Showing papers on "Mycophenolate published in 2001"

Mycophenolate mofetil prevents salt-sensitive hypertension resulting from nitric oxide synthesis inhibition

Abstract: Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild re...

Mycophenolate mofetil is effective in the treatment of atopic dermatitis.

Abstract: Objective To evaluate whether mycophenolate mofetil, a new immunosuppressive agent, is effective for treating moderate-severe atopic dermatitis (AD). Design In an open-label pilot study, mycophenolate mofetil, 1 g, was given orally twice daily for 4 weeks. At week 5, the dosage was reduced to 500 mg twice daily until study end (week 8). Patients were followed up for 20 weeks. Setting University hospital dermatology department. Patients Ten consecutive patients with moderate-severe AD nonresponsive to standard therapy. Main Outcome Measure Severity of AD as measured using the subjective SCORAD [SCORing Atopic Dermatitis] index. Results Clinical efficacy was measured every 2 weeks using the subjective SCORAD index. Treatment with mycophenolate notably reduced the severity of AD within 4 weeks in all patients ( P P Conclusions Mycophenolate is a highly effective drug for treating moderate-severe AD, with no serious adverse effects occurring in any patients. Thus, mycophenolate might develop into a promising alternative in the therapy of moderate-severe AD.

Sanglifehrin A, a Novel Cyclophilin-Binding Compound Showing Immunosuppressive Activity with a New Mechanism of Action

Abstract: We report here on the characterization of the novel immunosuppressant Sanglifehrin A (SFA). SFA is a representative of a class of macrolides produced by actinomycetes that bind to cyclophilin A (CypA), the binding protein of the fungal cyclic peptide cyclosporin A (CsA). SFA interacts with high affinity with the CsA binding side of CypA and inhibits its peptidyl-prolyl isomerase activity. The mode of action of SFA is different from known immunosuppressive drugs. It has no effect on the phosphatase activity of calcineurin, the target of the immunosuppressants CsA and FK506 when complexed to their binding proteins CypA and FK binding protein, respectively. Moreover, its effects are independent of binding of cyclophilin. SFA inhibits alloantigen-stimulated T cell proliferation but acts at a later stage than CsA and FK506. In contrast to these drugs, SFA does not affect IL-2 transcription or secretion. However, it blocks IL-2-dependent proliferation and cytokine production of T cells, in this respect resembling rapamycin. SFA inhibits the proliferation of mitogen-activated B cells, but, unlike rapamycin, it has no effect on CD154/IL-4-induced Ab synthesis. The activity of SFA is also different from that of other known late-acting immunosuppressants, e.g., mycophenolate mofetil or brequinar, as it does not affect de novo purine and pyrimidine biosynthesis. In summary, we have identified a novel immunosuppressant, which represents, in addition to CsA, FK506 and rapamycin, a fourth class of immunophilin-binding metabolites with a new, yet undefined mechanism of action.

Pharmacokinetics of mycophenolic acid after mycophenolate mofetil administration in liver transplant patients treated with tacrolimus.

Abstract: The pharmacokinetics of mycophenolic acid (MPA) was studied after oral administration of mycophenolate mofetil (MMF) in 8 liver transplant patients. The mean (± SD) maximum MPA plasma concentration of 10.6 (± 7.5) mg/ml was achieved within 0.5 to 5 hours. The mean (± SD) steady-state area under the plasma concentration versus time curve (AUC0-12) was 40 (± 30.9) mg/ml/h. The mean (± SD) half-life was 5.8 (± 3.8) hours. There was poor correlation between trough blood concentrations of tacrolimus (r = –0.004) or serum creatinine (r = 0.689) with MPA AUC, while the serum bilirubin concentrations correlated (r = 0.743) well with MPA AUC, suggesting impairment in MPA conjugation in patients with liver dysfunction. The mean (± SD) ratio of the AUC of mycophenolic acid glucuronide (MPAG) to MPA was 64 (± 84), which correlated significantly with serum creatinine (r = 0.72) but not with serum bilirubin concentrations (r = 0.309), indicating accumulation of MPAG in patients with renal dysfunction. In 7 primary liver transplant patients on the same dose of MMF, the trough plasma concentrations of MPA during the first week of therapy ranged from < 0.3 to 1.5 µg/ml. The MPA concentrations increased by several folds during the next few weeks, which correlates well with increases in serum albumin concentrations. Changes in albumin appear to partially contribute to the variations in the pharmacokinetics of MPA in liver transplant patients.

Effect of Cyclosporine Withdrawal on Mycophenolic Acid Pharmacokinetics in Kidney Transplant Recipients With Deteriorating Renal Function: Preliminary Report.

Abstract: Summary:Mycophenolic acid (MPA) concentrations are lower in transplant recipients receiving mycophenolate mofetil (MMF) and cyclosporine compared with MMF with tacrolimus. It is not clear whether this is due to an effect of cyclosporin or tacrolimus on MPA pharmacokinetics. To study this effect, kid

Treatment of cicatricial pemphigoid with mycophenolate mofetil as a steroid-sparing agent.

Abstract: Background: Cicatricial pemphigoid (CP) is a rare autoimmune bullous disease that affects the skin and mucous membranes. It commonly ends by serious complications such as blindness, stenosis, and stricture formation and is difficult to treat. Mycophenolate mofetil has been reported to be effective in the treatment of pemphigus vulgaris, pemphigus foliaceus, and bullous pemphigoid either as monotherapy or as a steroid-sparing agent. Objective: Our purpose was to evaluate the effectiveness of mycophenolate mofetil as a steroid-sparing agent in treating patients with CP. Methods: Three patients with CP were treated with mycophenolate mofetil and prednisolone. Results: All 3 patients responded very well to the therapy. None of them showed relapse of the disease for a follow-up period of 6 to 14 months after complete cessation of mycophenolate mofetil and prednisolone. No side effects were seen. Conclusion: Mycophenolate mofetil appears to be a safe and effective steroid-sparing agent in the treatment of CP. (J Am Acad Dermatol 2001;45:256-9.)

Treatment of systemic lupus erythematosus with mycophenolate mofetil.

Abstract: Mycophenolate mofetil is an immunosuppressive drug that is of established efficacy in renal transplantation. It inhibits the de novo pathway of purine synthesis and therefore lymphocyte proliferation. Mycophenylate mofetil has been shown to ameliorate the severity of renal injury in murine models of lupus nephritis. Recent studies suggest that it may also be effective in the treatment of patients with lupus nephritis when used in conjunction with steroids. These observations need to be confirmed in adequately sized randomised-controlled studies.

Mycophenolate-mofetil in the treatment of refractory multiple sclerosis.

Abstract: Sirs: Multiple sclerosis (MS) is thought to be an autoimmune disease stimulated by activated lymphocytes, and the entry of T and B cells into the central nervous system [1]. Despite the use of a variety of immunomodulatory and immunosuppressive agents including interferon beta, glatiramer acetate, intravenous immunoglobulins, azathioprine and escalating chemotherapy with mitoxantrone and cyclophosphamide, MS remains progressive in a large number of patients and there is an ongoing need for further rescue therapy [2, 3]. Mycophenolate-mofetil (MMF) is an inhibitor of inosine monophosphate dehydrogenase, which is necessary for de novo purine biosynthesis in lymphocytes. The drug is being successfully and increasingly used for prevention of organ transplant rejection [4]. Beneficial effects in the treatment of autoimmune diseases have been shown in Crohn’s disease [5]. The inhibition of lymphocytes by the drug may therefore result in improvement in patients with refractory MS. In this open surveillance trial, we treated seven patients with chronic progressive or relapsing MS (table). The patients were informed about the drug and its attendant risks, and all gave informed consent before initiation of treatment. Entry criteria in this trial included the diagnosis of MS, disease-progression in terms of EDSS despite established treatment (table), and no other diseases such as infections or liver or kidney disorders. All patients received the usual dose employed in the treatment of transplanted patients (2 g per day). The administration of MMF led to improvement or stopped progression in five cases (table). Three of the five patients emphasized improved movement, although EDSS did not change. One of the five patients (no. 7) had to reduce the dose from 2 to 1.5 gr per day because of frequent infections, one (no. 2) discontinued the treatment owing to uncontrolled nausea. Two patients without beneficial effects stopped the drug through nausea and/or non-response (nos. 3 and 5). MRI findings before and at least 6 months after treatment start were available in two patients (no. 1 and 7) and showed fewer lesions and no change, respectively. The four patients, who still receive MMF, are feeling well without progression and would like to continue this therapy. In all seven treated patients there was no deterioration concerning EDSS. Although the beneficial effects in five patients demonstrate that MMF may be of value in the treatment of MS, this open-label study does not allow a final conclusion. The question of whether more responsive patients would be found in an unselected group requires further study. LETTER TO THE EDITORS

In vivo higher glucuronidation of mycophenolic acid in male than in female recipients of a cadaveric kidney allograft and under immunosuppressive therapy with mycophenolate mofetil.

Abstract: Mycophenolate mofetil (MMF), an immunosuppressant drug used in organ transplantation to prevent rejection, is being used increasingly in association with cyclosporine and tacrolimus. Mycophenolic acid (MPA) is primarily metabolized in the liver to its 7-O-glucuronide (MPAG) derivative. The concentrations of MPAG in serum are many times the concentrations of MPA. Although MPAG has not shown immunosuppressant activity, it was postulated that it could displace MPA from its binding sites on albumin and hence increase the biologic effects of MPA. This effect could be important for patients with acute renal failure; under this condition, MPAG was shown to accumulate. The goal of this study was to document the MPAG/MPA concentration ratio in 100 renal transplant patients under a mixed immunosuppressive therapy. Further, the study addressed the question of whether MPAG can displace MPA in vivo from bound albumin in a representative renal transplant patient population under immunosuppressive therapy. Levels of MPAG and MPA were measured by high-performance liquid chromatography. The distribution of the ratios was not parametric as it tailed toward elevated values. After a square root transformation of the data, parametric analysis was possible. The average MPAG/MPA ratio was 15.0 +/- 2.2 for men versus 7.7 +/- 0.9 for women. Men treated with MMF and tacrolimus showed a lower ratio than patients treated with MMF and cyclosporine, confirming that tacrolimus inhibits glucuronidation of MPA. Further, it was determined that at physiologic concentrations, MPAG does not increase the amount of free MPA. Because MPAG can favor the elimination of MPA, it can be concluded that gender differences and cotreatment with tacrolimus must be taken into consideration when MMF is being administered.

Effect of mycophenolate mofetil therapy on inosine monophosphate dehydrogenase induction in red blood cells of heart transplant recipients.

Abstract: Background Mycophenolic acid is reported to provide effective immunosuppression by inhibiting inosine monophosphate dehydrogenase. In an attempt to monitor the biological effects of long-term therapy with mycophenolate mofetil, we measured levels of guanosine 5′ triphosphate and adenosine 5′ triphosphate in red blood cells (RBCs) of patients after heart transplantations. Methods Fifty-two patients enrolled in the study were randomly assigned to one of two groups. Patients in the control group (n = 27) received cyclosporine A (INN, ciclosporin), azathioprine, and prednisone. Patients in the study group (n = 25) were switched from azathioprine to mycophenolate mofetil 3 months after the heart transplantation. Adenosine 5′ triphosphate and guanosine 5′ triphosphate levels were determined by means of HPLC. The activities of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase, which are responsible for guanine nucleotide formation, were measured in RBCs by radiochemical methods. Results Adenosine 5′ triphosphate levels were unchanged in patients treated with mycophenolate mofetil, whereas those of the control group who received azathioprine (from 142 ± 26 pmol/106 RBCs to 165 ± 25 pmol/106 RBCs; P < .001) increased. As the length of mycophenolate mofetil therapy increased, patients in the study group showed significantly elevated guanosine 5′ triphosphate levels (15.6 ± 6.1 pmol/106 RBCs versus 6.6 ± 2.1 pmol/106 RBCs; P < .001) and a 5-fold increase in inosine monophosphate dehydrogenase activity (108.6 ± 13.3 pmol/mg of protein per hour versus 22.5 ± 1.7 pmol/mg of protein per hour; P < .001) compared with the control group. In addition, a slight but significant enhancement of hypoxanthine-guanine phosphoribosyltransferase activity was seen in the mycophenolate mofetil group. Conclusions Our studies have shown that long-term administration of mycophenolate mofetil is associated with increasing guanosine 5′ triphosphate levels in RBCs as the result of an induction of inosine monophosphate dehydrogenase and hypoxanthine-guanine phosphoribosyltransferase activities in erythrocytes. Clinical Pharmacology & Therapeutics (2001) 69, 137–144; doi: 10.1067/mcp.2001.114166

Mycophenolate mofetil in the therapy of severe myasthenia gravis.

Abstract: Mycophenolate mofetil is a novel immunosuppressive drug already established in transplantation medicine. Recently, results of three open clinical trials on mycophenolate mofetil in myasthenia gravis h

Apoptosis of superantigen-activated T cells induced by mycophenolate mofetil treatment.

Abstract: Background Mycophenolate mofetil (MMF), an ester prodrug of mycophenolic acid (MPA), is a potent immunosuppressive agent used in clinical organ transplantation. MPA preferentially inhibits the type II isoform of inosine monophosphate dehydrogenase, depletes GTP, suppresses transfer of mannose and fucose to glycoproteins, and prevents lymphocyte proliferation in vivo. Whether MMF can also delete activated T cells in vivo by triggering an apoptotic signal was addressed in this study. To this end we analyzed the activity of MMF in mice injected with the bacterial superantigen staphylococcal enterotoxin B (SEB). Superantigens bind to MHC class II molecules without requirement for processing, and activate subsets of CD4+ and CD8+ T cells whose T cell receptor beta chains express Vbeta family-specific homologous sequences. This model that shares several features with direct allorecognition has the unique advantage of allowing a precise monitoring of activated T cells. Methods BALB/c mice treated with MMF (100 mg/kg/ day) or vehicle were injected with SEB. Serum cytokines, CD4+ and CD8+ Vbeta8+ cells were monitored in blood and lymphoid tissues, and apoptosis was determined by externalization of membrane phosphatidyl serine, double strand DNA breaks, and expression of B220 antigen by Vbeta8+ cells. Results MMF treatment decreased tumor necrosis factor alpha, interferon gamma, and interleukin-10 secretion induced by SEB. It did not modify other early activation events (blast transformation, CD69 and CD25 expression) but completely inhibited SEB-induced expansion of Vbeta8+ cells by inducing apoptosis of SEB-reactive T cells. A similar effect was observed in CD95-ligand-deficient mice. Repeated SEB injections associated with MMF resulted in a marked decrease of CD8+ Vbeta8+ T cells. SEB-induced increase of Vbeta8+ thymocytes was not prevented by MMF treatment. Conclusion Results obtained in this in vivo model suggest that MMF treatment may induce deletion of activated peripheral T cells and decrease early cytokine responses.

Determination of mycophenolic acid and mycophenolate mofetil by high-performance liquid chromatography using postcolumn derivatization.

Abstract: An efficient method to lower the optical detection limit is described using the displacement of an absorption and emission band of an analyte after a polarity change in different solvents. This solvatochromic effect was used in a RP-HPLC assay for the fluorescence detection of mycophenolic acid (6-(4-hydroxy-6-methoxy-7-methyl-3-oxo-5-phthalanyl)-4-methyl-4-hexenoic acid, MPA) and the prodrug mycophenolate mofetil (MMF), the N-(2-hydroxyethyl)morpholino ester of MPA. The rational to use fluorescence detection is based on the behavior of MMF and MPA, which fluoresce in a basic medium (pH >9.5). Following a simple protein precipitation, the analytes were separated in an isocratic RP-HPLC system. The postcolumn generation of the phenolate anions of MPA and MMF was achieved by addition of an aqueous sodium hydroxide solution regulated by a newly developed continuous-flow liquid control system. MPAG, not directly accessible for fluorescence detection, was analyzed after enzymatic deglucuronidation to MPA. Compared to published quantification limits for MPA and MMF by UV detection, this method is more than 100-fold more sensitive, with a lower limit of quantification of 45 fmol for both MPA and MMF.

The immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin) inhibit allergen-induced proliferation and IL-5 production by PBMCs from atopic asthmatic patients.

Abstract: We have used an optimized, physiologically relevant in vitro assay system to show that in a concentration-dependent fashion the immunomodulatory drugs cyclosporin A, mycophenolate mofetil, and sirolimus (rapamycin), as well as the glucocorticoid dexamethasone, inhibit allergen-driven T-cell proliferation and IL-5 production in PBMCs from allergen-sensitized atopic asthmatic individuals at physiologic concentrations. This effect of cyclosporin A might at least partially account for its established clinical efficacy in sparing systemic glucocorticoid therapy while improving lung function in chronic, severe, glucocorticoid-dependent asthma. The data are also compatible with the hypothesis that the newer immunomodulatory drugs mycophenolate mofetil and sirolimus exert similar effects, perhaps with a more favorable benefit/risk ratio.

Positive effect on T-cell regulatory apoptosis by mycophenolate mofetil.

Abstract: The regulatory benefit of apoptosis (activation-induced cell death, AICD) in T cells may be impacted by immunosuppressive agents. We examined this for mycophenolate mofetil (MMF) compared with cyclosporine (CYA). Peripheral blood leukocytes (PBL) were stimulated by either Staph enterotoxin B (SEB) or by anti-CD3 plus anti-CD28. Cell division analysis (sequential reduction in carboxyflourescein diacetate succinimidyl ester, CFSE) was used to measure proliferation and determine status of different cell generations. Apoptosis was measured by annexin V staining, and FasL expression by anti-FasL antibody staining, of activated cells using flow cytometry. CSA and mycophenolic acid (MPA, the active agent of MMF) were added in titration in 3-day cultures. We found that CSA caused diminution in apoptosis but MPA increased it with SEB stimulation. The CSA effect on apoptosis was present when a more calcineurin-dependent stimulus. anti-CD3+ anti-CD28, was used but the MPA effect was less, producing a decrease only in the undivided cells. To look more directly at the differential effect on calcineurin-dependent AICD gene induction of the two agents, we measured Fas-L expression with anti-CD-3 + CD28 stimulation, and confirmed that CYA caused a major decrement in appearance of Fas-L, whereas MPA caused a converse accumulation of it. This seems to be explained by the block more distal in cell activation, resulting in a build-up of a precursor in the activation pathways. We conclude that MMF treatment may be rationale as an adjunct to calcineurin inhibitor treatment because of its converse effect on T cell regulatory apoptosis.

Quantification of Mycophenolic Acid in Plasma Samples Collected during and Immediately after Intravenous Administration of Mycophenolate Mofetil

Abstract: Mycophenolate mofetil [(MMF); CellCept®; Roche Pharmaceuticals, Inc.], a prodrug of the immunosuppressive agent mycophenolic acid (MPA), is used for the prevention of rejection after organ transplantation. It is also under investigation for therapy of several autoimmune diseases, as well as prophylaxis for graft-vs-host disease in hematopoietic stem cell transplantation (1)(2). After administration, MMF undergoes rapid and complete hydrolysis to MPA, its immunosuppressive active metabolite. The monitoring of plasma MPA is an important part of optimizing therapy with regard to pharmacologic and toxicologic effects (3)(4). In addition to the commonly used oral MMF formulations, an intravenous formulation has been approved recently for prophylaxis against organ rejection in adult patients receiving allogenic renal or heart transplants. This intravenous solution enables MMF to be administered to patients unable to tolerate oral medication. The intravenous CellCept is given as an infusion of 1–3 h duration (5). In spite of its rapid hydrolysis, the prodrug is potentially present in the plasma during and immediately after intravenous administration. Because MMF is very unstable and was found to undergo temperature-dependent degradation to produce MPA in human blood and plasma (6), its presence in patient samples may critically affect the accuracy and precision of the analysis of MPA concentrations if these have to be measured for pharmacokinetic investigations during intravenous administration. The use of the Emit procedure with MMF-containing samples to monitor MPA is not possible because MMF cross-reacts with the antibody used in this assay (7). However, most investigators are unaware of the potential analytic inaccuracy caused by MMF hydrolysis in samples containing this prodrug. Ongoing multicenter trials with both bone marrow and heart transplant recipients require MPA monitoring during MMF infusion therapy to establish therapeutic efficiency and therapeutic ranges for this route of application. According to the study protocols, MPA …