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

Mycophenolate mofetil (MMF) was evaluated either alone or combined with cyclosporine (CSP) for preventing graft-versus-host disease (GVHD) in dogs given 9.2 Gy total body irradiation and DLA-nonidentical unrelated marrow grafts. Marrow autograft studies showed gut toxicity as limiting MMF side effects. Four groups were studied for GVHD prevention: six dogs in group 1 received MMF 10 mg/kg twice daily subcutaneously (SC) on days 0 to 27. They died between 8 to 28 days from infection or GVHD; survival was better than that of 72 controls given no immunosuppression (P = .04), but not different from 19 dogs given CSP. Four dogs in group 2 received MMF as described, along with CSP at 10 to 15 mg/kg twice daily on days 0 to 27. They died at 6 to 98 days from CSP-associated toxicity, weight loss, or infection. Nine dogs in group 3 received MMF SC twice daily 6 mg/kg/d for 3 days, followed by 10 mg/kg twice daily until day 27, along with CSP as described; four died between 7 to 106 days with intussusception, infection, or GVHD, and five became long-term survivors. Six dogs in group 4 received shortened MMF (21 days) and reduced doses of CSP given through day 100. Three died with GVHD or infection between days 38 to 119, and three became long-term survivors. Results support the notion of synergism between MMF and CSP, as evidenced by stable graft-host tolerance in greater than 50% of dogs.
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PMID:Synergism between mycophenolate mofetil and cyclosporine in preventing graft-versus-host disease among lethally irradiated dogs given DLA-nonidentical unrelated marrow grafts. 951 60

Over the last few years, improved knowledge of the immunological mechanisms underlying transplant rejection have resulted in the development of new immunosuppressive agents capable of selectively blocking various steps of the immune response. It is anticipated that these agents will prove useful in the treatment of autoimmune disease and graft-versus-host disease. Neoral is a cyclosporin microemulsion characterized by better and more consistent absorption as compared to the conventional galenic form. Tacrolimus shares with cyclosporin an ability to inhibit calcineurin and may have similar indications. Rapamycin and RAD are two related molecules that inhibit signal transduction by cytokines to T-cells, although they have not yet been proved clinically effective in large studies of solid organ transplant recipients. Mycophenolate mofetil selectively inhibits purine synthesis and lymphocyte proliferation; it is easy to use and has been found effective in a number of autoimmune disorders. Further clinical work is needed to determine the therapeutic indications for each of these new drugs. Elucidation of their mechanisms of action may help to identify drug combinations providing both enhanced efficacy and improved safety.
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PMID:[New immunosuppressive agents]. 1057 3

Mycophenolate mofetil (MMF), a new immunosuppressive drug successfully used in renal and heart transplant recipients, was used in combination with cyclosporin A (CsA), methotrexate (MTX) and prednisolone for the prophylaxis of acute graft-versus-host disease (aGVHD) after bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) from human leukocyte antigen (HLA)-mismatched, unrelated (n = 9) and related donors (n = 4) in an open single-centre phase II study. Thirteen patients, transplanted from HLA-mismatched donors of 18-57 yr of age, received 1 g MMF daily, starting at day 10, in addition to CsA and prednisolone for aGVHD prophylaxis. All patients were engrafted between days 13 and 15. Four of the 13 patients experienced aGVHD grade I/II (n = 2) and grade III (n = 2). All patients except 3 were alive on day 100 post-transplantation. No severe adverse effects of MMF were recorded. In our pilot study, we demonstrated that MMF can be used safely for the prophylaxis of aGVHD.
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PMID:Mycophenolate mofetil for the prophylaxis of acute GVHD in HLA-mismatched bone marrow transplant patients. 1077 Apr 16

Mycophenolate mofetil (MMF) is an alternative immunosuppressant which inhibits the proliferation of T and B lymphocytes. The purpose of the present study was to evaluate the safety and efficacy of MMF as salvage therapy for chronic GVHD (cGVHD) in children receiving allogeneic bone marrow transplantation. Fifteen children, 3-16 years of age, who had received grafts from HLA-compatible siblings (n = 8), partially matched related donors (n= 2) or matched unrelated donors (n = 5), developed extensive cGVHD which had proved unresponsive to standard immunosuppressive therapy. Patients were treated with MMF at the dose of 15-40 mg/kg/day in combination with other immunosuppressive therapy for a median of 4 months (range 1-15 months). The overall response rate (complete or partial response) was 60%. Thirteen percent had only minor responses, whereas 27% of patients had progressive disease. Best responses were seen in patients with GI tract (60% of complete responses) or mouth (33% of complete responses) cGVHD and skin involvement (43% of complete responses) that did not include sclerodermatous manifestations. Once MMF was started, improvements in the clinical manifestations of cGVHD allowed a significant reduction of steroids in 45% of patients and discontinuation in 27% of cases. Six patients (40%) experienced adverse events, with gastrointestinal symptoms predominating. Five patients experienced opportunistic infections. MMF was discontinued after 35-180 days in six patients for the following reasons: parents choice (n = 2), liver toxicity (n = 1), poor compliance (n = 2), and no response (n = 1). In conclusion, these preliminary results suggest that MMF in combination with other immunosuppressive agents may have a role to play in patients with cGVHD. Prospective clinical trials are needed to establish exact indications for therapy and dosage scheduling. Bone Marrow Transplantation (2000).
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PMID:Mycophenolate mofetil (MMF) as therapy for refractory chronic GVHD (cGVHD) in children receiving bone marrow transplantation. 1122 81

The therapeutic benefits of allogeneic stem cell transplantation in patients with hematologic disorders are limited by the significant morbidity and mortality of graft-versus-host disease (GVHD). Current agents for the prevention and treatment of GVHD have limited efficacy and often result in toxic side-effects. Mycophenolate mofetil (MMF) is a new immunosuppressant with a selective mechanism of action. When employed following solid organ transplantation, MMF reduces the incidence and severity of acute rejection episodes. By selectively targeting activated lymphocytes, the active metabolite of MMF, mycophenolic acid (MPA), appears to augment the actions of standard immunosuppressant agents without adding overlapping toxicities. Studies of combination regimens that include MMF report that this agent permits a dose reduction of cyclosporine, tacrolimus, or corticosteroid, without increasing the incidence of acute rejection in solid organ transplants. Reports on the efficacy of MMF following stem cell transplantation in animal studies were mixed. However, the use of a non-myeloablative conditioning regimen with a post-graft immunosuppressive regimen of MMF and cyclosporine was able to sustain stable mixed chimeras in 60% to 80% of dogs who received hematopoietic grafts from DLA-identical littermates. MMF has demonstrated activity in preliminary clinical trials for GVHD prophylaxis, and treatment of acute or chronic GVHD. Larger clinical trials are warranted to determine the optimum dose and route of MMF administration for GVHD, as well as the comparative safety and efficacy of MMF-containing regimens.
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PMID:Mycophenolate mofetil for the prevention and treatment of graft-versus-host disease following stem cell transplantation: preliminary findings. 1154 43

Graft versus host disease (GVHD) remains the major obstacle to successful allogeneic bone marrow transplantation. Cyclosporin with methotrexate is the most common prophylactic regimen. Tacrolimus is associated with less GVHD and is gaining ground especially in unrelated donor transplants where current regimens are unsatisfactory. Mycophenolate mofetil (MMF) and rapamycin have not yet shown benefit in acute GVHD prophylaxis. In vivo T-cell depletion with Campath 1H or thymoglobulin used during transplant conditioning are increasingly used in place of ex vivo T-cell depletion, where results remain disappointing. Steroids remain first choice for therapy of GVHD but anti-CD25 antibodies, daclizumab or basiliximab are gaining popularity as second-line therapy ahead of ATG. Chronic GVHD is increasing with greater use of peripheral blood stem cell grafts and older patients. The combination of tacrolimus and MMF is promising for patients with extensive disease. Tolerance induction using CTLA-4-Ig, anti-CD40L, tresperimus and/or rapamycin may revolutionise GVHD therapy. However, due to the desirability of tumour intolerance, tolerance is likely to be developed in organ transplantation before bone marrow transplantation for traditional indications. Bone marrow transplants performed to induce organ tolerance may see increasing use of these agents. TNF blockade using infliximab or etanercept (Enbrel) is promising but the role of these agents is not yet defined.
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PMID:New developments in the prophylaxis and treatment of graft versus host disease. 1158 62

Acute and chronic graft versus host disease (GVHD) remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning;donor T-cell activation; andeffector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and interleukin (IL)-11 are cytokines that may be useful in disrupting phase I of the GVHD cascade by blocking gastrointestinal tract damage, and lowering serum levels of lipopolysaccharide and tumour necrosis factor (TNF)-alpha. Cyclosporin, tacrolimus (FK-506) and sirolimus (rapamycin) are some of the main agents that disrupt phase II (donor T-cell activation). Mycophenolate mofetil and tresperimus probably act on this phase as well. Other novel drugs that affect phase II are tolerance-induction agents such as CTLA-4 and anti-CD40-ligand monoclonal antibodies, and preliminary results using CTLA-4 monoclonal antibody in GVHD prevention are encouraging. Examples of agents that disrupt phase III are the IL-2 receptor antagonist daclizumab and the anti-TNFalpha monoclonal antibody infliximab. These anti-cytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will probably 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 treatment of both acute and chronic GVHD are likely to yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for patients with acute and chronic GVHD.
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PMID:Novel pharmacotherapeutic approaches to prevention and treatment of GVHD. 1192 36

Mycophenolate mofetil (MMF) is increasingly used for prophylaxis and therapy of GVHD in allogeneic stem cell transplantation. In some recent reports of use of MMF in solid organ transplantation a high incidence of CMV disease has been described. We evaluated the frequency and course of active CMV infection in patients who received MMF compared to those who did not receive MMF after allogeneic stem cell transplantation. We retrospectively analyzed 48 adult patients who consecutively underwent unmanipulated allogeneic bone marrow (n = 15) or peripheral stem cell transplantation (n = 33) from HLA-compatible family donors (n = 30) or unrelated donors (n = 18) from February 1997 to September 2000 at our institution. Only patients who were evaluable for the first 100 days were included in this analysis. Sixteen patients received MMF post transplant (MMF+). CMV-antigenemia was monitored by CMV-pp65 antigen. CMV-antigenemia occurred in 14 patients and was virtually only observed in CMV-IgG+ recipients (13/23, 56%). CMV-IgG+/MMF+ patients developed a higher incidence of CMV-antigenemia (8/9, 89%) compared to the CMV-IgG+/MMF- patients (5/14, 35%; P < 0.05). Moreover, five of six patients with persistent or recurrent CMV-antigenemia received MMF. No patient in either group developed CMV disease or died of CMV-related complications. In multivariate analysis including MMF treatment, unrelated vs related donor, GVHD, CMV-serostatus of the donor and stem cell graft type, only MMF treatment was found to be a significant risk factor for both overall and complicated CMV infection.
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PMID:Increased risk of complicated CMV infection with the use of mycophenolate mofetil in allogeneic stem cell transplantation. 1208 Mar 55

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: recipient conditioning, donor T cell activation and effector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and IL-11 are cytokines that may be useful in disrupting Phase I of the GVHD cascade by blocking gastrointestinal tract damage and lowering serum levels of lipopolysaccharide and TNF-alpha. Cyclosporin, FK506 and sirolimus are some of the main agents that disrupt Phase II (donor T cell activation). Mycophenolate mofetil likely acts on this phase as well. Other novel drugs that affect Phase II are tolerance-induction agents such as cytotoxic T lymphocyte antigen (CTLA)-4 Ig and anti-CD40 ligand, and preliminary results using CTLA-4 Ig in GVHD prevention are encouraging. Two exciting agents that appear to affect only activated lymphocytes are ABX-CBL and visilizumab. Examples of agents that disrupt Phase III are the IL-2 receptor antagonist daclizumab and the anti-TNF-alpha monoclonal antibody infliximab. These anticytokine antibodies have shown promising results in early studies. 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 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:Novel therapeutics for the treatment of graft-versus-host disease. 1222 48

Allogeneic haematopoietic stem cell transplantation remains the treatment of choice for a number of malignancies. However, graft-versus-host disease (GVHD) has long been regarded as a serious complication of this procedure. Although GVHD may affect any organ, intestinal GVHD is particularly important because of its frequency, severity and impact on the general condition of the patient. Recent studies have led to progressive elucidation of the mechanism of GVHD. Donor T cells are critical for the induction of GVHD, because depletion of T cells from bone marrow grafts effectively prevents GVHD but also results in an increase of leukaemia relapse. It has been shown that the gastrointestinal tract plays a major role in the amplification of systemic disease because gastrointestinal damage increases the translocation of endotoxins, which promotes further inflammation and additional gastrointestinal damage. Consequently, the management of intestinal GVHD (and the intestine itself) is a subject that should be highlighted. In this article, approaches to the prevention of intestinal GVHD are discussed after being classified into three categories: regimens in common clinical use, regimens under investigation and original regimens used at our hospital. The standard regimen that is used most widely for prevention of GVHD is cyclosporin plus short-term methotrexate. Corticosteroids can be added to this regimen but careful consideration of the adverse effects of these hormones should be considered. Tacrolimus is a newer, more potent alternative to cyclosporin. T-cell depletion (TCD) after transplantation has been shown to prevent acute GVHD, however, the survival benefit of TCD has not been as great as expected. Mycophenolate mofetil can be useful for the treatment of acute GVHD as part of combination therapy. Regimens currently under investigation in animal experiments include suppression of inflammatory cytokines and inhibition of T-cell activation, and, specifically at our institution, hepatocyte growth factor gene therapy. The evidence-based therapy used at our institution includes systemic antibacterial therapy (including eradication of intestinal bacteria) to prevent the intestinal translocation of lipopolysaccharide and avoid the subsequent increase of various inflammatory cytokines. In addition, because of the similarities between intestinal GVHD and ulcerative colitis, sulfasalazine, betamethasone enemas and eicosapentaenoic acid have been used to treat intestinal GVHD in some patients.
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PMID:Intestinal graft-versus-host disease: mechanisms and management. 1248 19


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