tacrolimus and mizoribine

Amelioration of podocyte injury, which can lead to podocyte detachment, is the target of therapeutic intervention in glomerular diseases. Since podocytes are terminally differentiated cells with little or no proliferative ability, their loss results in permanent glomerular dysfunction. In immune-mediated glomerular diseases, a variety of immunomodulatory agents are used to maintain podocytes by systemic immunosuppression, which indirectly ameliorates podocyte injury by interrupting the input of immunological stress. However, in contrast to the indirect therapeutic strategy mediated by immunosuppression, recent data now suggest that immunomodulatory agents directly act on podocytes in an agent-dependent manner. Indeed, the therapeutic efficacy of immunomodulatory agents is, at least in part, derived by the direct action on podocytes. In this review, we discuss the molecular targets and mechanisms by which immunomodulatory agents alleviate podocyte injury and examine their clinical significance.

Topics: Abatacept; Adjuvants, Immunologic; Calcineurin Inhibitors; Everolimus; Glomerulonephritis; Glomerulonephritis, Membranous; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Immunologic Factors; Immunosuppressive Agents; Levamisole; Mycophenolic Acid; Nephrosis, Lipoid; Nephrotic Syndrome; Podocytes; Ribonucleosides; Rituximab; Sirolimus; Tacrolimus; TOR Serine-Threonine Kinases

Conventional synthetic disease modifying anti-rheumatic drugs (csDMARDs) other than methotrexate (MTX: anchor csDMARDs) are effective for single use, reinforcement of MTX, biologics and induction and maintenance of biologics-free condition. Newly developed iguratimod (IGU) does not suppress immunological reaction, therefore, it is useful for single use or combination with other csDMARDs in patients with complications. IGU can be used as a first csDMARDs before MTX use during the screening for MTX. IGU might be effective for reinforcement of MTX, biologics and induction and maintenance of biologics-free condition just like other csDMARDs. IGU can be used in wide variety of situation of the treatment of rheumatoid arthritis and it is desired that after the all-case surveillance condition for approval, IGU become a standard csDMARDs all over the world which was made in Japan.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Chromones; Cysteine; Drug Discovery; Drug Interactions; Drug Substitution; Drug Therapy, Combination; Drugs, Generic; Female; Humans; Male; Ribonucleosides; Sulfasalazine; Sulfonamides; Tacrolimus

Lupus nephritis is a common and severe manifestation of systemic lupus erythematosus, and an important cause of both acute kidney injury and end-stage renal disease. Despite its aggressive course, lupus nephritis is amenable to treatment in the majority of patients. The paradigm of immunosuppressive treatment for lupus nephritis has evolved over the past few decades from corticosteroids alone to corticosteroids combined with cyclophosphamide. Sequential treatment regimens using various agents have been formulated for induction and long-term maintenance therapy, and mycophenolate mofetil has emerged as a standard of care option for both induction and maintenance immunosuppressive treatment. The current era has witnessed the emergence of multiple novel therapeutic options, such as calcineurin inhibitors and biologic agents that target key pathogenetic mechanisms of lupus nephritis. Clinical outcomes have improved in parallel with these therapeutic advances. This Review discusses the evidence in support of current standard of care immunosuppressive treatments and emerging therapies, and describes their roles and relative merits in the management of patients with lupus nephritis.

Topics: Antimalarials; Azathioprine; Biological Products; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lupus Nephritis; Mycophenolic Acid; Ribonucleosides; Severity of Illness Index; Sirolimus; Tacrolimus

The introduction of corticosteroids more than 50 years ago dramatically improved the prognosis of children with nephrotic syndrome. Corticosteroids remain the standard initial treatment for children with this disease, but a considerable proportion of patients do not respond and are therefore at risk of progressing to end-stage renal disease. Because of this risk, new therapeutic strategies are needed for steroid-resistant nephrotic syndrome. These strategies have historically focused on identifying effective alternative immunosuppressive agents, such as ciclosporin and tacrolimus, yet evidence now indicates that nephrotic syndrome results from podocyte dysfunction. Even conventional immunosuppressive agents, such as glucocorticoids and ciclosporin, directly affect podocyte structure and function, challenging the 'immune theory' of the pathogenesis of childhood nephrotic syndrome in which disease is caused by T cells. This Review summarizes the currently available treatments for childhood nephrotic syndrome, and discusses selected novel pathways in podocytes that could be targeted for the development of next-generation treatments for children with this syndrome.

Topics: Adalimumab; Anti-Inflammatory Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal, Murine-Derived; Antineoplastic Agents, Alkylating; Child; Cyclophosphamide; Cyclosporine; Enzyme Inhibitors; Galactose; Glucocorticoids; Homeostasis; Humans; Immunologic Factors; Immunosuppressive Agents; Interleukin-13; Intracellular Signaling Peptides and Proteins; MAP Kinase Signaling System; Mycophenolic Acid; Nephrotic Syndrome; p38 Mitogen-Activated Protein Kinases; Plasmapheresis; Protein Serine-Threonine Kinases; Receptors, Notch; Ribonucleosides; Rituximab; Signal Transduction; Tacrolimus; Thiazolidinediones; Unfolded Protein Response

Topics: Antineoplastic Combined Chemotherapy Protocols; Azathioprine; Calcineurin Inhibitors; Drug Therapy, Combination; Fluorouracil; Glomerulonephritis, Membranous; Humans; Immunosuppressive Agents; Lupus Nephritis; Mitomycin; Prognosis; Ribonucleosides; Semustine; Tacrolimus

Topics: Antibodies, Monoclonal, Murine-Derived; Azathioprine; Cyclophosphamide; Cyclosporine; Cytochrome P-450 Enzyme System; Drug Monitoring; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Polymorphism, Genetic; Ribonucleosides; Rituximab; Tacrolimus

Prognosis of the renal involvement of connective tissue diseases such as systemic lupus erythematosus or systemic sclerosis is getting better due to the induction of the new immunosuppressant such as tacrolimus and hypotonicas which reduce glomerular hypertension such as angiotensin converting enzyme inhibitor or angiotensin II receptor antagonist. Since patients with myeloperoxidase-anti-neutrophil cytoplasmic antibody related glomerulonephritis are older than those with Wegener's granulomatosis, the strong immunosuppressive treatment recommended in Western countries should be avoided. The treatment guideline issued by the Japanese Society of Nephrology is suitable for elderly Japanese patients. Recently, there have been some reports of the use of mizoribine, which is a mild immunosuppressant drug.

Topics: Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Connective Tissue Diseases; Humans; Immunosuppressive Agents; Kidney Diseases; Methylprednisolone; Pulse Therapy, Drug; Ribonucleosides; Tacrolimus

In recent years, novel immunosuppressive drugs applies to various autoimmune diseases and the evidences increase. Since immunosuppressive drugs inhibit nonselectively the whole immune system, there are possibilities that infection may be induced by decreasing the immunity against pathological agents and malignancy may develop by suppressing immune surveillance. In order to use the immunosuppressants safely and effectively, we should obey the indication and dosage, and be familiar with the side effects. It is also important to take informed consent from patients after explaining the benefit and risk. Therefore, the doctors who are going to use immunosuppressive drugs must know well about the indication, the side effects, the metabolism and the action mechanisms of those drugs.

Topics: Azathioprine; Calcineurin Inhibitors; Collagen Diseases; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Methotrexate; Rheumatic Diseases; Ribonucleosides; Risk Assessment; Tacrolimus

The nephrotic syndrome is commonly caused by various glomerulonephritides, i.e. minimal change nephrotic syndrome, focal segmental glomerulosclerosis and membranous nephropathy. A long term corticosteroid therapy is a first therapeutic approach for patients with nephrotic syndrome. In patients who have contraindication to steroids or in those who do not respond to steroids, immunosuppressive agents such as cyclosporine, mizoribine, azathioprine and cyclophosphamide are the next therapeutic approach for inducing the remission of the nephrotic syndrome. In this review, we described an appropriate use of systemic immunosuppressive agents for steroid resistant nephrotic syndrome, and the toxicity and side effects of each agent. And currently the clinical trials with new immunosuppressants like tacrolimus (FK 506) and mycophenolate mofetil are also described.

Topics: Azathioprine; Cyclophosphamide; Cyclosporine; Humans; Immunosuppressive Agents; Mycophenolic Acid; Nephrotic Syndrome; Ribonucleosides; Tacrolimus

Topics: Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Models, Biological; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; T-Lymphocytes; Tacrolimus; Transplantation Immunology

Maintenance immunosuppressive drugs act by partially blocking rate-limiting steps in the immune response. The new maintenance immunosuppressive drugs are either inhibitors of de novo synthesis of nucleotides (purines or pyrimidines), or are immunophilin-binding drugs that inhibit signal transduction in lymphocytes. The new inhibitors of de novo nucleotide synthesis include mycophenolate mofetil (MMF), mizoribine (MZ), brequinar (BQR), and leflunomide (LEF). MMF and MZ act to inhibit de novo purine synthesis, by inhibition of inosine monophosphate dehydrogenase (IMPDH). They create a selective immunodeficiency in T and B lymphocytes. MMF is hydrolyzed to mycophenolic acid (MPA), an uncompetitive inhibitor of IMPDH. MPA reduces the pools of guanine nucleotides, and increases some adenine nucleotides, inhibiting the cell cycle. Thus the number of specific effector T and B lymphocytes is reduced by limiting clonal expansion. MZ is a competitive inhibitor of IMPDH, which creates a similar defect. The relative clinical effectiveness of MMF versus MZ is not known. MMF has been approved in a number of countries; MZ has been approved in Japan. The inhibitors of de novo pyrimidine synthesis (BQR, LEF) act on the enzyme dehydroorotate dehydrogenase. Neither is currently in clinical trials in transplantation. The new immunophilin-binding drugs inhibit either the calcium-dependent phosphatase calcineurin (CN) [tacrolimus (or FK-506) and the microemulsion form of cyclosporine (CsA)] or signaling from growth factor receptors [rapamycin (sirolimus)]. Tacrolimus binds to FK binding protein-12 (FKBP-12) to create a complex that inhibits CN. CsA binds to cyclophilin to create a complex that inhibits CN. Inhibition of CN prevents activation of cytokine genes in T cells. The relative clinic effectiveness of tacrolimus versus microemulsion CsA is unknown. Rapamycin inhibits signaling from growth factor receptors, such as IL-2R. Rapamycin binds to FKBP to create a complex that engages proteins called TOR (target of rapamycin), or RAFT (rapamycin and FKBP target), which may be kinases. The result is a block in the ability of cytokine receptors to activate cell cycling, interfering with clonal expression. Deoxyspergualin, a parenteral drug in development for induction or antirejection therapy, may inhibit intracellular chaperoning by Hsc70, a member of the heat shock protein family. It may have its principal effect by inhibiting the activation of transcription factor NF-kappa B i

Topics: Amino Acid Isomerases; B-Lymphocytes; Biphenyl Compounds; Calcineurin; Calmodulin-Binding Proteins; Carrier Proteins; Cyclosporine; Enzyme Inhibitors; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Isoxazoles; Leflunomide; Mycophenolic Acid; Oxidoreductases; Peptidylprolyl Isomerase; Phosphoprotein Phosphatases; Polyenes; Purines; Pyrimidines; Receptors, Cytokine; Ribonucleosides; Signal Transduction; Sirolimus; T-Lymphocytes; Tacrolimus

Topics: Cyclosporine; Humans; Immunosuppressive Agents; Monitoring, Physiologic; Ribonucleosides; Tacrolimus; Tissue Transplantation

Topics: Biphenyl Compounds; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Spiro Compounds; Tacrolimus; Transplantation Immunology

Topics: Animals; Antimetabolites; Azathioprine; Biphenyl Compounds; Cell Differentiation; Cyclosporine; Guanidines; Humans; Immunosuppressive Agents; Isoxazoles; Leflunomide; Lymphocytes; Lymphokines; Oligonucleotides, Antisense; Polyenes; Receptors, Cytokine; Ribonucleosides; Signal Transduction; Sirolimus; Tacrolimus

Topics: Animals; Biphenyl Compounds; Cyclosporine; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Tacrolimus; Xenobiotics

BACKGROUND At 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 AND METHODS Between 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. RESULTS Compared 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. CONCLUSIONS This 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.

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome; Young Adult

Mizoribine (MZR) was effective and safe for living Chinese donor kidney transplantation (LDKT) on tacrolimus-based treatment 1 year after transplantation. We investigated whether MZR was effective and safe for LDKT on tacrolimus-based treatment with long follow-up periods.. We compared 22 LDKT recipients who were administered MZR, tacrolimus, and corticosteroids with a control group (n = 20) treated with mycophenolate mofetil (MMF), tacrolimus, and corticosteroids. Primary efficacy endpoints were 3-year patient survival, 3-year graft survival, and acute rejection (AR) rate within 3 years after transplantation.. The 3-year patient and graft survival rates for the MZR and MMF groups were 100%. The AR rate after transplantation was 18.2% for the MZR group and 10.0% for the MMF group; the difference was not significant (P = .665). There was no significant difference in serum creatinine levels, glomerular filtration rates (eGFR), serum urate levels, blood urea nitrogen, and cystatin C levels 12, 24, and 36 months after transplantation. No significant differences in the CD3, CD4, CD8, CD4/CD8, and CD45 were observed between the 2 groups 12, 24, and 36 months after transplantation. There were no significant differences in adverse events among the MZR or the MMF group, whereas the prevalence of gastrointestinal symptoms were significantly lower in the MZR treatment group (P = .003), especially acid reflux (P = .007). Compared with the MMF group, the MZR group should lighten the burden on patients.. MZR with tacrolimus and corticosteroids provides satisfactory immunosuppression and higher safety for Chinese LDKT over a 3-year follow-up.

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Ribonucleosides; Tacrolimus

To evaluate the utility and safety of high-dose mizoribine combination therapy using cyclosporine and tacrolimus as calcineurin inhibitors in patients undergoing kidney transplant.. The present study enrolled 156 patients who received kidney transplants in 18 institutions between 2009 and 2013. ABO-incompatible and/or pre-sensitized recipients were excluded. Immunosuppression used cyclosporine (88) or tacrolimus (68) as a calcineurin inhibitor, and the dosage was adjusted based on blood concentrations. Mizoribine was started at 6 mg/kg/day, and the target trough level was 1-2 ng/mL. Primary efficacy end-points of this study were 2-year patient survival, 2-year graft survival and the acute rejection rate within 2 years after transplantation.. The 2-year patient and graft survival rates in the cyclosporine group were 98.9% and 94.3%, respectively, whereas those in the tacrolimus group were 100% and 98.5%, respectively, with no significant difference between groups. Rates of onset of rejection during the observation period were also equivalent, at 22.7% in the cyclosporine group and 17.6% in the tacrolimus group. Furthermore, groups showed no significant differences in transplanted renal function. No notable differences in adverse events were observed between groups.. A regimen of high-dose mizoribine in combination with calcineurin inhibitors basiliximab, and corticosteroids can provide effective immunosuppression while lowering the rate of cytomegalovirus infection in kidney transplant patients.

Topics: Adult; Basiliximab; Calcineurin Inhibitors; Cyclosporine; Drug Therapy, Combination; Female; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Ribonucleosides; Survival Rate; Tacrolimus; Treatment Outcome

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.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Disease-Free Survival; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Intention to Treat Analysis; Japan; Kaplan-Meier Estimate; Kidney Transplantation; Leukopenia; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Ribonucleosides; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Recent advances in the management of lupus nephritis (LN) have also contributed to a favorable outcome in patients with pediatric-onset LN. Nevertheless, we believe that a more effective and less toxic treatment is needed to attain optimal control of pediatric-onset LN.. Seven consecutive children with biopsy-proven LN (four with class III/IV and three with class V) received multitarget induction therapy consisting of mizoribine (MZR), tacrolimus (Tac), and prednisolone (PDN). They were prospectively evaluated at three, six, and 12 months, and at the latest observation point after a mean period of 32 months. Post-treatment renal biopsy was performed in two patients with class III/IV.. Despite gradually tapering the dose of concomitantly administered PDN, a significant improvement compared with baseline values was observed in the urinary, serological, and clinical assessment measures even at three months of treatment, and the favorable changes persisted throughout the treatment period in most of the study participants except for one. In two patients who underwent post-treatment renal biopsy, a marked histologic improvement was confirmed. No serious adverse events were observed.. Multitarget therapy may be an attractive option for the treatment of pediatric-onset LN. Further studies involving a larger number of patients are needed.

Topics: Adolescent; Child; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Induction Chemotherapy; Lupus Nephritis; Male; Pilot Projects; Prednisolone; Prospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome

Mizoribine (MZR) was approved in 1984 in Japan for the suppression of rejection in renal transplantation with an approved administration dosage of 1-3 mg/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 12 mg/kg/day for MZR and 2 g/day for MMF. Dosages of FK and steroids were set according to the protocol of each institution.. Patient and graft survival rate at 1 year 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.

Topics: Adult; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Ribonucleosides; Tacrolimus; Uric Acid

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.

Topics: Adult; Aged; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Ribonucleosides; Tacrolimus; Young Adult

An effective treatment for children with refractory nephrotic syndrome (NS), especially in those with cyclosporine (CsA)-resistant or CsA-intolerant NS, has yet to be established. Recently, the efficacy of multidrug therapy consisting of tacrolimus (Tac), mycophenolate mofetil (MMF) in combination with prednisolone (PDN) in adult patients with refractory NS has been reported. We successfully treated 14 consecutive children with refractory CsA-resistant or CsA-intolerant NS using combination therapy consisting of relatively low-dose Tac, mizoribine (MZR), which has a mechanism of action very similar to that of MMF, and PDN. There were no serious clinical toxicities. Of the 14 children, 9 with a mean age of 13.0 years had steroid-dependent NS (SDNS) and 5 with a mean age of 9.6 years had steroid-resistant NS (SRNS). All SDNS patients had minimal change disease (MCD), 4 with SRNS had focal segmental glomerulosclerosis (FSGS), and the remaining child had MCD on renal biopsy. All patients were in a prospective cohort, but were evaluated retrospectively. The mean follow-up from the initiation of multidrug therapy was 18.4 months in SDNS and 18.6 months in SRNS patients. At the last observation point, the calculated relapse rate and minimum dose of PDN required for maintenance of clinical remission after the start of multidrug therapy were significantly decreased compared with those prior to this therapy, while on CsA, in SDNS patients (0.4 ± 0.5 times/year vs 2.9 ± 1.5 times/year, P = 0.0077, and 0.3 ± 0.2 mg/kg on alternate days vs 0.5 ± 0.2 mg/kg on alternate days, P = 0.0184 respectively). All SDNS and two SRNS patients (40%) achieved complete remission, allowing further decreases in the minimal doses of PDN required for maintenance of clinical remission in most our patients. However, one patient with FSGS remained refractory to multidrug therapy and subsequently developed end-stage renal disease. These clinical observations, although preliminary and involving a small number of patients, suggest that multidrug therapy consisting of relatively low-dose Tac, MZR, and PDN might be effective and safe for treating children with refractory CsA-resistant or CsA-intolerant NS. However, further studies involving larger numbers of patients are needed.

Topics: Adolescent; Child; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Male; Nephrotic Syndrome; Pilot Projects; Prednisone; Ribonucleosides; Tacrolimus; Young Adult

To compare the efficacy and safety of tacrolimus and mizoribine in patients with rheumatoid arthritis (RA).. Adult patients with RA with an insufficient response to at least one disease modifying antirheumatic drug (DMARD) were randomized to receive 28 weeks of double-blind treatment with tacrolimus 3 mg once daily or mizoribine 50 mg three times daily. The primary efficacy endpoint was the American College of Rheumatology 20% (ACR20) response. Safety was evaluated by adverse events.. A total of 204 patients were enrolled for study (103 in the tacrolimus group, 101 in the mizoribine group). Significantly more patients receiving tacrolimus achieved an ACR20 response compared with mizoribine (48.5 vs 10.0%, respectively; p = 0.001). Tacrolimus was also superior to mizoribine in ACR50 and ACR70 response rate, tender and painful joint counts, swollen joint counts and patient and physician assessments of pain, disease activity, and patient's physical function assessment based on the Modified Health Assessment Questionnaire (p < 0.001). Adverse events were more frequent in the tacrolimus group than the mizoribine group (65.0 vs 59.4%); however, there were no statistically significant differences between treatment groups.. Tacrolimus improves RA symptoms to a significantly greater extent than mizoribine in patients with RA inadequately controlled with at least one prior DMARD. Tacrolimus has the potential to be a useful and highly effective treatment for RA.

Topics: Arthritis, Rheumatoid; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ribonucleosides; Tacrolimus; Treatment Outcome

Topics: Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infections; Japan; Kidney Function Tests; Kidney Transplantation; Living Donors; Postoperative Complications; Ribonucleosides; Survival Analysis; Tacrolimus; Time Factors

Topics: Adolescent; Adult; Area Under Curve; Azathioprine; Child; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Half-Life; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Ribonucleosides; Tacrolimus

Topics: Administration, Oral; Adolescent; Adult; Azathioprine; Creatinine; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Transplantation; Methylprednisolone; Middle Aged; Prospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome

To understand the status of mizoribine use in patients with lupus nephritis (LN) and to collect safety- and efficacy-related data on 2-year treatment with mizoribine.. A continuous survey was conducted between March 2010 and July 2015.. The analysis set included 559 patients (mean age 39.5 years, females 82.6%, mean duration of systemic lupus erythematosus (SLE) 8.4 years, mean duration of LN 5.9 years). Renal function was satisfactory for 6 months, but worsened from 12 months, with significant worsening at 24 months. By the ACR 2006 remission criteria (eGFR >60), at 24 months, 26.5% of patients achieved complete remission, and 63.3% achieved complete or partial remission. The urine protein to creatinine ratio decreased significantly. The SLE Disease Activity Index 2000 score decreased significantly at 12 and 24 months. Overall, 98 (17.5%) patients experienced 124 adverse drug reactions (ADRs); 3.6% experienced serious ADRs. Mizoribine was used with a steroid in 99.3% and an immunosuppressant in 51.2%; tacrolimus was used in 43.8%. The oral steroid dosage decreased from baseline to 24 months. The incidence of ADRs was not significantly different with concomitant tacrolimus use.. The results suggest that long-term mizoribine is safe and effective, even when used with tacrolimus.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Lupus Nephritis; Male; Middle Aged; Product Surveillance, Postmarketing; Ribonucleosides; Tacrolimus

Despite the high efficacy of mycophenolate mofetil (MMF)/tacrolimus-based multitarget treatment, risks of infections are a matter of concern. In the present study, we clarified the potential of multitarget therapy using mizoribine opposed to MMF.. A total of 36 patients with biopsy-proven lupus nephritis were treated with mizoribine, tacrolimus, and glucocorticoids and then retrospectively evaluated. To determine the efficacy, proteinuria remission (≤ 0.2 g/day), complete remission (Liu et al. in Ann Intern Med 162:18-26, 2015) and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) remission rates, and the prednisolone dose at months 6 and 12 were evaluated. The associations between serum mizoribine/tacrolimus levels and clinical parameters were investigated. To assess safety, adverse events were inspected.. All patients could continue the original treatment regimen without withdrawal or exacerbations through month 12. At month 6, the proteinuria remission, complete remission, SLEDAI remission rates, and prednisolone dose were 69, 53, 36%, and 12.1 mg/day, respectively, whereas the values at 12 months were 92, 67, 50%, and 8.8 mg/day, respectively. The treatment was efficacious for every histologic type of nephritis and non-renal manifestations of SLE. Excluding one patient who was hospitalized due to upper respiratory tract infection, serious infections, including pneumonia and cytomegalovirus disease, were not observed. Higher trough tacrolimus levels were associated with normalization of complement, whereas higher peak mizoribine levels with prevention of cytomegalovirus viremia.. Our results suggest that multitarget therapy using mizoribine opposed to MMF is highly safe and effective through 12 months. The therapy may enable faster dose reduction of concomitant glucocorticoids.

Topics: Adolescent; Adult; Aged; Cytomegalovirus Infections; Female; Humans; Lupus Nephritis; Male; Middle Aged; Ribonucleosides; Tacrolimus; Young Adult

Topics: Autoantibodies; Dermatomyositis; Drug Monitoring; Drug Therapy, Combination; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Interferon-Induced Helicase, IFIH1; Lung Diseases, Interstitial; Male; Middle Aged; Prognosis; Ribonucleosides; Severity of Illness Index; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Universal prophylaxis and preemptive therapy are used to prevent cytomegalovirus (CMV) disease post-transplantation. Data regarding which strategy is superior are sparse, especially in high-risk recipients (donor CMV seropositive (D+) and recipient CMV seronegative (R-)).. This retrospective, single-center cohort study included recipients who underwent kidney transplantation between 2009 and 2015. The incidence of CMV infection/disease and patient and graft outcomes were analyzed and compared between high-risk recipients (D+/R-) and intermediate-risk recipients (D+/R+ or D-/R+), all managed with preemptive therapy.. Of 118 kidney transplant recipients, 21 were high-risk and 97 were intermediate-risk. Over a median follow-up period of 3 years, asymptomatic CMV infection developed significantly more frequently in high-risk patients than in intermediate-risk patients (38.1% vs. 16.5%, p=0.04), and CMV disease developed in a similar manner (28.6% vs. 3.1%, p<0.01). Among high-risk patients, CMV infection developed within the first 3 months post-transplantation and CMV disease within the first 9 months post-transplantation. Kaplan-Meier analysis showed no difference in the probability of mortality (log-rank p=0.63) or graft loss (log-rank p=0.50) between the patient groups. Graft rejection occurred more frequently in high-risk than in intermediate-risk patients, but the difference was not significant (log-rank p=0.24).. These results suggest that further studies on universal prophylaxis in high-risk patients are needed to elucidate whether preventing CMV infection/disease during the early post-transplant period leads to better outcomes, especially in terms of reducing graft rejection.

Topics: Adult; Antibodies, Monoclonal; Antiviral Agents; Basiliximab; Cytomegalovirus; Cytomegalovirus Infections; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kaplan-Meier Estimate; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Ribonucleosides; Risk Factors; Rituximab; Tacrolimus; Tissue Donors; Treatment Outcome

Topics: Adolescent; Diagnosis, Differential; Drug Therapy, Combination; Glucocorticoids; Humans; IgA Vasculitis; Immunosuppressive Agents; Male; Nephritis; Prednisolone; Ribonucleosides; Tacrolimus

The study aims to confirm the feasibility of new oral triple combination therapy using methotrexate (MTX), mizoribine (MZR), and tacrolimus (TAC) in patients with rheumatoid arthritis (RA) by in vitro and clinical analyses. Triple therapy with a combination of MTX, MZR, and TAC was used for an in vitro study with osteoclasts and a prospective clinical study in order to show the efficacy of these agents against refractory RA. In particular, low-dose TAC or MZR was added to treat 14 patients with RA that was resistant to MTX + MZR or MTX + TAC dual therapy. The combination of three pharmacological agents showed statistically significant differences to reduce differentiation induction and activity of osteoclasts compared with single and double agents. In clinical use, triple therapy showed a statistically significant difference in the improvement of Disease Activity Score-28-erythrocyte sedimentation rate and the Simple Disease Activity Index score at around 8 months. Additionally, the serum matrix metalloproteinase-3 level significantly decreased. No patients dropped out because of adverse effects. Based on this in vitro and prospective clinical study, oral triple therapy might be effective against refractory RA. Furthermore, this therapy might be safe and economical for clinical practice.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Bone Resorption; Cathepsin K; Cell Differentiation; Drug Therapy, Combination; Female; Humans; Male; Matrix Metalloproteinase 3; Matrix Metalloproteinase 9; Methotrexate; Middle Aged; Osteoclasts; Prospective Studies; Real-Time Polymerase Chain Reaction; Ribonucleosides; Severity of Illness Index; Tacrolimus

Topics: Antibodies, Antineutrophil Cytoplasmic; Biopsy; Cyclophosphamide; Drug Resistance; Drug Substitution; Drug Therapy, Combination; Female; Glomerulonephritis; Humans; Immunosuppressive Agents; Microscopic Polyangiitis; Middle Aged; Ribonucleosides; Tacrolimus; Treatment Outcome

Many papers have reported on pregnancy and delivery after liver transplantation, but there have been no reports on pregnancy after ABO-incompatible liver transplantation. This paper reports the first successful pregnancy and delivery of a newborn after ABO-incompatible liver transplantation for fulminant hepatic failure. The patient was a 39-year-old female. She had an ABO-incompatible liver transplantation, donated from her husband, due to subacute fulminant hepatitis of unknown etiology. She was taking tacrolimus, methylprednisolone, and mizoribine orally for the maintenance of immunosuppression at the time of discharge. She was discharged uneventfully on postoperative day 38 without any rejection episodes. At 1 year and 6 mo after transplantation, she indicated a wish to become pregnant. Therefore, treatment with mycophenolate mofetil was interrupted at that time. After two miscarriages, she finally became pregnant and delivered transvaginally 3 years after the transplantation. All of the pregnancies were conceived naturally. The newborn was female with a birth weight of 3146 g; the Apgar scores were 9 and 10. Delivery was performed smoothly, and the newborn exhibited no malformations. The mother and the newborn were discharged uneventfully. We suggest that pregnancy is possible for recipients after ABO-incompatible liver transplantation.

Topics: ABO Blood-Group System; Administration, Oral; Adult; Apgar Score; Biopsy; Blood Group Incompatibility; Delivery, Obstetric; Female; Hemodiafiltration; Hepatic Encephalopathy; Hepatitis; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant, Newborn; Liver Transplantation; Living Donors; Methylprednisolone; Pregnancy; Ribonucleosides; Rituximab; Spouses; Tacrolimus

Everolimus (EVR) has been used widely for the purpose of reducing the dosage of calcineurin inhibitor (CNI), leading to decreasing CNI nephrotoxicity. In Japan, high-dose mizoribine (MZR) (6 mg/kg/day) has been increasingly used because of incidences of virus infection and gastrointestinal disorder in kidney transplant recipients. However, the efficacy and safety of EVR and MZR combination therapy is still uncertain.. A total of 29 living kidney transplant recipients from October 2012 to June 2014 were analyzed. Tacrolimus (TAC), MZR, basiliximab, and prednisolone were administered to all recipients. EVR was added to the regimen for 10 recipients from postoperative day 10 to 14; TAC trough levels were minimized simultaneously (EVR group). The remaining 19 recipients were defined as the control group. We evaluated the outcomes between the 2 groups.. The mean TAC trough level was 5.17 ng/mL at 1 month after transplantation in the EVR group, and 7.89 ng/mL in the control group (P = .007), respectively. The mean TAC trough level was 4.0 ng/mL at 18 months after transplantation in the EVR group, and 6.97 ng/mL in the control group (P = .003) respectively. There were no differences in the rate of acute rejection and serum creatinine level. There was no significant difference in the incidence of histological nephrotoxicity between the 2 groups in the 1-year biopsy results.. We succeeded in reducing TAC trough level immediately after transplantation by adding EVR. Our study results suggest that this combination therapy is effective for kidney transplantation recipients.

Topics: Adult; Aged; Dose-Response Relationship, Drug; Drug Therapy, Combination; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Living Donors; Male; Middle Aged; Ribonucleosides; Tacrolimus; Transplant Recipients; Young Adult

Lipid abnormalities (LA) are related to an increased risk for cardiovascular diseases in kidney transplantation patients.. Multivariable logistic regression models were used to estimate the risk of LA associated with potential risk factors, including immunosuppressant use, patient background characteristics, and laboratory data.. In total, 386 patients who were undergoing kidney transplantation were included in the study. Statins were prescribed to 43% of patients. The LA composite outcome was defined as statin use and/or low density lipoprotein cholesterol level ≥120 mg/dL, and 229 patients (59.3%) developed LA as a result. LA was significantly related to everolimus, corticosteroid, age, and estimated glomerular filtration ratio in the multiple logistic regression analysis. The odds ratios were 2.264, 3.119, 1.186, and 0.870, respectively. Mycophenolate mofetil, mizoribine, azathioprine, cyclosporine (CYA), tacrolimus, proteinuria, body mass index, and male sex were not related to LA.. CYA influenced lipid metabolism but was not related to LA in our study. The mean post transplantation period was 8.4 years, and the CYA dose decreased over time. The CYA blood concentration was 70.0 ng/mL, which is relatively low, but it decreased the susceptibility to LA. Serum lipid levels were well controlled by statins, and the estimated glomerular filtration rate was maintained stably.. Everolimus and corticosteroid use, as well as a lower estimated glomerular filtration rate and higher age, were significant risk factors for LA. CYA is known for its adverse LA effects, but it was not a significant risk factor for LA in patients undergoing maintenance phase kidney transplantation.

Topics: Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Azathioprine; Cyclosporine; Dyslipidemias; Everolimus; Female; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Kidney Transplantation; Lipids; Male; Middle Aged; Mycophenolic Acid; Ribonucleosides; Risk Factors; Tacrolimus

Topics: Child; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Ribonucleosides; Tacrolimus; Takayasu Arteritis; Treatment Outcome

A substantial number of patients with lupus nephritis (LN) are refractory to conventional glucocorticoid (GC) treatment. Although many of these patients respond to immunosuppressive drugs such as intravenous cyclophosphamide (IVCY), azathioprine (AZA), mizoribine, tacrolimus, cyclosporine A (CSA) and mycofenolate mofetil (MMF), some remain refractory to such therapies. Recent studies of multi-target therapies have reported effective outcomes for immunosuppression following renal transplantation and refractory LN when therapy consists of two or more immunosuppressive drugs with different mechanisms of action. We herein report a case of LN unresponsive to IVCY that was successfully treated with the addition of tacrolimus and discuss the usefulness of multi-target therapy for LN.

Topics: Adolescent; Antihypertensive Agents; Biphenyl Compounds; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypertension, Renal; Immunosuppressive Agents; Infusions, Intravenous; Irbesartan; Lupus Erythematosus, Systemic; Lupus Nephritis; Nephrotic Syndrome; Prednisolone; Pulse Therapy, Drug; Recurrence; Ribonucleosides; Severity of Illness Index; Tacrolimus; Tetrazoles

Topics: Child; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Prednisolone; Ribonucleosides; Tacrolimus; Treatment Outcome

Conventional cyclophosphamide-based treatment regimens for lupus nephritis (LN) are still not considered to be optimal. The aim of this study was to evaluate the efficacy and safety of mizoribine, tacrolimus, and corticosteroid combination therapy for LN.. We retrospectively evaluated a combination treatment of mizoribine and tacrolimus with corticosteroids as induction therapy in eight newly diagnosed systemic lupus erythematosus (SLE) patients with biopsy-proven LN.. All patients were women, and their mean [standard deviation (SD)] age was 48.5 (20) years. All patients (100 %) had positive anti-double-stranded DNA (anti-dsDNA) antibody titers, and four (50.0 %) were nephrotic. Mean (SD) serum creatinine and daily proteinuria levels were 0.72 (0.4) mg/dl (range 0.33-1.55 mg/dl) and 4.56 (2.8) g (range 0.77-8.2 g), respectively. By month 2, significant improvements in the anti-dsDNA antibody titers, levels of proteinuria, serum albumin, and C3, and SLE disease activity index score were observed. By month 6, seven patients (87.5 %) were in complete remission, with normalized levels of both proteinuria and serum creatinine.. This pilot study suggests that mizoribine and tacrolimus treatment with corticosteroids is well tolerated and may prove to be an optimal alternative remission-inducing regimen for LN.

Topics: Adrenal Cortex Hormones; Adult; Aged; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Methylprednisolone; Middle Aged; Pilot Projects; Prednisolone; Proteinuria; Remission Induction; Retrospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome

Topics: Adolescent; Drug Therapy, Combination; Female; Humans; Lupus Nephritis; Prednisolone; Ribonucleosides; Tacrolimus

The prognosis of lupus nephritis (LN) has improved since the introduction of immunosuppressant therapies, but the safety and effectiveness of treatments can also be improved. We retrospectively assessed the treatment courses of 12 patients with systemic lupus erythematosus who were treated with glucocorticoid, mizoribine (MZR) and tacrolimus. This regimen was used as initial therapy for active LN in six patients (mean glucocorticoid dose, 66.6 mg); four of these six patients also received pulse methylprednisolone therapy. The starting doses of MZR and tacrolimus were 150 and 3 mg, respectively, and they were titrated as required. Five of six patients achieved complete remission and one achieved partial remission at 6 months. Five patients who completed 12-month analysis achieved complete remission. Another six patients were given the combination regimen for treating minor flares or for steroid sparing. The mean prednisolone doses were reduced from 11.0 mg at baseline to 6.6 mg at 12 months. Six patients experienced minor adverse events, including three minor infections. One patient stopped tacrolimus because of suspected toxicity. All 12 patients were successfully treated, and none experienced severe adverse events. Multitarget therapy combining glucocorticoid, MZR and tacrolimus may have the potential to become a treatment option which is effective and safe.

Topics: Adult; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Remission Induction; Retrospective Studies; Ribonucleosides; Tacrolimus; Time Factors; Treatment Outcome

We investigated the efficacy and safety of an immunosuppressive regimen consisting of tacrolimus or cyclosporine, with basiliximab, mycophenolate mofetil or mizoribine, and low-dose steroids (prednisone <2.5 mg/d) for kidney transplant recipients.. We conducted a prospective study of 51 recipients with stable graft function who underwent kidney transplantation between August 2005 and December 2009. The oral dose of prednisone was gradually tapered to <2.5 mg/d within 2 months after transplantation. We assessed, patient and graft survivals, incidence of rejection episodes, transplant function and steroid side effects.. Death-censored graft survival was 100%, and the mean serum creatinine levels remained stable at 1.31, 1.37, and 1.48 mg/dL at 1, 2, and 3 years, respectively, after transplantation. There were seven biopsy-proven rejection episodes (mean = 110 days; range = 14-436) after prednisone was decreased. The cumulative incidence of biopsy-proven rejection was 11.2%, 17.0%, and 17.0%, respectively. In addition, the mean blood pressure was stable (127/78 mm Hg, 125/77 mm Hg, and 125/76 mmHg, respectively), whereas the mean serum cholesterol and triglyceride levels remained within normal limits. Only 3 patients (7%) displayed new onset diabetes after transplantation.. Low-dose steroid maintenance therapy is safe with beneficial effects on cardiovascular risk factors.

Topics: Adult; Aged; Antibodies, Monoclonal; Basiliximab; Creatinine; Cyclosporine; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recombinant Fusion Proteins; Ribonucleosides; Tacrolimus

Topics: Animals; Dose-Response Relationship, Drug; Drug Synergism; Graft Survival; Immunosuppressive Agents; Kidney Transplantation; Lymphocyte Culture Test, Mixed; Macaca fascicularis; Ribonucleosides; Tacrolimus; Transplantation, Homologous

Topics: Adult; Azathioprine; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerulonephritis, IGA; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Recurrence; Retrospective Studies; Ribonucleosides; Survival Rate; Tacrolimus; Time Factors

Topics: Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Guanidines; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Muromonab-CD3; Retrospective Studies; Ribonucleosides; Tacrolimus; Treatment Outcome

Topics: Adult; Azathioprine; Cholesterol; Cholesterol, HDL; Cyclosporine; Drug Therapy, Combination; Female; Humans; Hypercholesterolemia; Hyperlipidemias; Hypertriglyceridemia; Immunosuppressive Agents; Incidence; Japan; Kidney Transplantation; Male; Methylprednisolone; Postoperative Complications; Retrospective Studies; Ribonucleosides; Risk Factors; Tacrolimus; Triglycerides

Topics: Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Infusions, Intravenous; Kidney Transplantation; Methylprednisolone; Postoperative Period; Ribonucleosides; Tacrolimus; Time Factors

Dark Agouti (DA) and Lewis rat strains were tested for susceptibility to collagen-induced arthritis (CIA) and for development of cellular and humoral immune responses to type II collagen (CII). All of the DA rats developed arthritis following a single intradermal injection of more than 20 microg of CII (130-150 microg/kg rat weight) and showed a swelling rate of more than 100% in the hind paws. The swelling rate showed little deviation among the animals. There was a strong correlation between the severity of the arthritis and the strength of the immune response to CII in DA rats with CIA. Following immunization with even 800 microg of CII (3.8-4.2 mg/kg rat weight), Lewis rats showed a maximum rate of hind paw swelling of only 45%. In the pharmacological studies, prednisolone, indomethacin, FK-506 and mizoribine all suppressed arthritis in DA rats. These findings suggest that DA rats are more susceptible to CIA than Lewis rats and that CIA in DA rats as well as in Lewis rats is serviceable as an experimental animal model of rheumatoid arthritis.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibody Formation; Arthritis; Collagen; Disease Models, Animal; Dose-Response Relationship, Drug; Edema; Enzyme-Linked Immunosorbent Assay; Female; Hindlimb; Hypersensitivity, Delayed; Immunosuppressive Agents; Indomethacin; Injections, Intradermal; Prednisolone; Rats; Rats, Inbred Lew; Rats, Inbred Strains; Ribonucleosides; Species Specificity; T-Lymphocytes; Tacrolimus

Topics: Animals; Benzopyrans; Cell Line; Cells, Cultured; Concanavalin A; Dogs; Drug Therapy, Combination; Female; Graft Survival; Immunosuppressive Agents; Interleukin-2; Kidney Transplantation; Liver Transplantation; Lymphocyte Activation; Lymphocytes; Male; Mice; Mice, Inbred C57BL; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Ribonucleosides; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Adult; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Guanidines; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Retrospective Studies; Ribonucleosides; Tacrolimus; Time Factors

Topics: Animals; Benzopyrans; Drug Therapy, Combination; Graft Survival; Immunosuppressive Agents; Liver Transplantation; Male; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Ribonucleosides; Tacrolimus; Time Factors

Topics: Animals; Cholesterol; Coronary Disease; Drug Therapy, Combination; Graft Rejection; Heart Transplantation; Hypercholesterolemia; Immunosuppressive Agents; Male; Rabbits; Ribonucleosides; Tacrolimus; Time Factors

Topics: Animals; Azathioprine; Drug Synergism; Drug Therapy, Combination; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Male; Mycophenolic Acid; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Ribonucleosides; Tacrolimus; Transplantation, Homologous

The effects of two new immunosuppressors, FK-506 and mizoribine, on antigen-induced bronchial inflammation and reactivity to acetylcholine in mice were studied in comparison with those of cyclosporin A and cyclophosphamide. Three inhalations of an antigen by actively sensitized BALB/c mice resulted in an increase in airway reactivity to acetylcholine. Twenty-four hours after the final inhalation, the number of leukocytes (mononuclear cells and eosinophils) and the amount of interleukin 5 (IL-5) increased significantly. In BALB/c nu/nu mice (athymic mice), three inhalations of antigen caused no significant change in either airway inflammation or hyperresponsiveness. The administration of each of the four immunosuppressors clearly inhibited antigen-induced airway eosinophilia. Moreover, FK-506, mizoribine and cyclophosphamide clearly inhibited the antigen-induced IL-5 production and cyclosporin A showed the tendency to inhibit IL-5 production. Whereas FK-506, mizoribine and cyclosporin A clearly inhibited the antigen-induced airway hyperreactivity in BALB/c mice, cyclophosphamide did not show a significant effect on this airway hyperreactivity. These results indicate that FK-506, mizoribine and cyclosporin A, but not cyclophosphamide, inhibit antigen-induced airway hyperreactivity in mice. The mechanism which inhibits antigen-induced airway eosinophilia and IL-5 production is not involved in the inhibitory mechanism of airway hyperreactivity by FK-506 and mizoribine.

Topics: Aerosols; Animals; Bronchial Provocation Tests; Chemotaxis, Leukocyte; Cyclophosphamide; Cyclosporine; Hypersensitivity; Immunosuppressive Agents; Interleukin-5; Mice; Mice, Inbred BALB C; Mice, Nude; Ovalbumin; Respiratory System; Ribonucleosides; Tacrolimus

Following rat heterotopic heart allotransplantation, low to lethal doses of the antimetabolites mizoribine (MIZ), RS-61443 (RS), and AZA were given alone or in combination with subtherapeutic doses of FK506 (0.04 mg/kg/day) for 14 days after transplantation. With the median effect analysis of Chou and Kahan for quantitative drug interactions, substantial therapeutic synergism was demonstrated between FK506 and non-toxic doses of MIZ (2.5, 5, and 10 mg/kg/day) or AZA (5, 30, and 45 mg/kg/day), which was particularly evident with the lowest dose MIZ (2.5 mg/kg/day). When FK506 was used in combination with MIZ or AZA but not with RS, the maximum effect (peak median graft survival) was enhanced significantly from 15 days (MIZ alone) to 26 days (P < 0.05), and from 19 days (AZA alone) to 32 days (P < 0.01). In contrast, RS interacted with FK506 no more than additively. Although RS was the most powerful single antimetabolite, the best overall survival was obtained by combining AZA and FK506. The addition of FK506 did not significantly increase the percent mortality and LD50 of the antimetabolites.

Topics: Animals; Azathioprine; Drug Synergism; Drug Therapy, Combination; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Lethal Dose 50; Male; Mycophenolic Acid; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Ribonucleosides; Tacrolimus; Transplantation, Homologous

Topics: Adult; Cyclosporine; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Middle Aged; Ribonucleosides; Tacrolimus; Transplantation, Homologous

Topics: Adult; Azathioprine; Blood Group Incompatibility; Child; Cyclosporine; Drug Therapy, Combination; Family; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Japan; Kidney Transplantation; Retrospective Studies; Ribonucleosides; Survival Rate; Tacrolimus; Time Factors; Tissue Donors

Topics: Animals; Cyclosporine; Dogs; Drug Therapy, Combination; Duodenum; Female; Immunosuppressive Agents; Male; Pancreas Transplantation; Ribonucleosides; Tacrolimus; Transplantation, Homologous

Our objective was to obtain new information on the in vitro antilymphocytic action of the cytokine synthesis inhibitor FK 506 and the purine biosynthesis inhibitors mycophenolic acid (MPA; the active moiety of RS61443) and mizoribine (MZB) when used alone or in combination. When added at the initiation of six-day human mixed lymphocyte cultures (MLC), FK 506, MPA or MZB exhibited dose-dependent inhibition of T-lymphocyte DNA synthesis. FK 506, however, was 100-fold more potent than MPA, and 10,000-fold more potent than MZB. Combination of FK 506 with either MPA or MZB, each at suboptional concentrations, produced no more than additive inhibitory effects on 3H thymidine incorporation. Two-colour flow cytometric analysis of lymphocytes revealed that none of the drugs affected cell surface activation molecule expression (CD25 = IL-2R 55 kD alpha-chain, HLA-DR or CD71 = transferrin receptor [TR]) on allostimulated CD4+ or CD8+ cells harvested at three days of culture. By day six, however, all three agents, at levels which markedly inhibited proliferation, suppressed the expression of activation markers on both CD4+ and CD8+ cells. Also at day six, inhibition of activation molecule expression on CD4+ cells was achieved with the combination of FK 506 and either MPA or MZB at concentrations which, on their own, were ineffective. These data provide new, additional information on the in vitro antilymphocytic action of FK 506, MPA and MZB when used alone and in combination.

Topics: Cells, Cultured; Depression, Chemical; DNA Replication; Drug Synergism; Guanine Nucleotides; HLA-DR Antigens; Humans; Lymphocyte Activation; Lymphocyte Culture Test, Mixed; Lymphocyte Subsets; Mycophenolic Acid; Receptors, Interleukin-2; Receptors, Transferrin; Ribonucleosides; Tacrolimus

Topics: Animals; Antibodies; Antineoplastic Agents; Azathioprine; Biphenyl Compounds; Cricetinae; Cyclophosphamide; Graft Survival; Guanidines; Heart Transplantation; Immunosuppressive Agents; Liver Transplantation; Male; Mesocricetus; Methotrexate; Mycophenolic Acid; Rats; Rats, Inbred Lew; Ribonucleosides; Tacrolimus; Transplantation, Heterologous

Topics: Aspartic Acid; Biphenyl Compounds; Calcimycin; Cells, Cultured; Cyclosporine; Humans; Immunosuppressive Agents; Interleukin-2; Lymphocyte Activation; Lymphocytes; Mycophenolic Acid; Phosphonoacetic Acid; Ribonucleosides; T-Lymphocytes; Tacrolimus; Tetradecanoylphorbol Acetate; Tumor Cells, Cultured

Topics: Animals; B-Lymphocytes; Biphenyl Compounds; Cells, Cultured; Dose-Response Relationship, Drug; Gene Expression Regulation; Immunosuppressive Agents; Interleukin-10; Interleukin-2; Lymphocyte Activation; Mice; Mycophenolic Acid; Polymerase Chain Reaction; Ribonucleosides; Tacrolimus

Topics: Animals; Guanidines; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; Spiro Compounds; Tacrolimus

Topics: Animals; Cyclosporine; Dogs; Duodenum; Female; Immunosuppression Therapy; Male; Pancreas Transplantation; Ribonucleosides; Survival Analysis; Tacrolimus

Topics: Animals; Anti-Bacterial Agents; Cyclosporins; Dogs; Drug Therapy, Combination; Duodenum; Female; Graft Rejection; Immunosuppressive Agents; Male; Pancreas Transplantation; Ribonucleosides; Tacrolimus

Topics: Cell Line; Cells, Cultured; Cyclosporine; Humans; Immunosuppressive Agents; Kinetics; Lymphocyte Activation; Mycophenolic Acid; Polyenes; Ribonucleosides; Sirolimus; T-Lymphocytes; Tacrolimus

Topics: Antigens, Differentiation, T-Lymphocyte; Azathioprine; CD3 Complex; Cells, Cultured; Cyclosporine; DNA Replication; Drug Interactions; Guanidines; Humans; Immunosuppressive Agents; Lymphocyte Activation; Lymphocytes; Phytohemagglutinins; Receptors, Antigen, T-Cell; Ribonucleosides; Tacrolimus

Topics: CD4 Antigens; CD8 Antigens; Cells, Cultured; Humans; Immunosuppressive Agents; Isoantigens; Lymphocyte Activation; Muromonab-CD3; Mycophenolic Acid; Receptors, Interleukin-2; Ribonucleosides; T-Lymphocyte Subsets; T-Lymphocytes; Tacrolimus; Tetradecanoylphorbol Acetate

Topics: Animals; Cyclosporine; Dogs; Drug Therapy, Combination; Female; Graft Survival; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Male; Ribonucleosides; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Animals; Anti-Bacterial Agents; Cyclosporins; Dogs; Drug Therapy, Combination; Duodenum; Female; Graft Rejection; Graft Survival; Immunosuppressive Agents; Male; Pancreas Transplantation; Ribonucleosides; Tacrolimus; Time Factors; Transplantation, Homologous

Topics: Azathioprine; Cells, Cultured; Colony-Forming Units Assay; Cyclosporins; Drug Therapy, Combination; Graft Rejection; Graft Survival; Guanidines; Humans; Immunosuppressive Agents; Kidney Transplantation; Monocytes; Prednisolone; Pyridines; Ribonucleosides; Tacrolimus; Transplantation, Homologous