Showing papers on "Mycophenolate published in 2002"

The Pharmacokinetic-Pharmacodynamic Relationship for Total and Free Mycophenolic Acid in Pediatric Renal Transplant Recipients: A Report of the German Study Group on Mycophenolate Mofetil Therapy

Abstract: . It is currently being debated whether pharmacokinetic monitoring of mycophenolic acid (MPA), the active constituent of mycophenolate mofetil (MMF), can optimize MMF therapy after organ transplantation. This open-label longitudinal study in pediatric renal transplant recipients was designed to investigate the pharmacokinetic (PK)/pharmacodynamic relationship of total and free MPA and to establish PK values for the assessment of an individual’s MPA PK parameters. Fifty-four children, aged 2.2 to 17.8 yr, on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and MMF (600 mg/m 2 body surface area twice daily) were investigated 1 wk and 3 wk (initial phase) and 3 mo and 6 mo (stable phase) after renal transplantation. MPA was measured by reverse phase HPLC, free MPA by HPLC after separation by ultrafiltration. There was an association between the risk of acute rejection episodes and MPA-AUC 0-12 values or MPA predose levels; by receiver operating characteristic analysis, an AUC 0-12 of 33.8 mg × h/L in the initial phase posttransplant had a diagnostic sensitivity of 75% and a diagnostic specificity of 64% for discrimination of patients with acute rejections. The respective discrimination threshold for the MPA predose concentration was 1.2 mg/L with a sensitivity of 83% and a specificity of 64%. In contrast, high free, but not total, MPA-AUC 0-12 values were associated with an increased risk of the MMF-related side effects leukopenia and/or infections. These data indicate that therapeutic drug monitoring of MPA has the potential for optimization of MMF efficacy in this patient population by steering patients away from the low values of MPA PK variables that are associated with an increased rejection risk. For the assessment of the toxic risk of MMF regarding leukopenia and/or infections, measurement of free MPA appears to be more appropriate.

Comparison of the Emit immunoassay with HPLC for therapeutic drug monitoring of mycophenolic acid in pediatric renal-transplant recipients on mycophenolate mofetil therapy.

Abstract: Background: HPLC is currently the preferred method for accurate measurement of mycophenolic acid (MPA). This study was designed to validate the Emit compared with HPLC in relation to clinical outcome measurements. Methods: Pediatric renal-transplant recipients (n = 50) on an immunosuppressive triple regimen consisting of cyclosporin A, prednisone, and mycophenolate mofetil (600 mg/m2 twice per day) were investigated in an open-label prospective study. Pharmacokinetic profiles over 12 h were obtained at 1 week, 3 weeks, 3 months, and 6 months posttransplant. Plasma MPA was measured by both reversed-phase HPLC and the Emit immunoassay. Results: There was an association between the risk of acute rejection episodes and low area under the curve values from t to t 12h (AUC0–12) for MPA (MPA-AUC0–12) or predose concentrations of MPA derived from both HPLC and Emit measurements. According to ROC analysis, an AUC value of 33.8 mg · h/L for MPA from t to t 12h (MPA-AUC0–12) determined by HPLC had a diagnostic sensitivity of 80% and a diagnostic specificity of 57%. The corresponding value of the Emit was 36.1 mg · h/L. For the predose concentration (MPA- c 12), a concentration of 1.2 mg/L determined by HPLC and 1.4 mg/L determined by Emit gave a sensitivity of 80% and a specificity of 60%, respectively. There was no association of any pharmacokinetic variables derived from total MPA measurements with an increased risk of side effects related to mycophenolate mofetil. Conclusions: The Emit assay appears to have a comparable diagnostic efficacy to HPLC for assessing the risk of acute rejection in pediatric renal-transplant recipients. However, because of the cross-reactivity of the antibody used in the Emit assay with the active MPA acyl glucuronide metabolite, the decision thresholds for the Emit were higher than those calculated from HPLC measurements.

Comparative study of cyclosporine and tacrolimus vs newer immunosuppressants mycophenolate mofetil and rapamycin on coronary endothelial function

Abstract: Background Endothelial dysfunction contributes to the development of intimal hyperplasia in transplanted hearts by decreasing the protective effects of endothelial-derived nitric oxide. Immunosuppressive drugs may increase the dysfunction caused by rejection and further accelerate the development of graft coronary vasculopathy. This study compares the effect of cyclosporine and tacrolimus vs two newer immunosuppressive drugs, mycophenolate mofetil and rapamycin, on coronary endothelial function. Methods An in vitro model of drug incubation in Krebs-bicarbonate solution (4 o C, 48 hours) using porcine epicardial coronary arteries was developed. Coronary endothelial function studies were performed in organ chamber experiments after incubation with cyclosporine (10 −4 , 10 −7 mol/liter), tacrolimus (10 −4 , 10 −7 mol/liter), mycophenolate mofetil (10 −4 , 10 −7 mol/liter), rapamycin (10 −7 , 10 −11 mol/liter), and their vehicles to assess effects on G-protein–mediated vasorelaxations leading to the release of nitric oxide. Results Exposure to cyclosporine and mycophenolate mofetil was associated with a dose-dependent decrease in endothelium-dependent relaxations to serotonin (an agonist that binds to 5-HT1D receptors coupled to Gi-protein) but no impairment of relaxations to bradykinin (an agonist that binds to B2 receptors coupled to Gq-proteins). Exposure to tacrolimus and rapamycin caused severe impairment of relaxations to serotonin and a lesser one to bradykinin. We observed alterations of relaxations to the calcium ionophore A23187 after exposure to mycophenolate mofetil and rapamycin. Exposure to rapamycin and mycophenolate mofetil vehicles impaired relaxation to all agonists. Conclusions These results suggest that cyclosporine and mycophenolate mofetil induce a dysfunction of the vasorelaxing properties of the endothelium that may lead to a decrease in the protective effects of nitric oxide on the vascular wall but that these drugs still have a more favorable vascular profile than do tacrolimus and rapamycin. Decreased endothelial function after mycophenolate mofetil and rapamycin exposure could be caused by their vehicles.

Mycophenolate mofetil decreases antibody production after cardiac transplantation.

Abstract: New immunosuppressive drugs are extensively being investigated for their effect on T-cell immunity, with far less being known about their effect on the humoral immune response. In view of the experimental and clinical evidence that humoral immunity contributes to acute and chronic rejection, we investigated post-transplant production of anti-vimentin and anti-HLA antibodies in 86 patients who were part of a worldwide clinical trial for mycophenolate mofetil in cardiac transplantation. The results demonstrate that patients taking MMF instead of azathioprine generated significantly fewer de novo anti-vimentin antibodies.

Mycophenolic Acid Inhibits IL-2-Dependent T Cell Proliferation, But Not IL-2-Dependent Survival and Sensitization to Apoptosis

Abstract: Mycophenolic acid (MPA), the active metabolite of the immunosuppressive drug mycophenolate mofetil, is a selective inhibitor of inosine 5'-monophosphate dehydrogenase type II, a de novo purine nucleotide synthesis enzyme expressed in T and B lymphocytes and up-regulated upon cell activation. In this study, we report that the blockade of guanosine nucleotide synthesis by MPA inhibits mitogen-induced proliferation of PBL, an effect fully reversed by addition of guanosine and shared with mizoribine, another inhibitor of inosine 5'-monophosphate dehydrogenase. Because MPA does not inhibit early TCR-mediated activation events, such as CD25 expression and IL-2 synthesis, we investigated how it interferes with cytokine-dependent proliferation and survival. In activated lymphoblasts that are dependent on IL-2 or IL-15 for their proliferation, MPA does not impair signaling events such as of the extracellular signal-regulated kinase 2 and Stat5 phosphorylation, but inhibits down-regulation of the cyclin-dependent kinase inhibitor p27(Kip1). Therefore, in activated lymphoblasts, MPA specifically interferes with cytokine-dependent signals that control cell cycle and blocks activated T cells in the mid-G(1) phase of the cell cycle. Although it blocks IL-2-mediated proliferation, MPA does not inhibit cell survival and Bcl-x(L) up-regulation by IL-2 or other cytokines whose receptors share the common gamma-chain (CD132). Finally, MPA does not interfere with IL-2-dependent acquisition of susceptibility to CD95-mediated apoptosis and degradation of cellular FLIP. Therefore, MPA has unique functional properties not shared by other immunosuppressive drugs interfering with IL-2R signaling events such as rapamycin and CD25 mAbs.

Mycophenolate mofetil in the therapy of polymyositis associated with a polyautoimmune syndrome.

Abstract: Mycophenolate mofetil 1.5 g daily (30 mg/kg body weight) was given to a patient with ankylosing spondylitis, ulcerative colitis, and severe refractory polymyositis after conventional treatment regimes had failed. No severe side effects occurred. Considerable improvement of clinical symptoms and electromyographic findings were seen within 6 months after the initiation of mycophenolate mofetil, allowing for tapering and discontinuation of methylprednisolone. Mycophenolate mofetil may be considered as an useful alternative in the treatment of polymyositis when standard therapeutic regimens fail.

Monitoring mycophenolic acid.

Abstract: The immunosuppressive agent mycophenolate mofetil is a prodrug for the active compound mycophenolic acid. Following organ transplantation, it is used mostly in combination with other immunosuppress...

Mycophenolate in treatment-resistant inflammatory neuropathies

Abstract: There has been an increasing interest in the use of mycophenolate as an immunomodulatory drug in neuromuscular diseases. We report five consecutive patients with treatment-resistant chronic inflammatory demyelinating polyradiculoneuropathy or multifocal motor neuropathy who were treated with mycophenolate. None showed clinically significant benefit. The use of mycophenolate did not result in the reduction in the dose of corticosteroid or other immunosuppressive agents in any patient. Side-effects, although not serious, were troubling enough for two patients to stop mycophenolate.

Effect of mycophenolate mofetil therapy on lymphocyte activation in heart transplant recipients.

Abstract: Background: Mycophenolic acid is reported to provide effective immunosuppression by inhibiting inosine monophosphate dehydrogenase. In an attempt to monitor the effects of therapy with mycophenolate mofetil, we measured the expression of the activation markers CD25, CD38, CD69 and HLA-DR on lymphocytes of patients after heart transplantation. Methods: Thirty-six patients enrolled in the study were randomly assigned to one of two groups. Patients in the control group ( n = 15) received cyclosporine, azathioprine and prednisone. Patients in the study group ( n = 21) were switched from azathioprine to mycophenolate mofetil (MMF) 3 months after heart transplantation. The expressions of the activation markers CD25, CD38, CD69 and HLA-DR on B cells, T cells and natural killer (NK) cells in peripheral blood were determined by flow cytometry. Results: In patients treated with MMF a significant reduction of the B-cell count was observed in comparison to a healthy control group and patients under therapy with azathioprine. The decline of B cells in the MMF group started 3 months after onset of therapy and, after 1 year, was nearly halved. In addition, the percentages of CD38-positive B cells, activated T cells (CD4 + /CD25 + , CD8 + /CD38 + ) and HLA-DR–expressing NK cells were reduced during therapy with MMF. Conclusions: Our studies have shown administration of MMF to be associated with a reduction of B lymphocytes and a downregulation of activation markers on B cells. In contrast to in vitro findings, our data indicate that the immunosuppressive effect of MMF in vivo is exhibited mainly on B cells.

Down-regulation of multiple low dose streptozotocin-induced diabetes by mycophenolate mofetil.

Abstract: SUMMARY The new immunosuppressive agent mycophenolate mofetil (MMF) has been shown recently to exert a protective effects in certain animal models of autoimmunity, including diabetes in diabetes-prone biobreeding (BB) rats. In the present study, the immunomodulatory potential of MMF was investigated in autoimmune diabetes induced by multiple low doses of streptozotocin (MLD-STZ) in genetically susceptible DA rats [20 mg STZ/kg body weight (b.w.) for 5 days] and CBA/H mice (40 mg STZ/kg b.w. for 5 days). In both species, short time treatment of animals with MMF (25 mg/kg) during the early development of the disease, as well as continuous MMF treatment, prevented the appearance of hyperglycaemia and inflammatory infiltrates in the pancreatic tissue. Moreover, clinical manifestations of diabetes were suppressed by application of the drug after the onset of clinical symptoms. Treatment with guanosine (1 mg/kg) in parallel with MMF completely reversed MMF activity in vivo, indicating that inhibition of inosine monophosphate dehydrogenase (IMPDH) was responsible for the observed suppressive effects. MMF-mediated protection from diabetes correlated with reduced ex vivo spontaneous spleen mononuclear cell (MNC) proliferation and defective adhesive cell interactions. MMF-treated animals also had lower local production of IFN-g, as well as IL-12 and nitric oxide (NO) production by peripheral tissues (spleen and peritoneal cells), compared to that in control diabetic groups, while IL10 level was elevated. Together, these data demonstrate that MMF interferes with autoimmune process in streptozotocin-induced diabetes at multiple levels, including lymphocyte proliferation and adhesion, as well as pro/anti-inflammatory cytokine balance.

Low-dose and rapid steroid withdrawal in renal transplant patients treated with tacrolimus and mycophenolate mofetil

Abstract: CORTICOSTEROIDS HAVE PROVED to be very effective for the immunosuppressive treatment of organ transplant patients, but unfortunately they are responsible for many undesirable side effects, such as cataracts, delayed growth in children, skin fragility, bone diseases, and other manifestations considered to be cardiovascular risk factors, such as glucose intolerance, arterial hypertension, and dyslipemias. The reduction in the incidence of acute rejection in patients treated with mycophenolate mofetil in combination with anticalcineurin agents (cyclosporine or tacrolimus) has led to the design of studies to reduce or suppress corticosteroid treatment. We analyzed the 2-year course of cadaveric kidney transplant patients treated with a triple therapy of tacrolimus, mycophenolate mofetil, and corticosteroids in whom steroid therapy was withdrawn after the 3rd posttransplant month.

Effects of immunosuppressive drugs on platelet aggregation in vitro.

Abstract: Disturbances in platelet functions are found in kidney diseases and may contribute to the progression of atherosclerosis with its thrombotic complications. Kidney allograft recipients are particularly prone to dyslipidemia and have a high risk of cardiovascular death. The purpose of this work was to assess effects of various immunosuppressive drugs on aggregation of platelets obtained from healthy volunteers and chronically hemodialyzed patients. Platelet aggregation in the whole blood and in PRP was induced by collagen (2-microgram/ml whole blood and PRP) arachidonic acid (0.75 mM whole blood and PRP), ADP (10 microM--whole blood and 5 microM--PRP), ristocetin (0.75 mg/ml--whole blood and 1.5 mg/ml--PRP) and was studied after preincubation with clinically relevant concentrations of cyclosporine A, FK 506, 15-deoxyspergualin, azathioprine, mizoribine, mycophenolic acid and mycophenolate mofetil. Preincubation with cyclosporine A resulted in a significant increase in platelet aggregation, whereas preincubation with FK 506, azathioprine, mizoribine, mycophenolic acid and mycophenolate mofetil caused a decrease in platelet aggregation. 15-deoxyspergualin did not affect platelet aggregation. Enhanced platelet aggregation in CSA-treated kidney allograft recipients may have clinical implications in regard to the reported tendency to thrombosis in those patients, and to CSA-induced nephrotoxicity. Thus, inhibition of platelet activity in these patients might be of clinical benefit.

Antiproliferative effect of mycophenolate mofetil on cultured human Tenon fibroblasts.

Abstract: Background. Wound healing after glaucoma filtering surgery is often complicated by exaggerated scarring of the subconjunctival Tenon's layer. Therefore, antiproliferatives are commonly employed. The immunosuppressive drug mycophenolate mofetil (MMF) is used to prevent graft rejection after kidney or liver transplantation. The effect is mediated by inhibition of lymphocyte proliferation. In this study we investigated the effect of MMF on human Tenon fibroblast proliferation in cell culture.

The immunosuppressive drug mycophenolic acid reduces endothelin-1 synthesis in endothelial cells and renal epithelial cells.

Abstract: Several studies have demonstrated that endothelin-1 (ET-1) plays an important pathophysiological role in ischaemic renal failure and drug-induced renal injury, such as cyclosporine A (CsA)- and tacrolimus-associated nephrotoxicity. This study aimed to investigate whether the new immunosuppressive drug mycophenolic acid (MPA), which in contrast with CsA and tacrolimus lacks nephrotoxic side eects, modulates ET-1 synthesis in endothelial cells and renal epithelial cells. ET-1 release by cultured human umbilical vein endothelial cells (HUVEC), human renal artery endothelial cells (RAEC) and rabbit proximal tubule cells was measured with a specific ELISA. ET-1 mRNA expression was investigated by reverse transcription‐PCR. MPA (2.5‐50 lg/ml) induced a significant decrease in ET-1 mRNA expression (minimum 51.8‡3.8% of control; P ! 0.001) in HUVEC and RAEC. After a 48 h incubation with MPA (1‐50 lg/ml), a significant decrease in ET-1 release per culture well (minimum 56.8‡1.7%; P ! 0.001) and DNA content per culture well (minimum 58.7‡1.9%; P ! 0.001) was observed with HUVEC and RAEC, whereas ET-1 release referred to the DNA content in the corresponding culture well did not dier significantly from controls. In rabbit proximal tubule cells, ET-1 release referred to the cell number in the corresponding culture well was also reduced after incubation with MPA (minimum 86.2‡2.4%; P ! 0.05). This study provides evidence that, in contrast with CsA and tacrolimus, MPA does not stimulate ET-1 synthesis. The present results might explain the clinical observation that renal function often improves when CsA or tacrolimus is replaced by mycophenolate mofetil.

Impairment of Mycophenolate Mofetil Absorption by Calcium Polycarbophil

Abstract: The effect of calcium polycarbophil on the absorption of mycophenolate mofetil, an immunosuppressive agent, was evaluated in healthy subjects. In vitro studies were performed to further evaluate the mechanism of the potential interaction. In the in vitro study, the release of mycophenolate mofetil from a cellulose membrane in the presence or absence of metal cations was measured using the dissolution test procedure. In the in vivo study, a randomized crossover design with two phases was used. In one phase, 6 male healthy volunteers received 1000 mg of mycophenolate mofetil alone (treatment 1); in the other phase, they received 1000 mg of mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 2). They received 30 mg of lansoprazole for 5 days and, on the 6th day, received mycophenolate mofetil and 2400 mg of calcium polycarbophil fine granules concomitantly (treatment 3). The serum concentration of mycophenolic acid was measured by high-performance liquid chromatography. In the in vitro study, the release from a cellulose membrane in the presence of calcium or iron ions was slower than that in the absence of these metal ions. In the in vivo study, the AUC0-12 and C(max) in treatment 2 were less than those in treatment 1. About 50% and 25% decreases in AUC0-12 in treatment 2 and treatment 3 were observed compared with those in treatment 1, respectively. These findings suggest that when mycophenolate mofetil and calcium polycarbophil were coadministered concomitantly, a decrease in mycophenolate mofetil absorption was observed. Therefore, it appears clear that the concomitant administration of mycophenolate mofetil and calcium polycarbophil should be avoided.

Effects of mycophenolate mofetil in mercury-induced autoimmune nephritis.

Abstract: . Mycophenolate mofetil (MMF) is a new immunosuppressive drug whose active metabolite, mycophenolic acid (MPA), blocks the action of inosine monophosphate dehydrogenase, resulting in the inhibition of the novo purine synthesis. Thus, MPA has an antiproliferative effect on T and B lymphocytes and also inhibits the glycosylation of cell surface adhesion proteins involved in cell-cell contact and in the recruitment of circulating leukocytes to sites of tissue damage and inflammation. In this study, the effect of MMF in the mercury model of nephritis was examined. Repeated exposure to HgCl 2 induces an autoreactive Th2 cell subset-inducing polyclonal B cell activation in the Brown Norway (BN) rat. This leads to the development of an autoimmune syndrome characterized by synthesis of autoantibodies (mainly anti–glomerular basement membrane [GBM] Abs) with glomerular linear deposits of IgG, proteinuria, and tubulointerstitial nephritis. Results show that MMF has a preventive effect on mercury-induced disease as it blocks anti-GBM Ab synthesis, thus avoiding glomerular IgG deposits and proteinuria and the development of interstitial nephritis. However, the therapeutic effect of MMF seems to be restricted to its antiinflammatory properties blocking the extravasation of circulating leukocytes to renal interstitium by interfering with the very late activation antigen 4/vascular cell adhesion molecule–1 (VCAM-1) cell adhesion pathway. Also, MMF administration to mercury-injected rats reduces the secretion of the proinflammatory cytokine tumor necrosis factor–α. These findings confirm that MMF has a strong effect on the primary immune response in this model. Nevertheless, when the disease is in progress, MMF acts exclusively on the inflammatory response. MMF could be useful in the treatment of diseases associated with renal inflammation.

Mycophenolic acid and methotrexate inhibit lymphocyte cytokine production via different mechanisms

Abstract: INTRODUCTION Mycophenolate mofetyl and methotrexate (MTX) are immunosuppressive drugs used for the treatment of immunological disorders. MTX has shown efficacy in rheumatoid arthritis (RA) versus placebo controlled trials [1, 2] whereas the use of mycophenolate mofetyl or its active molecule mycophenolic acid (MPA) for the treatment of RA is still experimental [3, 4]. MPA has been reported to be an effective drug in preventing rejection in renal [...]

Mycophenolate mofetil: a pharmacoeconomic review of its use in solid organ transplantation.

Abstract: UNLABELLED Most pharmacoeconomic studies of mycophenolate mofetil have focused on its use as part of maintenance immunosuppression for renal transplantation, involving short-term (3 to 12 months) time frames. In general, mycophenolate mofetil reduced the treatment costs for rejection episodes and graft failure which offset its higher drug acquisition cost compared with azathioprine. Several cost analyses have been modelled on the large multicentre trials of adult renal transplant recipients. The use of mycophenolate mofetil was associated with either cost savings or no additional costs after 6 or 12 months in French, US and Canadian analyses of triple or quadruple immunosuppressant therapy. A further cost analysis utilising a registry database of renal transplant recipients in the US found mycophenolate mofetil to be cost saving compared with azathioprine after 6.4 years when evaluating costs due to graft loss only. Of the limited cost-effectiveness analyses with the drug, one US study modelled the 1- and 10-year cost effectiveness of mycophenolate mofetil and various other immunosuppressants used in combined regimens. Long-term use of mycophenolate mofetil was less cost effective than other regimens, but the use of long-term mycophenolate mofetil in high-risk patients was shown to be a relatively cost-effective strategy. In another US analysis comparing mycophenolate mofetil with azathioprine as part of quadruple therapy, mycophenolate mofetil was associated with slightly lower costs during the first year after renal transplantation as well as improved clinical outcomes. CONCLUSION Pharmacoeconomic studies support the use of mycophenolate mofetil as part of immunosuppressant therapy in renal transplantation, at least in the short term. Although the cost effectiveness of mycophenolate mofetil in the long term is less clear, limited pharmacoeconomic data available appear promising. Among issues to be examined in future economic analyses in renal transplantation are the calcineurin-sparing potential of mycophenolate mofetil and the feasibility of using more efficient mycophenolate mofetil dosage regimens when using the drug on a long-term basis. Additional pharmacoeconomic analyses of mycophenolate mofetil are also needed in other types of solid organ transplantation.