Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0018133 (graft-versus-host disease)
 18,032 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppression in solid organ transplantation. Gastrointestinal toxicity, usually manifested as diarrhea, is the most common side effect of MMF. We evaluated colonic biopsies from 20 renal transplant patients with MMF-related diarrhea. The latter was defined by the absence of any other demonstrable etiology and improvement or resolution of symptoms by the discontinuation or reduction of the dose of MMF alone. These biopsies were compared with colon biopsies from patients with the following: acute graft-versus-host disease (GVHD, n=10), inflammatory bowel disease (IBD) or infectious colitis (n=10), and colon biopsies from renal transplant patients not receiving MMF (n=8). Normal colonic segments from surgical specimens served as normal controls (n=5). Colonic biopsies from patients with MMF-related diarrhea showed prominent crypt cell apoptosis and reactive/reparative changes including enterocyte cytologic atypia, increased neuroendocrine cells, and glandular architectural distortion. The changes were similar, although of milder degree to the ones seen in patients with acute intestinal GVHD. This pattern of injury was not seen in controls or in biopsies from transplant patients not receiving MMF, and it was markedly different from the one seen in idiopathic inflammatory or infectious colitis. The severity of histologic changes correlated significantly with the endoscopic degree of "colitis." There was no statistically significant correlation between histologic damage and the dose of MMF (corrected for body weight and renal function). MMF-related colitis is a distinct entity that displays histologic features remarkably similar to the ones associated with intestinal GVHD. This form of injury could be related to either direct toxicity or an "innocent by-stander" phenomenon secondary to the alteration of the immunologic microenvironment of the colon caused by the MMF.
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PMID:Histologic features of mycophenolate mofetil-related colitis: a graft-versus-host disease-like pattern. 1461 24

Lichen planus (LP) is an inflammatory skin disorder with a wide range of clinical appearances. The treatment of disseminated and especially erosive forms of LP is often difficult and disappointing. Activated T cells are important in the pathogenesis of LP as indicated by the dermal lymphocytic infiltrate leading to keratinocyte destruction and lesion formation. Similar histologic findings are present in graft-versus-host disease. Since T cells are key players in the development of both disorders and mycophenolate mofetil has been successfully introduced in the treatment of graft-versus-host disease, we have examined the therapeutic potential of this agent in 3 patients suffering from disseminated and erosive LP. Mycophenolate mofetil was well tolerated and induced complete remission in 2 patients, and substantial improvement in the third patient.
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PMID:Treatment of severe lichen planus with mycophenolate mofetil. 1463 85

Acute graft-versus-host disease (GVHD) and chronic GVHD remain the major barriers to successful haematopoietic cell transplantation. The induction of GVHD may be divided into three phases: (i) recipient conditioning, (ii) donor T cell activation, and (iii) effector cells mediating GVHD. Standard agents and agents under development to prevent and treat GVHD are discussed. The various pharmacological agents impact on different phases of the GVHD cascade. Sirolimus is a new immunophilin binding agent that appears to be synergistic with tacrolimus and cyclosporin. It also seems to promote allograft tolerance. Mycophenolate mofetil (MMF) is an antimetabolite that is currently under study for prophylaxis and treatment of acute and chronic GVHD; results are encouraging. Other agents such as the purine analogue pentostatin and the monoclonal antibodies alemtuzumab, daclizumab and infliximab are discussed at length within the GVHD context. The most effective approach to GVHD prevention will likely be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for the treatment of both acute and chronic GVHD will likely yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for acute and chronic GVHD.
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PMID:Emerging therapies for graft-versus-host disease. 1466 92

Mycophenolate mofetil (MMF) is a newly developed immunosuppressor, widely used in allogeneic bone marrow transplant. The purpose of this study was to evaluate the effects of mycophenolic acid (MPA), the active metabolite of MMF in vivo, on the maturation and immunologic function of murine bone marrow-derived dendritic cells (DC), and to explore the underlying mechanisms of MMF in graft versus host disease. Cultured DC were treated with MPA at doses of 0.01 and 0.1 micro mol/L. The immunophenotype of DC in control and treated groups was analyzed by flow cytometry. The capability of antigen presentation and the stimulatory activity of the DC on allogeneic T cells were tested by incorporation of (3)H-TdR and mixed lymphocyte reaction respectively. IL-12 production in culture supernatant and the levels of Th1/Th2 cytokines such as IL-2, IFN-gamma, IL-4 and IL-10 in mixed lymphocyte reaction (MLR) supernatant were examined by ELISA assay. The results showed that DCs cultured in the presence of MPA expressed low levels of CD40, CD80 and CD86, and exhibited weak activity in stimulating the proliferation of allogeneic T cells and antigen presenting function with a concurrent reduction of IL-12 production. Allogeneic T cells stimulated by MPA-treated DC expressed higher levels of Th2 cytokines such as IL-4 and IL-10 but lower levels of Th1 cytokines such as IL-2 and IFN-gamma than those stimulated by DC without MPA treatment. It is concluded that MPA, and hence MMF, exerts a negative effect on the maturation and immunologic functions of DC in culture, and drives a shift of Th1 to Th2 cytokines in MLR.
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PMID:[The effects of mycophenolic acid on the maturation and immunologic function of murine bone marrow-derived dendritic cells]. 1515 35

Current treatment of chronic graft-versus-host disease (cGVHD) with prednisone (PSE) alone or with added cyclosporine or tacrolimus still has a very high failure and complication rate, and new treatment approaches are needed for both primary and salvage therapy. Mycophenolate mofetil (MMF) is an immunosuppressive agent currently in use for acute graft-versus-host disease prophylaxis. To determine whether MMF had activity in the treatment of cGVHD, we added MMF to standard cyclosporine, tacrolimus, and/or PSE as salvage/second-line (n = 24) or first-line (n = 10) therapy in 34 patients. Nine (90%) of 10 patients receiving first-line and 18 (75%) of 24 receiving second-line MMF therapy responded. Twelve (35%) patients had a complete remission, 15 (44%) had a partial remission, 5 (15%) had stable disease, and only 2 (6%) had progressive disease. Out of 30 patients receiving PSE, 22 (73%) were able to decrease PSE doses (median decrease of 50%; range, 25%-100%). With a median follow-up of 24 months (range, 6-28 months), 29 (85%) patients are alive. Three patients had to discontinue MMF because of abdominal cramps within 3 months of starting treatment. These data suggest that MMF is an active, well-tolerated agent in the treatment of cGVHD and may have a beneficial effect on the survival of patients with this complication.
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PMID:Efficacy of mycophenolate mofetil in the treatment of chronic graft-versus-host disease. 1581 96

Mycophenolate mofetil is used increasingly to provide immunosuppression after nonmyeloablative allogeneic hematopoietic cell transplantation. There is wide variability in the pharmacokinetics of mycophenolic acid (MPA), the active metabolite, and low concentrations are associated with rejection after organ transplantation. We hypothesized that low MPA was associated with poorer engraftment and a higher incidence of acute graft versus host disease. We evaluated the pharmacokinetics in 87 adult subjects undergoing nonmyeloablative-related and nonmyeloablative-unrelated hematopoietic cell transplantation who were receiving 1 g mycophenolate mofetil orally or intravenously every 12 hours plus cyclosporine (INN, ciclosporin). Subjects with an unbound MPA area under the curve (AUC) from 0 to 6 hours of less than 150 ng . h/mL had a higher cumulative incidence of grade II-IV acute graft versus host disease than subjects with a greater AUC (68% versus 40%, P = .02). An unbound AUC from 0 to 12 hours of less than 300 ng . h/mL was also associated with more frequent acute graft versus host disease (58% versus 35%, P = .05). There was no association between graft versus host disease and trough concentrations (P < or = .62). A higher cumulative incidence of engraftment was associated with total MPA trough concentrations greater than 1 microg/mL (P < .01). All engraftment failures occurred in the cord blood recipients. About one half of subjects were below the unbound AUC target after oral dosing with nearly a 5-fold variability in AUC. Intravenous dosing achieved unbound targets better than oral dosing. The current practice of dosing with 1 g twice daily provides inadequate plasma concentrations in many patients, and doses of at least 3 g/d are likely necessary. Therapeutic monitoring of MPA concentrations with dose adjustment into the therapeutic target appears to be necessary for the most effective use of mycophenolate mofetil.
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PMID:Relationship of mycophenolic acid exposure to clinical outcome after hematopoietic cell transplantation. 1632 15

Aplastic anemia is a relatively uncommon disease and conventional management options include immunosuppressive drugs and/or haematopoeitic stem cell transplantation. It is now known that the pathogenesis of aplastic anemia is immune mediated. Mycophenolate mofetil is a common immunosuppressive drug now used mainly in prophylaxis of graft rejection in organ transplant and also for prevention/treatment for graft versus host disease in haemtopoeitic stem cell transplantation. It is thought that mycophenolate mofetil may be useful in this group of patients. In this short report, mycophenolate mofetil was tried in 6 patients who had severe aplastic anemia with variable doses for a minimum duration of 9 months. The result has however not been encouraging.
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PMID:The use of mycophenolate mofetil in treating patients with non responding aplastic anemia. 1637 85

Mycophenolate mofetil (MMF), a prodrug of mycophenolic acid (MPA), is increasingly used in the prophylaxis of graft-versus-host disease (GVHD) after hematopoietic stem cell transplantation (HCT). Few pharmacokinetic data are available about the use of MMF for this indication. This case series aimed at analyzing the pharmacokinetics of MMF in a population of HCT recipients representative for everyday practice. From 15 HCT recipients, serial plasma samples were taken after twice-daily oral intake of MMF. Plasma concentrations of total MPA and its glucuronide metabolites, as well as free MPA, were quantified. Median apparent oral MPA clearance (CL/F), apparent half-life, and total MPA area under the curve for hours 0 to 12 (AUC0-12, normalized to 1000 mg MMF) were, respectively, 56 L/h (range: 29-98 L/h), 2.3 hours (range: 0.8-5.7 hours), and 18.0 mg*h/L (range: 10-35 mg*h/L). Total MPA concentrations were below 2 mg/L 8 hours after MMF administration, indicating reduced enterohepatic recirculation. Median free MPA AUC0-12 (normalized to 1000 mg MMF) was 224 microg*h/L (range: 56-411 microg*h/L). Because of high CL/F, total MPA exposure in HCT recipients is low and apparent half-life is short in comparison with reference values from renal transplantation. Exposure may be improved in HCT recipients by higher or more frequent MMF dosing.
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PMID:Pharmacokinetics of mycophenolate mofetil in hematopoietic stem cell transplant recipients. 1752 94

Mycophenolate mofetil (MMF) has been used successfully in solid organ transplantation (SOT) and more recently in nonmyeloablative hematopoietic stem cell transplantation (HSCT) for prophylaxis of graft rejection and acute graft-versus-host disease. However, the pharmacokinetics of MMF seem to differ when applied in HSCT compared to SOT. Here, we analyzed pharmacokinetics of mycophenolic acid (MPA), the active metabolite of MMF, in a nonmyeloablative canine HSCT model. Dogs received nonmyeloablative TBI for conditioning followed by leukocyte antigen-identical littermate HSCT and immunosuppression containing cyclosporin A (CsA) and different doses of MMF. Pharmacokinetics were performed on days 2, 14 and 27. Dose escalation of MMF from 10 to 30 mg/kg tended to increase area under the curve (AUC) and the apparent oral clearance by 45 and 110%, respectively. Doses applied had no linear association with MPA concentration or blood trough level. No significant drug accumulation occurred over time. Using a twice daily MMF regimen, we conclude that an AUC of 30-60 mug/ml h as recommended for SOT cannot be reached in HSCT. Toxicities did not permit single doses higher than 30 mg/kg. Thus, if larger AUCs are desired in order to assure sufficient immunosuppression in HSCT, MMF might have to be administered at least three times daily.
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PMID:Pharmacokinetics of oral mycophenolate mofetil in combination with CsA in dogs after nonmyeloablative allogeneic hematopoietic stem cell transplantation. 1808 33

Mycophenolate mofetil (MMF) is a commonly used immunosuppressive drug used in the management of transplant recipients. Although gastrointestinal (GI) toxicity is a known complication of MMF, the literature characterizing the pathologic features of MMF in the GI tract is sparse. This study characterizes the pathologic features of MMF toxicity in both the upper and lower GI tract, correlating it with clinical and endoscopic findings. Seventy-five GI biopsies (9 esophageal, 15 gastric, 16 duodenal, 5 ileal, 30 colonic) from 46 transplant recipients from 2002 to 2006 were obtained and assessed for multiple histologic features. Clinical features were recorded for all cases and endoscopic findings. Only MMF patients showed ulcerative esophagitis (5/7 cases) and reactive gastropathy (4/10 cases). Only MMF patients showed graft-versus-host disease (GVHD)-like features in duodenal (4/12 cases) and ileal (1/5 cases) biopsies. GVHD-like changes were seen more frequently among patients on MMF compared with those not on MMF [9 (56%) vs. 2 (14%); P=0.017]. Crypt architectural disarray [12 (75%) vs. 2 (14%); P=0.001], lamina propria edema [9 (56%) vs. 2 (14%); P=0.017], increased lamina propria inflammation [13 (81%) vs. 3 (21%); P=0.001], dilated damaged crypts [7 (44%) vs. 1 (7%); P=0.024], and increased crypt epithelial apoptosis [9 (56%) vs. 2 (14%); P=0.017] were more common with MMF patients compared with non-MMF patients. In conclusion, pathologists should be aware of the potential manifestations of MMF toxicity throughout the GI tract, including ulcerative esophagitis, reactive gastropathy, and GVHD-like features in intestinal biopsies.
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PMID:Mycophenolate mofetil-related gastrointestinal mucosal injury: variable injury patterns, including graft-versus-host disease-like changes. 1876 24


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