuppressive need. The primary efficacy outcome was the incidence of biopsy-proven acute rejection episodes (BPAR). The safety of the study drug was assessed using the incidences of adverse events, drug discontinuations, and abnormal laboratory results. The 7 (6.4%) BPARs above grade II were observed in the MZR group noninferior to the 2 (1.8%) in the MMF group (95% confidence interval, −0.007–0.097 > noninferiority limit [−0.2]). BPAR was significantly decreased in the MZR group after the dose change (17/41 [41.4%] vs 8/69 [11.6%]; P < .0001) and the incidence of BPAR was similar between the MZR and MMF groups after the dose change (P = .592). The uric acid level was significantly elevated in the MZR group (P = .002). In conclusion, the efficacy and safety of MZR were similar and statistically noninferior to MMF in combination therapy with tacrolimus.

Randomized comparative trial of mizoribine versus mycophenolate mofetil in combination with tacrolimus for living donor renal transplantation

Mizoribine (MZR) was approved in 1984 in Japan for the suppression of rejection in renal transplantation with an approved administration dosage of 1-3mg/kg/day. The action of MZR resembles that of mycophenolate mofetil (MMF), but MZR dosing is markedly lower than that of MMF. To examine whether higher dosing of MZR could obtain efficacy similar to MMF in renal transplantation, we conducted a comparative study of MZR and MMF using a high daily dose of MZR. A prospective, randomized comparative study of MZR versus MMF using tacrolimus (FK) and steroids as the base was conducted in 35 patients who had undergone living-donor renal transplantation (ABO-incompatible patients were not included) at 8 institutions in Japan between July 2005 and June 2007. Starting doses were 12mg/kg/day for MZR and 2g/day for MMF. Dosages of FK and steroids were set according to the protocol of each institution. Patient and graft survival rate at 1year after transplantation was 100% in each group, with no significant difference in rejection rate apparent between groups. Adverse events found in both groups were characteristic, frequently involving infection and digestive organ disorder in the MMF group and elevated uric acid levels in the MZR group. Based on these results, MZR and MMF are considered almost equivalent in terms of efficacy and safety.